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Abstracts

Obesity
Updated: 08/26/2004

ABSTRACTS

Obesity. In Cecil-Loeb Textbook of Medicine.

Albrick M.

1971; Thirteenth Edition:1448-58.

Weight loss increases and fat loss decreases all-cause mortality rate: results from two independent cohort studies.

Allison DB, Zannolli R, Faith MS, et al.

Int J Obes Relat Metab Disord. 1999 Jun; 23(6):603-11.

OBJECTIVE: In epidemiological studies, weight loss is usually associated with increased mortality rate. Contrarily, among obese people, weight loss reduces other risk factors for disease and death. We hypothesised that this paradox could exist because weight is used as an implicit adiposity index. No study has considered the independent effects of weight loss and fat loss on mortality rate. We studied mortality rate as a function of weight loss and fat loss. DESIGN: Analysis of 'time to death' in two prospective population-based cohort studies, the Tecumseh Community Health Study (1890 subjects; 321 deaths within 16y of follow-up) and the Framingham Heart Study (2731 subjects; 507 deaths within 8y of follow-up), in which weight and fat (via skinfolds) loss were assessable. RESULTS: In both studies, regardless of the statistical approach, weight loss was associated with an increased, and fat loss with a decreased, mortality rate (P or = 34) obese individuals is unclear. CONCLUSIONS: Among individuals that are not severely obese, weight loss is associated with increased mortality rate and fat loss with decreased mortality rate

Weight loss and delayed gastric emptying following a South American herbal preparation in overweight patients.

Andersen T, Fogh J.

J Hum Nutr Diet. 2001 Jun; 14(3):243-50.

BACKGROUND: Obesity and overweight may soon affect more than half of the population in some regions of the world and are associated with diabetes, hypertension and other diseases that cause morbidity, mortality and high health-care expenditure. No one approach, whether dietetic management, medication, or commercial weight loss programme, can alone solve the problem--all potential treatments need to be investigated and exploited. Among the herbal preparations known to non-western cultures are materials which may have applications in modulating physiological processes which influence gut motility, food intake and energy balance. One such mixed herbal preparation is 'YGD' containing Yerbe Mate (leaves of Ilex paraguayenis), Guarana (seeds of Paullinia cupana) and Damiana (leaves of Turnera diffusa var. aphrodisiaca). AIMS: This study had two distinct aims: to determine the effect of a herbal preparation 'YGD' containing Yerbe Mate, Guarana and Damiana on gastric emptying; to determine the effect of the same preparation on weight loss over 10 days and 45 days and weight maintenance over 12 months. METHODS: Gastric emptying was observed using ultrasound scanning in seven healthy volunteers following YGD and placebo capsules taken with 420 mL apple juice. Body weight was observed before and after 10 days of treatment with three YGD capsules or three placebo capsules before each meal for 10 days in 44 healthy overweight patients attending a primary health care centre. Forty-seven healthy overweight patients entered a double-blind placebo-controlled parallel trial of three capsules of YGD capsules before each main meal for 45 days compared with three placebo capsules on body weight. Body weight was monitored in 22 patients who continued active (YGD capsules) treatment for 12 months. RESULTS: The herb preparation YGD was followed by a prolonged gastric emptying time of 58 +/- 15 min compared to 38 +/- 7.6 min after placebo (P = 0.025). Body weight reductions were 0.8 +/- 0.05 kg after YGD capsules compared to 0.3 +/- 0.03 kg after placebo capsules over 10 days, and 5.1 +/- 0.5 kg after PGD capsules compared to 0.3 +/- 0.08 kg after placebo over 45 days. Active treatment with YGD capsules resulted in weight maintenance of the group (73 kg at the beginning and 72.5 kg at the end of 12 months). CONCLUSIONS: The herbal preparation, YGD capsules, significantly delayed gastric emptying, reduced the time to perceived gastric fullness and induced significant weight loss over 45 days in overweight patients treated in a primary health care context. Maintenance treatment given in an uncontrolled context resulted in no further weight loss, nor weight regain in the group as a whole. The herbal preparation is thus shown to be one that significantly modulates gastric emptying. Further clinical studies with dietetic monitoring of energy intake, dietary quality, satiety ratings, body weight and body composition are now indicated, and examination of the active principles contained in the three herbal components may prove rewarding

The role of dietary fat in the prevention and treatment of obesity. Efficacy and safety of low-fat diets.

Astrup A.

Int J Obes Relat Metab Disord. 2001 May; 25 Suppl 1:S46-S50.

BACKGROUND: Does dietary fat play a central role in weight gain and development of obesity? Do low-fat diets have adverse effects on blood lipids? OBJECTIVE AND DESIGN: To answer these questions we have reviewed the evidence linking the dietary fat content to energy balance and obesity, and examined the efficacy and safety of ad libitum low fat, high carbohydrate/protein diets in the prevention and management of obesity. RESULTS: Physiological studies have provided insight into the mechanisms by which the macronutrients differ in their effect on energy balance: (1) energy from fat is less satiating than energy from carbohydrate, and a high fat/carbohydrate ratio in the diet promotes passive overconsumption, a positive energy balance and weight gain in susceptible individuals; (2) fat is more readily absorbed from the intestine and fecal energy loss is much lower with a high dietary fat/carbohydrate ratio; (3) carbohydrate is more thermogenic than fat and energy expenditure is lower during positive energy balance produced by a diet with a high fat/carbohydrate ratio than during positive energy balance produced by a diet with a low fat/carbohydrate ratio. Randomized intervention studies comparing low fat diets to normal fat diets show that low fat diets prevent weight gain in normal weight subjects and produce weight loss in overweight individuals. In our meta-analysis of ad libitum low fat interventions we included 16 trials involving 1728 individuals. The difference in weight loss between intervention and control groups was 2.5 kg (95% CI, 1.5-3.5; P

Low-fat diets and energy balance: how does the evidence stand in 2002?

Astrup A, Astrup A, Buemann B, et al.

Proc Nutr Soc. 2002 May; 61(2):299-309.

The role of high-fat diets in weight gain and obesity is assessed by evidence-based principles. Four meta-analyses of weight change occurring on ad libitum low-fat diets in intervention trials consistently demonstrate a highly significant weight loss of 3-4 kg in normal-weight and overweight subjects (P < 0.001). The analyses also find a dose-response relationship, i.e. the reduction in percentage energy as fat is positively associated with weight loss. Weight loss is also positively related to initial weight; a 10 % reduction in dietary fat is predicted to produce a 4-5 kg weight loss in an individual with a BMI of 30 kg/m2. The non-fat macronutrient composition of the diet is also important. Whereas the glycaemic index of the carbohydrate may play a role for cardiovascular risk factors, there is so far no evidence that low-glycaemic index foods facilitate weight control. In contrast, intervention studies show that sugar in drinks is more likely to produce weight gain than solid sugar in foods. Although the evidence is weak, alcoholic beverages promote a positive energy balance, and wine may be more obesity-promoting than beer. Protein is more satiating and thermogenic than carbohydrates, and one intervention study has shown that an ad libitum low-fat diet where carbohydrate was replaced by protein produced more weight loss after 6 months (8.1 v. 5.9 kg). The evidence linking particular fatty acids to body fatness is weak. If anything, monounsaturated fat may be more fattening than polyunsaturated and saturated fats, and no ad libitum dietary intervention study has shown that a normal-fat high-monounsaturated fatty acid diet is equivalent or superior to a low-fat diet in the prevention of weight gain and obesity. The evidence strongly supports the low-fat diet as the optimal choice for the prevention of weight gain and obesity, while the use of a normal-fat high-monounsaturated fatty acid diet is unsubstantiated

Effect of dietary composition on fasting-induced changes in serum thyroid hormones and thyrotropin.

Azizi F.

Metabolism. 1978 Aug; 27(8):935-42.

[Effect of chromium yeast and chromium picolinate on body composition of obese, non-diabetic patients during and after a formula diet].

Bahadori B, Wallner S, Schneider H, et al.

Acta Med Austriaca. 1997; 24(5):185-7.

The objective of this study was to assess the effects of chromium yeast and chromium picolinate on lean body mass during and after weight reduction with a very-low-calorie diet. 36 obese (BMI 33.7 +/- 5.4 kg/m2), non-diabetic patients aged 45 +/- 6 years undergoing a 8-week very-low-calorie diet followed by a 18-week maintenance period. During the whole 26 week treatment period subjects received either placebo or chromium yeast (200 micrograms/d) or chromium-picolinate (200 micrograms/d) in a double-blind manner. Body weight was measured as BMI and body composition after calculation from skinfold thickness. As a result all three groups showed comparable weight loss after 8 and 26 weeks. Lean body mass was reduced in all groups after 8 weeks. However, after 26 weeks chromium picolinate supplemented subjects showed increased lean body mass (p < 0.029) whereas the other treatment groups still had reduced lean body mass. Chromium picolinate, but not chromium yeast, is able to increase lean body mass in obese patients in the maintenance period after a very-low-calorie diet without counteracting the weight loss achieved

Obesity and insurance risk: the insurance industry's viewpoint.

Baird IM.

Pharmacoeconomics. 1994; 5(Suppl 1):62-5.

Obesity is regarded by insurance companies as a substantial risk for both life and disability policies. This risk increases proportionally with the degree of obesity. Mortality statistics for life insurance were the earliest indicator that the cost of obesity to the individual was a decreased life span and increased illness, particularly that affecting the cardiovascular and musculoskeletal systems. The prevalence of coronary heart disease rises with increases in the body mass index in both men and women. Cigarette smoking greatly augments these risks in both sexes. Hypertension and diabetes are very common in obese persons and add further to the risks of vascular disease. Abdominal obesity (when the abdominal girth measured round the umbilicus exceeds the maximum measurement round the hips) is correlated with the risk of cardiac disease and stroke, independently of bodyweight. Insurance companies consider abdominal obesity as unfavourable and rate it accordingly. Obesity (even that of moderate degree) greatly increases the chances of disability due to cardiovascular disease or musculoskeletal illness. In one study of 51 522 adult Finns, 25% of disability pensions in women were found to result directly from obesity. Obesity causes increased health expenditure, decreased life span and productivity, and premature retirement. Insurance companies are compelled to build these risks into their policies. However, because the excess mortality occurs late in mild to moderate obesity, some companies may minimise this risk for life policies that mature early

Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid.

Banni S, Angioni E, Casu V, et al.

Carcinogenesis. 1999 Jun; 20(6):1019-24.

Previous research suggested that conjugated linoleic acid (CLA) feeding during the period of pubescent mammary gland development in the rat resulted in diminished mammary epithelial branching which might account for the reduction in mammary cancer risk. Terminal end buds (TEB) are the primary sites for the chemical induction of mammary carcinomas in rodents. One of the objectives of the present study was to investigate the modulation of TEB density by increasing levels of dietary CLA and to determine how this might affect the risk of methylnitrosourea-induced mammary carcinogenesis. The data show a graded and parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1% CLA. No further decrease in either parameter was observed when CLA in the diet was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the mammary gland. Since both CLA and linoleic acid are likely to share the same enzyme system for chain desaturation and elongation, it is possible that increased CLA intake may interfere with the further metabolism of linoleic acid. Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2% CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to 1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose-response effect on cancer protection in the mammary gland. This information is critical in providing new insights regarding the biochemical action of CLA

The effect of a 72-h fast on plasma levels of pituitary, adrenal, thyroid, pancreatic and gastrointestinal hormones in healthy men and women.

Beer SF, Bircham PM, Bloom SR, et al.

J Endocrinol. 1989 Feb; 120(2):337-50.

Seventeen human subjects fasted without electrolyte replacement for 3 days and hormone levels were measured before, during and after the fast. Immediate consequences of the fasting state in healthy human subjects include a marked increase in plasma cortisol. ACTH, beta-endorphin, beta-lipotrophic hormone, adrenaline, noradrenaline and dopamine. Levels of all these hormones were much greater on the first morning of the fast than in the post-prandial state, even though the plasma glucose level was no lower than that observed on the morning before the fast began. A clear fall in TSH and tri-iodothyronine (T3) levels was observed, but thyroxine levels did not change significantly. Insulin levels fell whereas proinsulin levels did not fall during the fast, though they did rise markedly upon re-feeding. An increase in GH levels was particularly apparent in male subjects, but was also seen in females when evening samples were compared. Pancreatic glucagon showed a modest rise during the fast, but fell again on refeeding; total glucagon also rose as the fast proceeded, but increased markedly upon re-feeding. Levels of gastrin and peptide YY remained low during the fast. Plasma electrolyte levels were unchanged. The following were closely correlated: cortisol with ACTH, T3 with log10 TSH, dopamine with noradrenaline, and (negatively, during the fast) pancreatic glucagon with glucose

Cecil-Loeb Textbook of Medicine.

Beeson P.

1968; Twelfth Edition

Cecil-Loeb Textbook of Medicine.

Beeson P.

1971; Thirteenth Edition

Thyroid disease in the elderly. Part 1. Prevalence of undiagnosed hypothyroidism.

Bemben DA, Winn P, Hamm RM, et al.

J Fam Pract. 1994 Jun; 38(6):577-82.

BACKGROUND. The purpose of this study was to examine the prevalence of previously unrecognized hypothyroidism in elderly patients. METHODS. The study was conducted in a primary care geriatrics clinic. Three hundred seventy elderly patients (287 women, 83 men) between 60 and 97 years of age were included in the study. Medical records of patients were reviewed retrospectively. Serum thyroid-stimulating hormone (TSH), free thyroxine (T4), height, weight, demographic variables, clinical signs and symptoms of hypothyroidism, history of thyroid diseases and treatment with thyroid medications, comorbidities, and current medications were obtained from the medical records. Patients who had both elevated TSH levels (5.0 to 14.9 microU/mL) and normal free T4 levels (0.7 to 2.0 ng/dL) met the criteria for "subclinical hypothyroidism." The criteria for "overt hypothyroidism" were TSH levels > or = 15 microU/mL and low free T4 levels (< 0.7 ng/dL). RESULTS. At the initial visit to the clinic, 18.1% of the patients (62 female and 5 male) had an established history of past or current thyroid disease. Another 20 women (5.4%) had a history of thyroid surgery. Of the remaining 283 patients with no history of thyroid disease, 14.6% of the women and 15.4% of the men had subclinical hypothyroidism. Overt hypothyroidism was discovered and subsequently treated in two female patients and one male patient (1.0% and 1.3%, respectively). Thyroid status was not significantly related to age group (60 to 64 years; 65 to 74; 75 to 84; 85 and older). Comorbidities typically associated with hypothyroidism were no more prevalent in hypothyroid patients than in euthyroid patients. CONCLUSIONS. We found a high prevalence of newly diagnosed subclinical hypothyroidism in both elderly male and female patients. Thyroid status was not related to age or to coexisting diseases. The clinical significance of treating subclinical hypothyroidism merits investigation

Induction of obesity by psychotropic drugs.

Bernstein JG.

Ann N Y Acad Sci. 1987; 499:203-15.

Evidence from published studies and clinical experience indicates that neuroleptic drugs, tricyclic and heterocyclic antidepressants, monoamine oxidase inhibitor antidepressants, and lithium all possess varying abilities to increase appetite, stimulate carbohydrate craving, and cause weight gain over prolonged periods of administration. Sedatives and benzodiazepine-type antianxiety drugs fail to stimulate appetite or induce weight gain, and it is unlikely that the sedative or calming effects of other psychotropic drugs contribute significantly to changes in appetite or weight. Studies of the endocrine and metabolic aspects of psychotropic drugs suggest that these mechanisms do not contribute significantly to explaining the observed effects on appetite or weight. Numerous studies indicate that a wide variety of compounds, including the serotonin precursor, tryptophan, the serotonin receptor stimulant, fenfluramine, and the serotonin reuptake inhibitor, fluoxetine, are all capable of decreasing carbohydrate hunger, reducing consumption of carbohydrate-rich foods, and inhibiting weight gain in humans and animals. Widely divergent psychotropic drugs produce antagonistic effects at serotonin receptor sites, and it is likely that this action contributes to their ability to stimulate appetite, carbohydrate craving, and weight gain. Those psychotropic drugs that inhibit serotonin reuptake mechanisms, increasing serotonin activity within the central nervous system, either fail to stimulate carbohydrate hunger and weight gain or are actually capable of decreasing carbohydrate craving and facilitating weight loss. Because many antidepressants, including trazodone and amitriptyline, the neuroleptic, chlorpromazine, and the mood stabilizer, lithium, may all, under some circumstances, inhibit serotonin reuptake mechanisms and may simultaneously block serotonin receptor sites, their effects on appetite and weight gain may represent a balance between serotonergic and antiserotonin activities. Monoamine oxidase inhibitors, which slow the metabolic degradation of monoamines, including serotonin and norepinephrine, allow for increased levels of these neurotransmitters within the brain. It is conceivable that the relative noradrenergic effect related to an amphetamine-like structure of tranylcypromine may explain its lesser ability to stimulate appetite and weight gain than the appetite and weight effects observed with phenelzine. Furthermore, the production of dry mouth and thirst by psychotropic drugs appears to contribute to weight gain, secondary to consumption of high-calorie beverages.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term effect of fibre supplement and reduced energy intake on body weight and blood lipids in overweight subjects.

Birketvedt GS, Aaseth J, Florholmen JR, et al.

Acta Medica (Hradec Kralove). 2000; 43(4):129-32.

A weight-reducing potential has been ascribed to high dietary fibre intake. To investigate the practical reliability of this hypothesis, fifty-three moderately overweight females (BMI > 27.5 kg/m2) on reduced energy intake (1200 kcal/day) were treated for 24 weeks with a fibre supplement on a randomly, double-blind, placebo-controlled basis. The fibre was administered as an initial dose of 6 g and a maintenance dose of 4 g. Body weight and blood pressure were recorded weekly during the first 3 months and thereafter every second week. Blood samples were drawn at start and at end of the study. Initial body weights were 75.6 +/- 1.6 kg in the fibre group versus 75.5 +/- 1.6 kg in the placebo group. After treatment, mean weight loss in the fibre group was 8.0 kg versus 5.8 kg in the placebo group (p < 0.05). Systolic and diastolic blood pressures were significantly reduced in both groups without differences between the groups. Serum concentrations of cholesterol, triglycerides and uric acid were significantly reduced in the group with reduced energy intake, whereas no additional effect was observed when fibre was supplemented. Serum concentrations of potassium and sodium did not change significantly. The results suggest that a dietary fibre supplement in combination with a hypocaloric diet is of value as an adjunct in the management of overweight

The regulation of adipose tissue distribution in humans.

Bjorntorp P.

Int J Obes Relat Metab Disord. 1996 Apr; 20(4):291-302.

The regulation of adipose tissue distribution is an important problem in view of the close epidemiological and metabolic associations between centralized fat accumulation and disease. With visceral fat accumulation multiple endocrine perturbations are found, including elevated cortisol and androgens in women, as well as low growth hormone (GH) and, in men, testosterone (T) secretion. These abnormalities probably derive from a hypersensitive hypothalamo-pituitary-adrenal axis, with hyperinsulinemia related to a marked insulin resistance as a consequence. These hormonal changes exert profound effects on adipose tissue metabolism and distribution. At the adipocyte level cortisol and insulin promote lipid accumulation by expressing lipoprotein lipase activity, while T, GH and probably estrogens exert opposite effects. The consequences will most likely be more expressed in visceral than subcutaneous adipose tissues because of a higher cellularity, innervation and blood flow. Furthermore, the density of cortisol and androgen receptors seems to be higher in this than other adipose tissue regions. The endocrine perturbations found in visceral obesity with an abundance of the lipid accumulating hormones cortisol and insulin, and a relatively low secretion of the lipid mobilizing sex steroid hormones and GH would therefore be expected to be followed by visceral fat accumulation. The potential significance of local synthesis of steroid hormones in adipose tissue requires more attention. Although studies in vitro are informative when elucidating detailed mechanisms of hormonal interactions, they might not give a true picture of the regional integrated regulation of adipose tissue lipid storage and mobilization. Such information can be obtained by regional measurements of lipid mobilization by free fatty acid turnover or by microdialysis techniques, both showing lower rates of mobilization in leg than in upper body adipose tissues. More detailed information can be obtained by physiological oral administration of triglycerides, labelled with a small amount of oleic acid, followed by measurements of the regional uptake and turn-over of adipose tissue triglycerides. Such studies show lipid uptake in the order omental = retroperitoneal > subcutaneous abdominal > subcutaneous femoral adipose tissues in men, with a similar rank order for half-life of the triglyceride, indicating also a turn-over of triglycerides in that order. T amplifies these differences in men. In premenopausal women subcutaneous abdominal has a higher turnover than femoral adipose tissue. Results of studies in vitro indicate that this difference is diminished at the menopause, and restored by estrogen substitution, suggesting that the functional effects of estrogens in women are similar to those of T in men. The mechanisms are, however, probably indirect because of the apparent absence of specific estrogen and progesterone receptors in human adipose tissue. This interpretation from the studies referred to above fits well with physiological, and clinical conditions with increased visceral fat mass, where the balance between the lipid accumulating hormone couple (cortisol and insulin) and the hormones which prevent lipid accumulation and instead activate lipid mobilization pathways (sex steroid hormones and GH) is shifted to the advantage of the former. Such conditions include Cushing's syndrome, the polycystic ovary syndrome, menopause, aging, GH-deficiency, depression, smoking and excess alcohol intake. With appropriate interventions against hypercortisolemia and substitution of deficient sex steroids and GH, visceral fat mass is decreasing. Based on this evidence from physiological, clinical, interventional observations and detailed studies of mechanisms at cellular and molecular levels it is suggested that the combined endocrine abnormalities in the syndrome of visceral obesity direct storage fat to visceral adipose depots. Therefore, measurements of visceral fat accumulat

Conjugated linoleic acid reduces body fat mass in overweight and obese humans.

Blankson H, Stakkestad JA, Fagertun H, et al.

J Nutr. 2000 Dec; 130(12):2943-8.

Conjugated linoleic acid (CLA) has been shown to reduce body fat mass (BFM) in animals. To investigate the dose-response relationships of conjugated linoleic acid with regard to BFM in humans, a randomized, double-blind study including 60 overweight or obese volunteers (body mass index 25-35 kg/m(2)) was performed. The subjects were divided into five groups receiving placebo (9 g olive oil), 1.7, 3.4, 5.1 or 6.8 g conjugated linoleic acid per day for 12 wk, respectively. Dual-energy X-ray absorptiometry was used to measure body composition [measurements at wk 0 (baseline), 6 and 12]. Of the 60 subjects, 47 completed the study. Eight subjects withdrew from the study due to adverse events; however, no differences among treatment groups were found regarding adverse events. Repeated-measures analysis showed that a significantly higher reduction in BFM was found in the conjugated linoleic acid groups compared with the placebo group (P: = 0.03). The reduction of body fat within the groups was significant for the 3.4 and 6.8 g CLA groups (P: = 0.05 and P: = 0.02, respectively). No significant differences among the groups were observed in lean body mass, body mass index, blood safety variables or blood lipids. The data suggest that conjugated linoleic acid may reduce BFM in humans and that no additional effect on BFM is achieved with doses > 3.4 g CLA/d

Severe sexual impairment produced by morbid obesity. Report of a case.

Blum I, Marilus R, Barasch E, et al.

Int J Obes. 1988; 12(3):185-9.

A 45-year-old man, was admitted for investigation of severe sexual impairment. During 20 years of marriage, he had had no normal sexual intercourse and the couple was childless. Physical examination disclosed a severely obese man (weight 300 kg, height 1.75 m), with a relatively small and invaginated penis and small (5 ml) soft testes. Laboratory examinations disclosed the following: low serum testosterone (1 ng/ml), with a reduced response to HCG (3.8 ng/ml). Sex hormone binding globulin was at the lower limit of normal (0.38 microgram/dl), serum free testosterone was low (0.98% of total testosterone) as well as non-SHBG bound testosterone (22% of total testosterone). Daily total urinary estrogen excretion was increased (107 micrograms), the plasma estrone (78 pg/ml) and estradiol (74 pg/ml) were elevated. The gonadotropins were normal and responded adequately to LRH. Plasma growth hormone was decreased, prolactin, T4 and adrenal steroids were normal and responded normally to stimuli and inhibitors. Chromosomal constitution was 46XY. Thus, in this man the marked obesity produced a significant increase in estrogens which subsequently induced a severe decrease in testosterone and its free counterpart in excessive impairment of sexual function

The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids.

Borkman M, Storlien LH, Pan DA, et al.

N Engl J Med. 1993 Jan 28; 328(4):238-44.

BACKGROUND. Insulin resistance and hyperinsulinemia are features of obesity, non-insulin-dependent diabetes mellitus, and other disorders. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty-acid composition of the phospholipids within the muscle membranes involved in the action of insulin. METHODS. We determined the relation between the fatty-acid composition of skeletal-muscle phospholipids and insulin sensitivity in two groups of subjects. In one study, we obtained samples of the rectus abdominis muscle from 27 patients undergoing coronary artery surgery; fasting serum insulin levels provided an index of insulin sensitivity. In the second study, a biopsy of the vastus lateralis muscle was performed in 13 normal men, and insulin sensitivity was assessed by euglycemic-clamp studies. RESULTS. In the patients undergoing surgery, the fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individual long-chain polyunsaturated fatty acids in the phospholipid fraction of muscle, particularly arachidonic acid (r = -0.63, P < 0.001); the total percentage of C20-22 polyunsaturated fatty acids (r = "-0.68," P < 0.001); the average degree of fatty-acid unsaturation (r = "-0.61," P < 0.001); and the ratio of the percentage of C20:4 n-6 fatty acids to the percentage of C20:3 n-6 fatty acids (r = "-0.55," P < 0.01), an index of fatty-acid desaturase activity. In the normal men, insulin sensitivity was positively correlated with the percentage of arachidonic acid in muscle (r = "0.76," P < 0.01), the total percentage of C20-22 polyunsaturated fatty acids (r = "0.76," P < 0.01), the average degree of fatty-acid unsaturation (r = "0.62," P < 0.05), and the ratio of C20:4 n-6 to C20:3 n-6 (rho = "0.76," P = "0.007)." CONCLUSIONS. Decreased insulin sensitivity is associated with decreased concentrations of polyunsaturated fatty acids in skeletal-muscle phospholipids, raising the possibility that changes in the fatty-acid composition of muscles modulate the action of insulin

French's Index of Differential Diagnosis.

Bouchier IAEDH.

1997;

Glycemic index and obesity.

Brand-Miller JC, Holt SH, Pawlak DB, et al.

Am J Clin Nutr. 2002 Jul; 76(1):281S-5S.

Although weight loss can be achieved by any means of energy restriction, current dietary guidelines have not prevented weight regain or population-level increases in obesity and overweight. Many high-carbohydrate, low-fat diets may be counterproductive to weight control because they markedly increase postprandial hyperglycemia and hyperinsulinemia. Many high-carbohydrate foods common to Western diets produce a high glycemic response [high-glycemic-index (GI) foods], promoting postprandial carbohydrate oxidation at the expense of fat oxidation, thus altering fuel partitioning in a way that may be conducive to body fat gain. In contrast, diets based on low-fat foods that produce a low glycemic response (low-GI foods) may enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity. This hypothesis is supported by several intervention studies in humans in which energy-restricted diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods. Long-term studies in animal models have also shown that diets based on high-GI starches promote weight gain, visceral adiposity, and higher concentrations of lipogenic enzymes than do isoenergetic, macronutrientcontrolled, low-GI-starch diets. In a study of healthy pregnant women, a high-GI diet was associated with greater weight at term than was a nutrient-balanced, low-GI diet. In a study of diet and complications of type 1 diabetes, the GI of the overall diet was an independent predictor of waist circumference in men. These findings provide the scientific rationale to justify randomized, controlled, multicenter intervention studies comparing the effects of conventional and low-GI diets on weight control

In Werner and Ingbar's The Thyroid.

Braverman E.

1996; Seventh Edition(Chapters 6 and 7)

Effect of diet and triiodothyronine on the activity of sn-glycerol-3-phosphate dehydrogenase and on the metabolism of glucose and pyruvate by adipose tissue of obese patients.

Bray GA.

J Clin Invest. 1969 Aug; 48(8):1413-22.

An aqueous extract of guarana (Paullinia cupana) decreases platelet thromboxane synthesis.

Bydlowski SP, D'Amico EA, Chamone DA.

Braz J Med Biol Res. 1991; 24(4):421-4.

The effects of an aqueous extract of guarana (Paullinia cupana) on rabbit platelet aggregation and thromboxane synthesis were examined. The guarana extract (100 mg/ml) and fractions separated by TLC (origin and xanthines) decreased platelet aggregation (37, 27 and 31% of control values, respectively) and platelet thromboxane formation from [14C]-arachidonic acid (78, 70 and 50% of control values, respectively). The decreased thromboxane synthesis could be responsible, at least in part, for the antiaggregatory action of guarana

Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin, and thyroid hormones in starved obese men.

Carlson HE, Drenick EJ, Chopra IJ, et al.

J Clin Endocrinol Metab. 1977 Oct; 45(4):707-13.

To investigate further the alterations in pituitary-thyroid function seen during starvation, we have measured basal and TRH-stimulated serum levels of thyrotropin (TSH), prolactin (PRL), growth hormone, thyroxine (T4), triiodothyronine (T3), free T4, free T3, and reverse T3 during prolonged fasting in seven obese men. Fasting was associated with a significant decrease in serum (4, (3, and free T3, while there was an increase in serum reverse T3; these values tended to return toward pre-fast levels as the fast continued beyond 3 weeks. No significant changes were seen in basal serum TSH, PRL, growth hormone, or free T4. Although the TSH response to TRH was diminished during fasting, PRL, T4, and T3 responses were unchanged. In addition to transient alterations in the peripheral metabolism of T4, these findings suggest that alterations in the thyroid hormone binding capacity of serum carrier proteins may occur during fasting. The blunted TSH response to TRH despite reduction of serum T3 concentration suggests that subtle alterations in hypothalamic-pituitary function may also occur

Outcomes of pharmacological and surgical treatment for obesity.

Cerulli J, Malone M.

Pharmacoeconomics. 1998 Sep; 14(3):269-83.

The purpose of this article is to review the data from pharmacotherapeutic and surgical intervention studies for the management of obesity. Clinical outcomes assessed include weight changes over time and the effects of weight loss on blood pressure, serum lipid profiles and blood glucose control. Quality of life and economic data have been incorporated where available. Double-blind, randomised controlled trials were used preferentially over shorter term open studies. The literature evaluation was based on a Medline search of published data between January 1990 and January 1998. Obesity affects 65 million adults in the US. Estimates based on 1990 data suggest that obesity and comorbid illness contributed to $US46 billion in direct costs and $US23 billion in indirect costs in the US. Obesity is a chronic condition which requires long term management. The risk of developing cardiovascular disease, hypertension, type 2 (non-insulin-dependent) diabetes mellitus, osteoarthritis, Pickwickian syndrome and cancer is increased in the obese population, resulting in excess morbidity and mortality. There are no long term prospective studies that have demonstrated that weight reduction in obese patients improves survival. However, on the basis of epidemiological data using the prevalence of disease and associated body mass index, it is generally accepted that weight reduction of 5 to 10% in obese patients is associated with significant health benefits. Current treatment modalities include diet and behaviour modification, exercise and, where indicated, pharmacological intervention. Surgical intervention is reserved for the clinically severe obese patient [body mass index (BMI) > 40 kg/m2]. Many studies have demonstrated weight loss and improved metabolic fitness over 6 to 12 months. Few studies have been conducted over a longer period. Limited data are available regarding reduced morbidity and mortality, improved quality of life and functional or employment status and even fewer have incorporated any economic assessments of the impact of medical or surgical intervention. Although prospective data have demonstrated reduced morbidity following surgical intervention, only retrospective data have demonstrated reduced mortality. Studies of new drugs and interventions under development should demonstrate long term safety and efficacy in terms of sustained weight loss and subsequent weight maintenance. Future studies should incorporate assessment of patient perceived satisfaction with weight loss, health status and quality-of-life evaluations and pharmacoeconomic data to aid clinicians in the decision-making process in terms of weight management of their obese patients

Opposite effects of linoleic acid and conjugated linoleic acid on human prostatic cancer in SCID mice.

Cesano A, Visonneau S, Scimeca JA, et al.

Anticancer Res. 1998 May; 18(3A):1429-34.

The relationship between dietary fat intake (level and type) and cancer development is a matter of concern in Western society. The purpose of this study was to determine the effect of three different diets on the local growth and metastatic properties of DU-145 human prostatic carcinoma cells in severe combined immunodeficient (SCID) mice. Animals were fed a standard diet or diets supplemented with 1% LA or 1% CLA for 2 weeks prior to subcutaneous (s.c.) inoculation of DU-145 cells and throughout the study (total of 14 weeks). Mice receiving LA-supplemented diet displayed significantly higher body weight, lower food intake and increased local tumor load as compared to the other two groups of mice. Mice fed the CLA-supplemented diet displayed not only smaller local tumors than the regular diet-fed group, but also a drastic reduction in lung metastases. These results support the view that dietary polyunsaturated fatty acids may influence the prognosis of prostatic cancer patients, thus opening the possibility of new therapeutic options

Economic costs of obesity and inactivity.

Colditz GA.

Med Sci Sports Exerc. 1999 Nov; 31(11 Suppl):S663-S667.

PURPOSE: The purpose of this paper is to assess the economic costs of inactivity (including those attributable to obesity). These costs represent one summary of the public health impact of increasingly sedentary populations in countries with established market economies. Components of the costs of illness include direct costs resulting from treatment of morbidity and indirect costs caused by lost productivity (work days lost) and forgone earnings caused by premature mortality. METHODS: We searched the Medline database for studies reporting the economic costs of obesity or inactivity, or cost of illness. From the identified references those relating to obesity or conditions attributable to obesity were reviewed. Chronic conditions related to inactivity include coronary heart disease (CHD), hypertension, Type II diabetes, colon cancer, depression and anxiety, osteoporotic hip fractures, and also obesity. Increasing adiposity, or obesity, is itself a direct cause of Type II diabetes, hypertension, CHD, gallbladder disease, osteoarthritis and cancer of the breast, colon, and endometrium. The most up-to-date estimates were extracted. To estimate the proportion of disease that could be prevented by eliminating inactivity or obesity we calculated the population-attributable risk percent. Prevalence based cost of illness for the U.S. is in 1995 dollars. RESULTS: The direct costs of lack of physical activity, defined conservatively as absence of leisure-time physical activity, are approximately 24 billion dollars or 2.4% of the U.S. health care expenditures. Direct costs for obesity defined as body mass index greater than 30, in 1995 dollars, total 70 billion dollars. These costs are independent of those resulting from lack of activity. CONCLUSION: Overall, the direct costs of inactivity and obesity account for some 9.4% of the national health care expenditures in the United States. Inactivity, with its wide range of health consequences, represents a major avoidable contribution to the costs of illness in the United States and other countries with modern lifestyles that have replaced physical labor with sedentary occupations and motorized transportation

Differential Diagnosis in Primary Care.

Collins DR.

1981;

Genotoxic and mutagenic effects of guarana (Paullinia cupana) in prokaryotic organisms.

da Fonseca CA, Leal J, Costa SS, et al.

Mutat Res. 1994 May; 321(3):165-73.

Aqueous extracts of Paullinia cupana (guarana), a species that belongs to the Sapindaceae family, were analyzed for the presence of genotoxic activities in bacterial cells. The extracts of guarana were genotoxic as assessed by lysogenic induction in Escherichia coli and they were also able to induce mutagenesis in Salmonella typhimurium. Addition of S9 microsomal fraction, catalase, superoxide dismutase or thiourea counteracted the genotoxic activity of guarana, suggesting that oxygen reactive species play an essential role in the genotoxicity of aqueous guarana extracts. The genotoxic activity in the extracts was related to the presence of a molecular complex formed by caffeine and a flavonoid (catechin or epicatechin) in the presence of potassium

Fat tissue: a steroid reservoir and site of steroid metabolism.

Deslypere JP, Verdonck L, Vermeulen A.

J Clin Endocrinol Metab. 1985 Sep; 61(3):564-70.

Sex steroid concentrations and 17 beta-hydroxy-steroid dehydrogenase and aromatase activities were determined in fat tissue removed at surgery or, in order to allow comparisons in different sites, postmortem. Except for dehydroepiandrosterone (DHEA) sulfate (DHEAS), there existed a positive tissue/plasma gradient for all steroids studied (testosterone, androstenedione, DHEA, androstenediol, estrone, and estradiol), suggesting androgen uptake and estrogen synthesis in situ. Androgen concentrations did not vary according to site of origin of fat tissue, except that the DHEAS concentration was significantly lower in abdominal sc and omental fat than in breast, pericardial, or sc pubic fat. Tissue androgen concentrations were positively correlated with their plasma concentrations, but tissue and plasma estrogen concentrations were not correlated. All tissue steroid concentrations, with the exception of estradiol in men, decreased with age. Aromatase activity [androstenedione----estrone; mean maximum velocity, 7.4 +/- 3.7 (+/- SD) fmol estrone/mg protein . h] did not vary between sexes or with site of origin of fat tissue. 17 beta-Hydroxysteroid dehydrogenase activity (estradiol----estrone, mean maximum velocity 9.8 +/- 5.4 pmol/mg protein . h) was higher in fat from women than in that from men, higher in premenopausal than in postmenopausal women, and higher in omental than in sc fat. Its activity was noncompetitively inhibited in vitro by DHEA and DHEAS in near-physiological concentrations, and the enzyme activity was inversely correlated (P less than 0.001) with the tissue DHEA and DHEAS concentrations. We conclude that fat tissue is an important steroid hormone reservoir, that it is the site of active aromatase and 17 beta-hydroxysteroid dehydrogenase, and that tissue DHEA(S) may have a modulating effect on tissue estrogen production

Hyperinsulinemia as an independent risk factor for ischemic heart disease.

Despres JP, Lamarche B, Mauriege P, et al.

N Engl J Med. 1996 Apr 11; 334(15):952-7.

BACKGROUND. Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels. METHODS. In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls. RESULTS. Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P

Treatment of obesity with a low protein calorically unrestricted diet.

DOLE VP, SCHWARTZ IL, THAYSEN JH, et al.

Am J Clin Nutr. 1954 Nov; 2(6):381-91.

Pharmacological activity of Guarana (Paullinia cupana Mart.) in laboratory animals.

Espinola EB, Dias RF, Mattei R, et al.

J Ethnopharmacol. 1997 Feb; 55(3):223-9.

Mice that ingested a suspension of guarana (Paullinia cupana, Sapindaceae) in a dose of 0.3 mg/ml showed a significant increase in physical capacity when subjected to a stressful situation such as forced swimming after 100 and 200 days of treatment. Such an effect, however, was not obtained with a concentration of 3.0 mg/ml, nor with the ingestion of a suspension of ginseng 5.0 mg/ml, nor of a solution of caffeine 0.1 mg/ml. Guarana, both after a single (3.0 and 30 mg/kg) or chronic administrations (0.3 mg/ml), was able to partially reverse the amnesic effect of scopolamine as measured through a passive avoidance test in mice and rats, indicating a positive effect on memory acquisition. However, no effect was observed when an active avoidance task was used in rats, even after 20 days of guarana administration. There was also a tendency of rats treated with 0.3 mg/ml of guarana to better maintain the memory of a Lashley III maze path. The animals had the same average lifespan, indicating a low toxicity of guarana, even after 23 months of treatment

Experimental Biology Meeting.

FASEB (Federation of American Societies for Experimental Biology).

2002;2002 Mar; 16(5):1.

Abstr. 301.8

The Facts About Weight Loss Products and Programs 1992.

FDA.

1992 DHHS Publ. No. 92-1189

Plasma amino acid levels and insulin secretion in obesity.

Felig P, Marliss E, Cahill GF, Jr.

N Engl J Med. 1969 Oct 9; 281(15):811-6.

A Manual of Laboratory and Diagnostic Tests.

Fischbach F.

1996;

Overweight and obesity in the United States: prevalence and trends, 1960-1994.

Flegal KM, Carroll MD, Kuczmarski RJ, et al.

Int J Obes Relat Metab Disord. 1998 Jan; 22(1):39-47.

OBJECTIVE: To describe the prevalence of, and trends in, overweight and obesity in the US population using standardized international definitions. DESIGN: Successive cross-sectional nationally representative surveys, including the National Health Examination Survey (NHES I; 1960-62) and the National Health and Nutrition Examination Surveys (NHANES I: 1971-1974; NHANES II: 1976-1980; NHANES III: 1988-94). Body mass index (BMI:kg/m2) was calculated from measured weight and height. Overweight and obesity were defined as follows: Overweight (BMI > or = 25.0); pre-obese (BMI 25.0-29.9), class I obesity (BMI 30.0-34.9), class II obesity (BMI 35.0-39.9), and class III obesity (BMI > or = 40.0). RESULTS: For men and women aged 20-74 y, the age-adjusted prevalence of BMI 25.0-29.9 showed little or no increase over time (NHES I: 30.5%, NHANES I: 32.0%, NHANES II: 31.5% and NHANES III: 32.0%) but the prevalence of obesity (BMI > or = 30.0) showed a large increase between NHANES II and NHANES III (NHES I: 12.8%; NHANES I, 14.1%; NHANES II, 14.5% and NHANES III, 22.5%). Trends were generally similar for all age, gender and race-ethnic groups. The crude prevalence of overweight and obesity (BMI >> 25.0) for age > or = 20 y was 59.4% for men, 50.7% for women and 54.9% overall. The prevalence of class III obesity (BMI > or = 40.0) exceeded 10% for non-Hispanic black women aged 40-59 y. CONCLUSIONS: Between 1976-80 and 1988-94, the prevalence of obesity (BMI > or= 30.0) increased markedly in the US. These findings are in agreement with trends seen elsewhere in the world. Use of standardized definitions facilitates international comparisons

Ultrastructure of B-cells of Langerhans islets in rats after the administration of L-leucine.

Galabova R, Petkov P.

Endocrinol Exp. 1976; 10(3):217-23.

The results of studies with electron microscope supported the earlier biochemical findings on the stimulation of insulin secretion with the aid of L-leucine. The changes of the cell organelles of B-cells showed that both the synthesis and the release of insulin were activated, while the secretion by specific granules was unchanged. The stimulation of B-cells was accompanied by numerous membrane-like structures ("myelin-like figures") which were presumably formed from the endoplasmic reticulum

The effects of long-term administration of guarana on the cognition of normal, elderly volunteers.

Galduroz JC, Carlini EA.

Rev Paul Med. 1996 Jan; 114(1):1073-8.

Paulinia cupana (guarana) is a Brazilian plant given great prestige in popular medicine, for example as being a potent stimulator of brain functions. The authors assessed the effects of the long-term administration of guarana on the cognition of normal, elderly volunteers. Forty-five volunteers were studied, with a random distribution in three experimental groups: placebo (n = 15), caffeine (n = 15), and guarana (n = 15), in a double-blind study. There were no significant cognitive alterations in these volunteers

Decreased pancreatic islet response to L-leucine in the spontaneously diabetic GK rat: enzymatic, metabolic and secretory data.

Giroix MH, Saulnier C, Portha B.

Diabetologia. 1999 Aug; 42(8):965-77.

AIMS/HYPOTHESIS: Pancreatic islets from hereditarily non-insulin-dependent diabetic Goto-Kakizaki (GK) rats have a deficient insulin response not only to D-glucose but also to L-leucine. Our aim was to explain the cellular mechanism(s) underlying the beta-cell unresponsiveness to this amino acid. METHODS: Freshly collagenase isolated islets from GK rats and healthy Wistar control rats matched with them for sex and age were compared. Leucine uptake, metabolic fluxes and insulin secretory capacity were investigated on batch incubated-islets. Enzymatic activities were measured on sonicated islets. RESULTS: In GK rat islets, neither leucine transport nor leucine transaminase activity was disturbed. By contrast, 14CO2 production from either L-[U-14C]leucine or L-[1-14C]leucine was decreased. The L-[U-14C]leucine oxidation: L-[1-14C]leucine decarboxylation ratio was unaffected, indicating that the acetyl-CoA generated from leucine undergoes normal oxidation in the Krebs cycle. The leucine non-metabolizable analogue 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid induced insulin release and enhanced the secretory response to leucine as in controls, whereas leucine failed to amplify the response to the leucine analogue. Moreover, the potentiating action of L-glutamine on leucine-mediated insulin release was preserved. This coincided with normal glutamate dehydrogenase activity and L-[U-14C]glutamine oxidation. Finally, the secretory response to the leucine deamination product 2-ketoisocaproate was decreased, as was the 2-keto[1-14C]isocaproate oxidation. CONCLUSION/INTERPRETATION: In islet beta cells from GK rats, the defective secretory response to leucine cannot be ascribed to a deteriorated leucine-stimulated glutamate metabolism but rather to an impaired leucine catabolism. A reduced generation of acetyl-CoA from 2-ketoisocaproate, due to the defective oxidative decarboxylation of this keto-acid by the mitochondrial branched-chain 2-ketoacid dehydrogenase, is incriminated

Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution.

Haffner SM, Stern MP, Mitchell BD, et al.

Diabetes. 1990 Mar; 39(3):283-8.

Few data exist on predictors of non-insulin-dependent (type II) diabetes mellitus. We examined body mass index (BMI), ratio of subscapular-to-triceps skin fold (centrality index), and fasting glucose and insulin concentrations as predictors of decompensation to type II diabetes in Mexican Americans, a population at high risk for this disorder. Twenty-eight of 474 initially nondiabetic Mexican Americans developed type II diabetes after 8 yr of follow-up. Converters to diabetes were older and had higher BMIs, centrality indices, and fasting glucose and insulin concentrations than nonconverters. Subjects in the highest quartile of the insulin distribution had 6.6 times the risk of developing type II diabetes as subjects in the remaining three quartiles combined (95% confidence interval [CI] = 3.14-13.7). In multivariate analysis, fasting glucose (odds ratio [OR] = 5.80, 95% CI = 2.57-13.1) and insulin (OR = 3.12, 95% CI = 1.36-7.14) remained significantly related to conversion to diabetes. However, BMI and centrality index, which were significantly related to conversion in the univariate analysis, were no longer significant in the multivariate analysis once glucose and insulin concentrations were taken into consideration, suggesting that the effect of these variables may be mediated by insulin resistance. Nearly half of the incident cases developed in a subset of the population who were simultaneously in the highest quartile of both fasting insulin and glucose concentrations (population-attributable risk 44.2%). Our results support the insulin resistance/pancreatic exhaustion theory of type II diabetes

A twin study of weight loss and metabolic efficiency.

Hainer V, Stunkard A, Kunesova M, et al.

Int J Obes Relat Metab Disord. 2001 Apr; 25(4):533-7.

OBJECTIVE: To assess the genetic contribution to determinants of therapeutic weight loss in obese female identical twins. DESIGN: Subjects were studied for 40 days on an inpatient unit in three phases: 7 baseline days; 28 days of weight reduction by a very low calorie diet (1.6 MJ per day); and 5 days after weight reduction. SUBJECTS: Fourteen pairs of premenopausal obese female identical twins (age: 39.0+/-1.7 y; body weight (BW): 93.9+/-21.2 kg; body mass index (BMI): 34.2+/-7.8 kg/m2). MEASUREMENTS:: Body composition by hydrodensitometry and resting metabolic rate by indirect calorimetry were assessed before and after weight loss. RESULTS:: There was great variability among pairs in loss of weight (5.9-12.4 kg) and body fat (3.1-12.4 kg). By contrast, the intraclass correlation (ICC) within twin pairs was 0.85, P

Common Medical Diagnosis: An Algorithmic Approach.

Healey PM.

1994;

Divergent trends in obesity and fat intake patterns: the American paradox.

Heini AF, Weinsier RL.

Am J Med. 1997 Mar; 102(3):259-64.

PURPOSE: To compare recent changes in diet and physical activity with trends in body weight and obesity prevalence, using large survey studies representative of the US population. MATERIALS AND METHODS: Secular-trends survey studies were made from databases of NHANES II and III, USDA Nationwide Food Consumption Survey, Behavioral Risk Factor Survey System, and Calorie Control Council Report providing data on obesity prevalence, body mass index, calorie and fat intake, exercise-related physical activity, and consumption of low-calorie food extracted from surveys for the adult US population and specific subgroups. RESULTS: In the adult US population the prevalence of overweight rose from 25.4% from 1976 to 1980 to 33.3% from 1988 to 1991, a 31% increase. During the same period, average fat intake, adjusted for total calories, dropped from 41.0% to 36.6%, an 11% decrease. Average total daily calorie intake also tended to decrease, from 1,854 kcal to 1,785 kcal (-4%). Men and women had similar trends. Concurrently, there was a dramatic rise in the percentage of the US population consuming low-calorie products, from 19% of the population in 1978 to 76% in 1991. From 1986 to 1991 the prevalence of sedentary lifestyle represented almost 60% of the US population, with no change over time. CONCLUSIONS: Reduced fat and calorie intake and frequent use of low-calorie food products have been associated with a paradoxical increase in the prevalence of obesity. These diverging trends suggest that there has been a dramatic decrease in total physical activity related energy expenditure. Efforts to increase the average American's total exercise- and nonexercise-related physical activities may be essential for the prevention of obesity

Hyperinsulinemic obesity and carbohydrate addiction: the missing link is the carbohydrate frequency factor.

Heller RF, Heller RF.

Med Hypotheses. 1994 May; 42(5):307-12.

It is proposed that chronic hyperinsulinemia is largely responsible for hunger, cravings and weight gain observed in many obese. This form of obesity can be treated by decreasing frequency of daily intake of carbohydrates to one well-balance meal each day and allowing for additional meals that are low in fat, low carbohydrates and high fiber. Animal experimentation and epidemiological evidence support the role of chronic hyperinsulinemia as a major factor in obesity and accounts for the frequent failures of diet and behavioral modification programs. Chronic hyperinsulinemia upsets metabolic balances and favors anabolic metabolism; fosters carbohydrate cravings; promotes insulin resistance which further promotes anabolic metabolism; and insulin resistance in turn exacerbates chronic hyperinsulinemia. This vicious cycle maintains excess weight and defeats diet and behavioral modification attempts to treat obesity. An eating program focused on reduction of chronic hyperinsulinemia coupled with appropriate exercise and behavior modification can successfully and permanently bring down cravings, hunger and body weight

EFFECTS OF PROLONGED FASTING ON SUBSEQUENT FOOD INTAKE IN OBESE HUMANS.

HOLLIFIELD G, OWEN JA, Jr., LINDSAY RW, et al.

South Med J. 1964 Sep; 57:1012-6.

Dietary fiber and weight regulation.

Howarth NC, Saltzman E, Roberts SB.

Nutr Rev. 2001 May; 59(5):129-39.

The influence of dietary fiber on energy regulation remains controversial. This review summarizes published studies on the effects of dietary fiber on hunger, satiety, energy intake, and body composition in healthy individuals. Under conditions of fixed energy intake, the majority of studies indicate that an increase in either soluble or insoluble fiber intake increases postmeal satiety and decreases subsequent hunger. When energy intake is ad libitum, mean values for published studies indicate that consumption of an additional 14 g/day fiber for >2 days is associated with a 10% decrease in energy intake and body weight loss of 1.9 kg over 3.8 months. Furthermore, obese individuals may exhibit a greater suppression of energy intake and body weight loss (mean energy intake in all studies was reduced to 82% by higher fiber intake in overweight/obese people versus 94% in lean people; body weight loss was 2.4 kg versus 0.8 kg). These amounts are very similar to the mean changes in energy intake and body weight changes observed when dietary fat content is lowered from 38% to 24% of energy intake in controlled studies of nonobese and obese subjects. The observed changes in energy intake and body weight occur both when the fiber is from naturally high-fiber foods and when it is from a fiber supplement. In view of the fact that mean dietary fiber intake in the United States is currently only 15 g/day (i.e., approximately half the American Heart Association recommendation of 25-30 g/day), efforts to increase dietary fiber in individuals consuming

Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats.

Ip C, Banni S, Angioni E, et al.

J Nutr. 1999 Dec; 129(12):2135-42.

Conjugated linoleic acid (CLA) is a potent cancer preventive agent in animal models. To date, all of the in vivo work with CLA has been done with a commercial free fatty acid preparation containing a mixture of c9,t11-, t10,c12- and c11,t13-isomers, although CLA in food is predominantly (80-90%) the c9,t11-isomer present in triacylglycerols. The objective of this study was to determine whether a high CLA butter fat has biological activities similar to those of the mixture of free fatty acid CLA isomers. The following four different endpoints were evaluated in rat mammary gland: 1) digitized image analysis of epithelial mass in mammary whole mount; 2) terminal end bud (TEB) density; 3) proliferative activity of TEB cells as determined by proliferating cell nuclear antigen immunohistochemistry; and 4) mammary cancer prevention bioassay in the methylnitrosourea model. It should be noted that TEB cells are the target cells for mammary chemical carcinogenesis. Feeding butter fat CLA to rats during the time of pubescent mammary gland development reduced mammary epithelial mass by 22%, decreased the size of the TEB population by 30%, suppressed the proliferation of TEB cells by 30% and inhibited mammary tumor yield by 53% (P < 0.05). Furthermore, all of the above variables responded with the same magnitude of change to both butter fat CLA and the mixture of CLA isomers at the level of CLA (0.8%) present in the diet. Interestingly, there appeared to be some selectivity in the uptake or incorporation of c9,t11-CLA over t10,c12-CLA in the tissues of rats given the mixture of CLA isomers. Rats consuming the CLA-enriched butter fat also consistently accumulated more total CLA in the mammary gland and other tissues (four- to sixfold increases) compared with those consuming free fatty acid CLA (threefold increases) at the same dietary level of intake. We hypothesize that the availability of vaccenic acid (t11-18:1) in butter fat may serve as the precursor for the endogenous synthesis of CLA via the Delta9-desaturase reaction. Further studies will be conducted to investigate other attributes of this novel dairy product

Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture.

Ip MM, Masso-Welch PA, Shoemaker SF, et al.

Exp Cell Res. 1999 Jul 10; 250(1):22-34.

The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, beta II, delta, epsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, epsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis

Trial of mannoheptulose in man.

Johnson BF, Wolff FW.

Metabolism. 1970 May; 19(5):354-62.

Hyperinsulinemia cluster predicts the development of type 2 diabetes independently of family history of diabetes.

Kekalainen P, Sarlund H, Pyorala K, et al.

Diabetes Care. 1999 Jan; 22(1):86-92.

OBJECTIVE: The aim of this prospective study was to determine risk factor clusters predicting type 2 diabetes in subjects with and without family history of diabetes by applying factor analyses. RESEARCH DESIGN AND METHODS: The study population consisted of 309 siblings of diabetic (DM+) or nondiabetic (DM-) probands. Risk factors, including lipids, lipoproteins, blood pressure, and glucose tolerance status, were measured at the baseline study and 8 years later. RESULTS: Siblings in the DM+ group had a significantly higher risk of diabetes (odds ratio [OR] = 3.25; P = 0.002) than siblings in the DM- group. Altogether, factor analyses revealed four significant factors in both the DM+ and DM- groups (the percentage of cumulative variance explained 62-66%). Of these, factor 1 (percentage of variance, 27-29%) was characterized by high loadings for BMI, hypertension, glucose area, insulin area (the highest loading), and triglycerides in both the DM+ and DM- groups; therefore, factor 1 can be interpreted as a hyperinsulinemia factor. Also, other factors were essentially similar in both groups. Hyperinsulinemia factor was similarly associated with the risk of developing diabetes in the DM+ group (OR = 4.33, 95% CI 2.29-8.19; P < 0.001) and the DM- group (OR = "4.22," 95% CI 2.02-8.81; P < 0.001) in logistic regression analyses. CONCLUSIONS: Our results indicate that a cluster of cardiovascular risk factors around hyperinsulinemia is an important predictor of diabetes in 8-year follow-up independent of family history of diabetes

Lower endogenous androgens predict central adiposity in men.

Khaw KT, Barrett-Connor E.

Ann Epidemiol. 1992 Sep; 2(5):675-82.

Central adiposity, sometimes described as male pattern fat distribution, is adversely related to cardiovascular risk and mortality independent of other measures of obesity. In a cohort of 511 men aged 30 to 79 years in 1972 to 1974, levels of androstenedione, testosterone, and sex hormone-binding globulin measured at baseline were inversely related to subsequent central adiposity, estimated 12 years later using the waist-hip circumference ratio. The observed differences in waist-hip ratio between top and bottom tertiles of these hormones and sex hormone-binding globulin were similar to mean waist-hip ratio differences between men with stroke or ischemic heart disease and those without in another prospective study. These findings, consistent with studies suggesting that testosterone seems to mobilize the abdominal depot on males, suggest that "male pattern" fat distribution may be a misleading description for central adiposity, at least, in men. Degree of maleness as indicated by total androgen levels is, in fact, negatively associated with central adiposity. However, the role of sex hormone-binding globulin in regulating androgenic activity warrants further investigation

The relationship between aromatase activity and body fat distribution.

Killinger DW, Perel E, Daniilescu D, et al.

Steroids. 1987 Jul; 50(1-3):61-72.

The metabolism of androstenedione (A) to estrone (E1) and 5 alpha-reduced androgens was studied in stromal cells derived from human adipose tissue from different body sites. The tissue was obtained from non-obese patients undergoing cosmetic liposuction or at the time of surgery for reduction mammoplasty. The conversion of A to E1 per 1x 10(6) cells was between 6- and 30-fold greater in the upper thigh, buttock, and flank than in the abdomen. These differences were present in primary culture and persisted to at least the third subculture. Estrogen formation in breast adipose tissue was similar to that found in cells from abdominal fat. The formation of 5 alpha-reduced metabolites (5 alpha-androstenedione, androsterone, and dihydrotestosterone) varied from patient to patient but was similar in cells from different body sites. These studies show that the regional distribution of fat may influence the metabolism of androgens in adipose tissue, with upper body fat tending to form a lower ratio of estrogens to 5 alpha-reduced androgens than lower body fat

Modulation of insulin signaling in human skeletal muscle in response to exercise.

Kirwan JP, Jing M.

Exerc Sport Sci Rev. 2002 Apr; 30(2):85-90.

Exercise is widely recommended for the treatment of obesity, insulin resistance, and type II diabetes mellitus. Recent discoveries in the molecular and cellular regulation of insulin-mediated glucose metabolism in skeletal muscle have provided a deeper understanding of how exercise modulates insulin action

Enhanced conversion of androstenedione to estrogens in obese males.

Kley HK, Deselaers T, Peerenboom H, et al.

J Clin Endocrinol Metab. 1980 Nov; 51(5):1128-32.

In normal and obese young males [90--120% and > 160% of ideal body weight (IBW); IBW = 100%], plasma concentrations of testosterone, androstenedione, estrone, and estradiol were measured. Metabolic clearance and production rates of androstenedione and the conversion ratios of androstenedione to testosterone, estrone, and estradiol were determined using the constant infusion technique. In the obese subjects, IBW was inversely correlated (P < 0.001) with plasma concentrations of androstenedione (r = "0.81)" and testosterone (r = "0.87)," while the levels of estrone (r = "0.92)" and estradiol (r = "0.95)" increased with IBW (P < 0.001). Thus, when normal and obese subjects were compared as groups, plasma androstenedione decreased form 1.24 +/- 0.13 to 0.93 +/- 0.15 ng/ml (mean +/- SD) and plasma testosterone decreased from 5.89 +/- 0.82 to 3.29 +/- 0.92 ng/ml (P < 0.001), while estrone increased from 28.2 +/- 3.4 to 60.0 +/- 9.4 pg/ml, and estradiol increased from 21.7 +/- 3.5 to 43.9 +/- 5.3 pg/ml. The testosterone to androstenedione and the estradiol to estrone ratios were not different in obesity, but changes in IBW were positively correlated (P < 0.001) with differences in the estrone to androstenedione (r = "0.93)" and estradiol to testosterone ratios (r = "0.93)," indicating that fat tissue may aromatize androgens, whereas reduction of 17-oxo-steroid appears to be of minor importance. As the MCR of androstenedione increased with IBW (from 2156 to 2636 liters/day P < 0.05) while plasma levels decreased, the apparent production rate of androstenedione was not influenced by the degree of obesity. The conversion of androstenedione to estrone (r = "0.89)" and of androstenedione to estradiol (r = "0.82)" was enhanced in obese subjects (P < 0.001). We suggest that enhanced aromatization of androstenedione due to an increased adipose tissue mass may account for the high plasma estrogen levels observed in obese men

Relationship of plasma sex hormones to different parameters of obesity in male subjects.

Kley HK, Edelmann P, Kruskemper HL.

Metabolism. 1980 Oct; 29(11):1041-5.

Relationships between plasma sex hormones and different parameters of obesity (weight, ideal body weight [IBW], overweight, fat mass, and body surface) were investigated in 70 healthy nonobese and obese males, 20-40 yr of age and with a body weight of 85%-245% of IBW. Plasma sex hormones remained unaffected by weight up to approximately 160% of the IBW. Only in the massively obese subjects was plasma testosterone decreased to 40% of controls (from 6.2 to 2.5 ng/ml), whereas free testosterone remained almost constant. On the other hand, plasma estrone and estradiol exhibited significant increases in obese subjects, ranging from 31.5 +/- 52.3 +/- 5.8 pg/ml for estrone, and 25.4 +/- 5.4 increasing to 44.7 +/0 5.0 pg/ml for estradiol. Similarly, free estradiol was shown to significantly increase with obesity in men from 505 +/- 118 to 991 +/- 123 fg/ml (p < 0.001). The ratios of testosterone/androstenedione, as well as of estradiol/estrone, were not affected by obesity, suggesting that reduction of the 17-oxo-group of the steroids is not influenced by the amount of fat tissue. A significant (p < 0.001) correlation was found between IBW and estrone (r = "0.80)" and estradiol (r = "0.75)," as well as the ratios of estrone/androstenedione (r = "0.62)" and estradiol/testosterone (r = "0.86)." This is consistent in its evidence indicating that fat tissue may be able to aromatize androgens. In the obese subjects, there were significant correlations between plasma sex hormones (testosterone, estrone, estradiol, and free estradiol) and the parameters of obesity used. Among these, correlations were best with IBW, overweight, and fat mass (r = "0.74-0.89;" p < 0.001); body weight and body surface were less favorable

A genetic analysis of weight and overweight in 4-year-old twin pairs.

Koeppen-Schomerus G, Wardle J, Plomin R.

Int J Obes Relat Metab Disord. 2001 Jun; 25(6):838-44.

OBJECTIVE: Although many twin and adoption studies document genetic influence on individual differences in weight, much less is known about genetic influences on overweight, about the genetic links between weight and overweight, or about the origins of weight and overweight in childhood, an age that might provide a good target for prevention of obesity. We tested the hypothesis that, in early childhood, overweight is as heritable as weight and that weight and overweight are linked genetically. DESIGN: Model-fitting analyses were used to compare monozygotic (MZ) and dizygotic (DZ) twins (same-sex and opposite-sex) for weight and overweight. SUBJECTS: The sample included 3636 4-y-old twins born in the UK in 1994. MEASUREMENTS: Heights and weights reported by parents were used to assess weight corrected for height, which yields results similar to body mass index (BMI) but corrects more completely for genetic effects on height. RESULTS: At 4 y of age, genetic factors contributed substantially both to individual differences in weight throughout the distribution and to the mean weight difference between overweight children and the rest of the population. Unlike results later in life, weight and overweight in 4-y-olds also suggest substantial shared family environmental influence. Results are similar for boys and girls. CONCLUSIONS: Overweight is the quantitative extreme of genetic and environmental factors responsible for normal variation in weight in childhood. Genes associated with overweight are likely to be associated with variation in weight throughout the distribution, as assumed by quantitative trait locus (QTL) theory. These findings linking weight and overweight in childhood have far-reaching implications for molecular genetic attempts to identify specific genes responsible for genetic influence, for investigating pathways between genes and behaviour, and for intervention and prevention

Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

Kolterman OG, Insel J, Saekow M, et al.

J Clin Invest. 1980 Jun; 65(6):1272-84.

To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. In conclusion: (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated

Obesity as a medical problem.

Kopelman PG.

Nature. 2000 Apr 6; 404(6778):635-43.

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being

Insulin sensitivity and sodium excretion in normotensive offspring and hypertensive patients.

Kopf D, Muhlen I, Kroning G, et al.

Metabolism. 2001 Aug; 50(8):929-35.

Insulin resistance and hyperinsulinemia have been suggested to precede and promote hypertension, possibly by impairing sodium balance. We examined insulin sensitivity and the influence of acute hyperinsulinemia on sodium excretion after acute sodium loading in hypertension-prone individuals. Insulin sensitivity and sodium excretion in response to a 1,000-mL isotonic saline bolus were examined in 24 strictly normotensive offspring of at least 1 hypertensive parent, 19 controls without a family history of hypertension, and 8 untreated, young hypertensive patients. After the saline bolus, urinary sodium excretion was measured at baseline and during a 2-hour euglycemic, hyperinsulinemic clamp, and insulin sensitivity was determined. Insulin, pressor hormones, and atrial natriuretic peptide (ANP), were measured by radioimmunoassay (RIA) or high-performance liquid chromatography (HPLC). Results are given as means +/- SEM. Offspring and controls were well matched in age (23.7 +/- 0.5; 24.6 +/- 0.5 years, respectively), blood pressure (113.0 +/- 2.9/68.5 +/- 1.9; 110.6 +/- 2.5/71.7 +/- 2.2 mm Hg, respectively), bone mass index (BMI), plasma glucose, and lipid parameters. Insulin sensitivity index did not significantly differ between offspring and controls (0.102 +/- 0.012; 0.112 +/- 0.018 micromol/min/kg/body weight [BW]/pmol, respectively), but was markedly reduced in hypertensives (0.045 +/- 0.006, P

Assessment of dietary and genetic factors influencing serum and adipose fatty acid composition in obese female identical twins.

Kunesova M, Hainer V, Tvrzicka E, et al.

Lipids. 2002 Jan; 37(1):27-32.

Fourteen pairs of obese female monozygotic twins were recruited for a study of genetic influences on serum and adipose fatty acid (FA) composition. Following 1 wk of inpatient stabilization, fasting serum and adipose tissue obtained by surgical excision were analyzed by thin-layer and gas chromatography. Intrapair resemblances (IPR) for individual FA were assessed by Spearman rank correlation and by analysis of variance and were found in serum cholesteryl esters (CF), triglycerides (TG), and adipose TG. With two exceptions (CE linoleate and adipose eicosapentaenoate), these IPR were limited to the nonessential FA. Palmitate had significant IPR in four lipid fractions; in serum CE and adipose TG palmitate was strongly correlated with multiple measures of adiposity. In contrast to other lipid fractions, serum phosphatidylcholine (PC) FA had 12 [PR, of which 6 were essential FA including arachidonate (r = 0.76, P < 0.0005), eicosapentaenoate (r = "0.78," P < 0.0005), and docosahexaenoate (r = "0.86," P< 0.0001). The PC [PR could not be explained by analysis of preadmission 7-d food records. After dividing the pairs into two groups differing and nondiffering according to fat intake of individuals in the pair, there was no evidence of a gene-environment interaction between fat intake and FA composition. The IPR for nonessential FA indicate that there is active genetic control of either food choices or postabsorptive metabolic processing. The high level of IPR in the PC fraction in contrast to the other lipid fractions suggests strong genetic influence over selection of specific FA for this membrane fraction independent of diet

The responses of serum and adipose Fatty acids to a one-year weight reduction regimen in female obese monozygotic twins.

Kunesova M, Phinney S, Hainer V, et al.

Ann N Y Acad Sci. 2002 Jun; 967:311-23.

We have reported strong intrapair resemblances (IPRs) in serum phosphatidylcholine (PC) fatty acid composition within adult monozygotic twins living apart. This study assessed the contribution of genetic factors to changes in serum and adipose tissue fatty acids resulting from weight loss and followed by a subsequent year of weight maintenance. Eleven pairs of female obese monozygotic twins (age: 38.9 +/- 1.8; BMI: 32.5 +/- 0.9) were recruited for the study. Fasting serum and adipose tissue were obtained after 1 week of inpatient stabilization, after 1 month of inpatient very-low-calorie diet (VLCD), and again after 1 year of outpatient weight maintenance. Fatty acids in serum lipid fractions and adipose tissue were quantitated by gas chromatography. Using multiple regression adjusted for age and initial value, IPRs were determined for the changes induced by VLCD and by the year of weight maintenance. There were few IPRs in nonessential fatty acids. By contrast, there were numerous IPRs for essential fatty acids (EFA), especially in the n-3 family across the VLCD. Following the maintenance year, however, frequent IPRs for nonessential fatty acids were seen, particularly in serum PC, and strong IPRs were seen for 18:3 n-3 and 20:5 n-3 across multiple fractions. These results infer the existence of strong genetic factors determining both the nonessential and EFA compositions of tissue lipids in humans independent of diet. Of particular note were the consistent IPRs for n-3 fatty acids despite dietary stress, indicating that the conservation and distribution of this EFA family are subject to considerable genetic variance in humans

D-Mannoketoheptose, a new sugar from the avocado.

La Forge FB.

J Biol Chem. 1916;(28):511-27.

Use of primary cultures of rat hepatocytes for the study of ageing and caloric restriction.

Lambert AJ, Merry BJ.

Exp Gerontol. 2000 Aug; 35(5):583-94.

Primary cultures of hepatocytes are widely used to investigate liver function, but this technology has not been exploited fully in the study of ageing and caloric restriction (CR). Hepatocytes were isolated from adult and aged, fully fed, and calorie restricted male Sprague-Dawley rats and their viability and biochemical status assessed over 48h in primary culture. The in vivo differences in cellular protein and DNA content due to age and CR were maintained over the 48h experimental period. The results of this study confirm earlier reports that protein synthesis and degradation rates decline with age in liver tissue, and this decline is retarded by CR. Rates of protein synthesis and degradation in the first year of life were depressed in response to CR feeding and were only significantly higher than recorded for control animals during the second year of life. Cells from rats of both ages and diets maintained linear rates of extracellular protein synthesis, intracellular protein synthesis, protein degradation and albumin secretion between 24 and 48h in culture. These findings indicate that hepatocytes from CR rats did not respond adversely to the relatively rich culture medium and cells from CR animals did not immediately revert to the fully fed phenotype

Changes in food intake and meal patterns following injection of D-mannoheptulose in rats.

Langhans W, Scharrer E.

Behav Neural Biol. 1983 Jul; 38(2):269-86.

Behavioral and metabolic effects of intraperitoneal D-mannoheptulose (MH) injections were investigated in rats fed a high carbohydrate (HC) or a high fat (HF) diet. Injection of 125 or 250 mg/kg body weight (body wt) MH did not affect food intake in HC rats. Injection of 400 mg/kg body wt MH inhibited feeding in HC rats by primarily reducing meal size. In contrast, none of the MH doses tested (125, 250, 400, 800 mg/kg body wt) affected food intake or meal patterns in HF rats. The hyperglycemia following MH injection (400 mg/kg body wt) was more pronounced in HC compared to HF rats. MH injection (400 mg/kg body wt) induced a strong taste aversion in HC rats, but had only weak aversive consequences in HF rats. The data throw some doubt on the hypothetical role of insulin in the production of satiety. In addition, the results suggest that a hedonic shift takes place following MH injection in HC rats. The strong dislike for the HC diet after MH injection might be triggered by the severe disturbance of glucose homeostasis and might contribute to the transient hypophagia in HC rats by primarily reducing meal size

Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria.

Lass A, Sohal BH, Weindruch R, et al.

Free Radic Biol Med. 1998 Dec; 25(9):1089-97.

The purpose of this study was to understand the nature of the causes underlying the senescence-related decline in skeletal muscle mass and performance. Protein and lipid oxidative damage to upper hindlimb skeletal muscle mitochondria was compared between mice fed ad libitum and those restricted to 40% fewer calories--a regimen that increases life span by approximately 30-40% and attenuates the senescence-associated decrement in skeletal muscle mass and function. Oxidative damage to mitochondrial proteins, measured as amounts of protein carbonyls and loss of protein sulfhydryl content, and to mitochondrial lipids, determined as concentration of thiobarbituric acid reactive substances, significantly increased with age in the ad libitum-fed (AL) C57BL/6 mice. The rate of superoxide anion radical generation by submitochondrial particles increased whereas the activities of antioxidative enzymes superoxide dismutase, catalase, and glutathione peroxidase in muscle homogenates remained unaltered with age in the AL group. In calorically-restricted (CR) mice there was no age-associated increase in mitochondrial protein or lipid oxidative damage, or in superoxide anion radical generation. Crossover studies, involving the transfer of 18- to 22-month-old mice fed on the AL regimen to the CR regimen, and vice versa, indicated that the mitochondrial oxidative damage could not be reversed by CR or induced by AL feeding within a time frame of 6 weeks. Results of this study indicate that mitochondria in skeletal muscles accumulate significant amounts of oxidative damage during aging. Although such damage is largely irreversible, it can be prevented by restriction of caloric intake

Gene expression profile of aging and its retardation by caloric restriction.

Lee CK, Klopp RG, Weindruch R, et al.

Science. 1999 Aug 27; 285(5432):1390-3.

The gene expression profile of the aging process was analyzed in skeletal muscle of mice. Use of high-density oligonucleotide arrays representing 6347 genes revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction, the only intervention known to retard aging in mammals. Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage

[Magnesium and glucose metabolism].

Lefebvre PJ, Paolisso G, Scheen AJ.

Therapie. 1994 Jan; 49(1):1-7.

The interrelationships between magnesium and carbohydrate metabolism have regained considerable interest over the last few years. Insulin secretion requires magnesium: magnesium deficiency results in impaired insulin secretion while magnesium replacement restores insulin secretion. Furthermore, experimental magnesium deficiency reduces the tissues sensitivity to insulin. Subclinical magnesium deficiency is common in diabetes. It results from both insufficient magnesium intakes and increase magnesium losses, particularly in the urine. In type 2, or non-insulin-dependent, diabetes mellitus, magnesium deficiency seems to be associated with insulin resistance. Furthermore, it may participate in the pathogenesis of diabetes complications and may contribute to the increased risk of sudden death associated with diabetes. Some studies suggest that magnesium deficiency may play a role in spontaneous abortion of diabetic women, in fetal malformations and in the pathogenesis of neonatal hypocalcemia of the infants of diabetic mothers. Administration of magnesium salts to patients with type 2 diabetes tend to reduce insulin resistance. Long-term studies are needed before recommending systematic magnesium supplementation to type 2 diabetic patients with subclinical magnesium deficiency

Effect of intravenous infusion of D-mannoheptulose on blood glucose and insulin levels in man.

Lev-Ran A, Laor J, Vins M, et al.

J Endocrinol. 1970 May; 47(1):137-8.

Absorption and subjective effects of caffeine from coffee, cola and capsules.

Liguori A, Hughes JR, Grass JA.

Pharmacol Biochem Behav. 1997 Nov; 58(3):721-6.

Coffee is often perceived as producing greater pharmacological effects than cola. The present study compared the magnitude and rapidity of peak caffeine levels and subjective effects between coffee and cola. Thirteen users of both coffee and cola (mean daily caffeine consumption = 456 mg) ingested 400 mg caffeine via 12 oz unsweetened coffee, 24 oz sugar-free cola or 2 capsules in a random, double-blind, placebo-controlled, within-subjects design. Subjects provided a saliva sample and completed subjective effect scales 15 min before and 30, 60, 90, 120, 180 and 240 min after ingestion. Mean peak saliva caffeine levels did not differ between coffee (9.7 +/- 1.2 micrograms/ml) and cola (9.8 +/- 0.9 micrograms/ml) and appeared to be greater with these beverages than with the capsule (7.8 +/- 0.6 micrograms/ml; p = NS). Saliva caffeine levels peaked at similar times for coffee (42 +/- 5 min) and cola (39 +/- 5 min) but later for capsule (67 +/- 7 min; p = 0.004). There was no main effect of vehicle or interaction of vehicle and drug on magnitude of peak effect or time to peak increase on self-report scales. In summary, peak caffeine absorption, time to peak absorption, and subjective effects do not appear to be influenced by cola vs. coffee vehicle. Perceived differences in the effects of coffee vs. cola may be due to differences in dose, time of day, added sweetener, environmental setting or contingencies

The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease.

Ludwig DS.

JAMA. 2002 May 8; 287(18):2414-23.

The glycemic index was proposed in 1981 as an alternative system for classifying carbohydrate-containing food. Since then, several hundred scientific articles and numerous popular diet books have been published on the topic. However, the clinical significance of the glycemic index remains the subject of debate. The purpose of this review is to examine the physiological effects of the glycemic index and the relevance of these effects in preventing and treating obesity, diabetes, and cardiovascular disease

The stimulus-secretion coupling of amino acid-induced insulin release metabolic interaction of L-asparagine and L-leucine in pancreatic islets.

Malaisse WJ, Malaisse-Lagae F, Sener A.

Biochim Biophys Acta. 1984 Feb 14; 797(2):194-202.

Because L-asparagine augments insulin release evoked by L-leucine, the metabolism of these two amino acids was investigated in rat pancreatic islets. L-Leucine inhibited the uptake and deamidation of L-asparagine, but failed to exert any obvious primary effect upon the further catabolism of aspartate derived from exogenous asparagine. L-Asparagine augmented the oxidation of L-leucine, an effect possibly attributable to activation of 2-ketoisocaproate dehydrogenase. The association of L-asparagine and L-leucine exerted a sparing action on the utilization of endogenous amino acids, so that the integrated rate of nutrients oxidation was virtually identical in the sole presence of L-leucine and simultaneous presence of L-asparagine and L-leucine, respectively. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine is attributable to an increased generation rate of cytosolic NADPH rather than any increase in nutrients oxidation

Androgen treatment of middle-aged, obese men: effects on metabolism, muscle and adipose tissues.

Marin P, Krotkiewski M, Bjorntorp P.

Eur J Med. 1992 Oct; 1(6):329-36.

OBJECTIVES: This pilot investigation was conducted to explore the relationship between androgens and glucose tolerance in obese men and to select an optimal mode for androgen treatment. METHODS: For exploratory purposes, testosterone (T) or dihydrotestosterone (DHT) were given in different doses and preparations for different periods of time to obese, middle-aged men. The administration forms were selected in order to by-pass the liver. In the first two studies T was given as a single intramuscular injection of 250 or 500 mg and the results evaluated after 1 week. In two subsequent studies testosterone was administered in moderate doses either as oral T undecanoate or a T and DHT in preparations applied on the skin for transdermal absorption for 6 weeks and 3 months respectively. Before and after treatment the following examinations were performed: glucose tolerance tests with insulin determinations or euglycemic clamps at submaximal insulin levels. Anthropometric measurements including the waist/hip circumference ratio and estimations of body fat and lean body mass (from measurements of whole body potassium content) were performed. Plasma triglyceride and cholesterol concentrations, liver function tests and blood pressure were followed. Physical examination including the prostate was performed before and after study. Muscle function, glycogen synthase and morphology were examined in the 3-month study. RESULTS: Administration of T was followed by moderate increases of circulating T concentrations in all studies, except after injection of 500 mg, where large increases were seen. Follicle stimulating hormone and luteinizing hormone levels decreased consistently. Injection of 500 mg T resulted in a decreased glucose tolerance. In the other treatment groups, plasma insulin decreased or glucose disappearance rate increased in clamp measurements, suggesting improved insulin sensitivity. This was most pronounced in men with relative hypogonadism from the outset. In the study of 3 months duration, a decrease in the waist/hip ratio, without a change in body fat mass, was also seen. Plasma lipids, liver function tests and blood pressure did not change. Muscle strength, the fractional velocity of glycogen synthase as well as the percentage and diameter of type IIB fibres increased after T treatment. No adverse effects were seen. 17 -beta oestradiol concentrations were unaltered and DHT administration was less effective than T, suggesting that T rather than derivatives of this hormone was mainly responsible for the effects observed. CONCLUSION: The results suggest that T administration to middle-aged, obese man may have beneficial effects

Androgens and abdominal obesity.

Marin P, Arver S.

Baillieres Clin Endocrinol Metab. 1998 Oct; 12(3):441-51.

Central or visceral obesity is recognized as a main risk factor for cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral obesity, increased blood lipid levels, hypertension and impaired glucose tolerance defines the metabolic syndrome that today is widely recognized as one of the prime factors behind cardiovascular morbidity and mortality. Endocrine disorders such as insulinoma, hypothyroidism and hypercortisolism are known to cause obesity. However, it is only hypercortisolism that is associated with increased abdominal fat accumulation. Recently, new findings have shed light on subtle endocrinopathies that are prevalent in individuals presenting with the metabolic syndrome. Such derangements are of borderline character and often fall within the normal reference range. Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis of the underlying mechanism has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrates that relatively low testosterone levels are a risk factor for development of visceral obesity. The primary event that triggers the initial development of visceral obesity is not known, but it seems plausible that increased activity in the hypothalamus-pituitary-adrenal axis can be of major importance

Guarana (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidants activity in vitro.

Mattei R, Dias RF, Espinola EB, et al.

J Ethnopharmacol. 1998 Mar; 60(2):111-6.

The effects on toxic and behavioral levels of guarana (Paullinia cupana) were assessed in rats and mice subsequent to acute and chronic administrations and were compared to those produced by Ginseng (Panax ginseng). Experimental parameters included tests for antioxidant capacity in vitro and measured in vivo, toxicological screening, progress in weight, motor activity, death rate, and histopathological examination of the viscera. Guarana showed an antioxidant effect because, even at low concentrations (1.2 microg/ml), it inhibited the process of lipid peroxidation. In high doses of 1000-2000 mg/kg (i.p. and p.o.) it did not induce significant alterations in parameters for toxicological screening. No effects on motor activity were observed, neither did guarana alter the hypnotic effect of pentobarbital. Ginseng (250-1000 mg/kg i.p.), however, elicited reductions in motor activity, eyelid ptosis and bristling fur. Consumption of liquids containing guarana or ginseng and progress in weight of the animals remained at levels similar to the controls, even after prolonged administration. The percentage mortality was equivalent in control and in treated groups. The absence of toxicity of guarana was also demonstrated by histopathological examination, with no alteration being detected in heart, lungs, stomach, small and large intestine, liver, pancreas, kidneys, bladder and spleen

Neuroprotective signaling and the aging brain: take away my food and let me run.

Mattson MP.

Brain Res. 2000 Dec 15; 886(1-2):47-53.

It is remarkable that neurons are able to survive and function for a century or more in many persons that age successfully. A better understanding of the molecular signaling mechanisms that permit such cell survival and synaptic plasticity may therefore lead to the development of new preventative and therapeutic strategies for age-related neurodegenerative disorders. We all know that overeating and lack of exercise are risk factors for many different age-related diseases including cardiovascular disease, diabetes and cancers. Our recent studies have shown that dietary restriction (reduced calorie intake) can increase the resistance of neurons in the brain to dysfunction and death in experimental models of Alzheimer's disease, Parkinson's disease, Huntington's disease and stroke. The mechanism underlying the beneficial effects of dietary restriction involves stimulation of the expression of 'stress proteins' and neurotrophic factors. The neurotrophic factors induced by dietary restriction may protect neurons by inducing the production of proteins that suppress oxyradical production, stabilize cellular calcium homeostasis and inhibit apoptotic biochemical cascades. Interestingly, dietary restriction also increases numbers of newly-generated neural cells in the adult brain suggesting that this dietary manipulation can increase the brain's capacity for plasticity and self-repair. Work in other laboratories suggests that physical and intellectual activity can similarly increase neurotrophic factor production and neurogenesis. Collectively, the available data suggest the that dietary restriction, and physical and mental activity, may reduce both the incidence and severity of neurodegenerative disorders in humans. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is also leading to novel therapeutic agents that mimick the beneficial effects of dietary restriction and exercise

Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms.

Mattson MP, Duan W, Lee J, et al.

Mech Ageing Dev. 2001 May 31; 122(7):757-78.

Dietary restriction (reduced calorie intake with nutritional maintenance) can extend lifespan and may increase the resistance of the nervous system to age-related diseases including neurodegenerative disorders. An environment enriched in intellectual and physical activities can also allay many of the adverse effects of aging on the brain. The mechanisms underlying the beneficial effects of dietary restriction and environmental enrichment on the brain involve stimulation of the expression of neurotrophic factors and 'stress proteins'. The neurotrophic factors and stress proteins induced by dietary restriction may protect neurons by suppressing oxyradical production, stabilizing cellular calcium homeostasis and inhibiting a form of programmed cell death called apoptosis. Interestingly, dietary restriction and environmental enrichment also increase numbers of newly-generated neural cells in the adult brain suggesting that these behavioral modifications can increase the brain's capacity for plasticity and self-repair. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is leading to novel therapeutic agents that mimick their beneficial effects

Enhancing central and peripheral insulin activity as a strategy for the treatment of endogenous depression--an adjuvant role for chromium picolinate?

McCarty MF.

Med Hypotheses. 1994 Oct; 43(4):247-52.

Depression is often associated with insulin resistance, owing to cortisol overproduction; conversely, many studies suggest that diabetics are at increased risk for depression. Recent evidence indicates that insulin is transported through the blood-brain barrier and influences brain function via widely distributed insulin receptors on neurons. These receptors are particularly dense on catecholaminergic synaptic terminals, and, while effects are variable dependent on brain region, several studies indicate that insulin promotes central catecholaminergic activity, perhaps by inhibiting synaptic re-uptake of norepinephrine. Additionally, it is well known that insulin enhances serotonergic activity in increasing blood-brain barrier transport of tryptophan. Since impaired monoaminergic activity in key brain pathways is believed to play an etiological role in depression, techniques which promote effective insulin activity, both centrally and peripherally, may be therapeutically beneficial in this disorder. This may rationalize anecdotal reports of improved mood in clinical depressives and diabetics receiving the insulin-sensitizing nutrient chromium picolinate. This nutrient, perhaps in conjunction with other insulin-sensitizing measures such as low-fat diet and aerobic exercise training (already shown to be beneficial in depression), should be tested as an adjuvant for the treatment and secondary prevention of depression

Activation of PPARgamma may mediate a portion of the anticancer activity of conjugated linoleic acid.

McCarty MF.

Med Hypotheses. 2000 Sep; 55(3):187-8.

A number of human cancer cell lines express the PPARgamma transcription factor, and agonists for PPARgamma are reported to promote apoptosis in these cell lines and impede their clonal expansion both in vitro and in vivo. Conjugated linoleic acid (CLA) can activate PPARgamma in rat adipocytes, possibly explaining CLA's antidiabetic effects in Zucker fatty rats. It is thus reasonable to suspect that a portion of CLA's broad spectrum anticarcinogenic activity is mediated by PPARgamma activation in susceptible tumors

Signals for insulin secretion.

McIntyre N.

Ciba Found Symp. 1978;(50):153-60.

Starvation-induced alterations of circulating thyroid hormone concentrations in man.

Merimee TJ, Fineberg ES.

Metabolism. 1976 Jan; 25(1):79-83.

Serum concentrations of triiodothyronine (T3), thyroxine (T4), and TSH were examined in seven men and seven women of normal weight during a 60-hr fast. Similar studies were conducted in two women who received daily for 1 mo before and during a similar fast, 0.4 mg and 0.5 mg of 1-thyroxine. The serum concentrations of T3 decreased in each of the untreated normal subjects (sign test of significance, P less than 0.001). The mean control concentration of T3 in women was 152 +/- 9 ng/100 ml (X +/- SEM); after 24 hr of fasting, 131 +/- 31 ng/100 ml; and at the termination of the fast, 90 +/- 15 ng/100 ml. The latter value differed from the control value with a p value of less than 0.01. Similar changes of T3 concentration occurred in men (mean basal T = 160 +/- 11 ng/100 ml; mean at termination of fast = 87 +/- 16 ng/100 ml). The range of decrease for T3 in all subjects varied from 24% to 55%. The mean T4 concentration at the beginning of the fast was 6.9 +/- 0.9, and at the termination of the fast, 7.5 +/- 0.6 (p = NS). TSH concentrations remained unchanged (Control, 3.8 +/- 0.45 muU/ml; at 60 hr, 4.0 +/- 0.26 muU/ml, p = NS). Studies in two women who received, before and during a fast, T4, indicate that a decreased peripheral conversion of T4 to T3 is the most likely mechanism responsible for this change

The continuing epidemics of obesity and diabetes in the United States.

Mokdad AH, Bowman BA, Ford ES, et al.

JAMA. 2001 Sep 12; 286(10):1195-200.

CONTEXT: Recent reports show that obesity and diabetes have increased in the United States in the past decade. OBJECTIVE: To estimate the prevalence of obesity, diabetes, and use of weight control strategies among US adults in 2000. DESIGN, SETTING, AND PARTICIPANTS: The Behavioral Risk Factor Surveillance System, a random-digit telephone survey conducted in all states in 2000, with 184 450 adults aged 18 years or older. MAIN OUTCOME MEASURES: Body mass index (BMI), calculated from self-reported weight and height; self-reported diabetes; prevalence of weight loss or maintenance attempts; and weight control strategies used. RESULTS: In 2000, the prevalence of obesity (BMI >/=30 kg/m(2)) was 19.8%, the prevalence of diabetes was 7.3%, and the prevalence of both combined was 2.9%. Mississippi had the highest rates of obesity (24.3%) and of diabetes (8.8%); Colorado had the lowest rate of obesity (13.8%); and Alaska had the lowest rate of diabetes (4.4%). Twenty-seven percent of US adults did not engage in any physical activity, and another 28.2% were not regularly active. Only 24.4% of US adults consumed fruits and vegetables 5 or more times daily. Among obese participants who had had a routine checkup during the past year, 42.8% had been advised by a health care professional to lose weight. Among participants trying to lose or maintain weight, 17.5% were following recommendations to eat fewer calories and increase physical activity to more than 150 min/wk. CONCLUSIONS: The prevalence of obesity and diabetes continues to increase among US adults. Interventions are needed to improve physical activity and diet in communities nationwide

Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects.

Mori TA, Bao DQ, Burke V, et al.

Am J Clin Nutr. 1999 Nov; 70(5):817-25.

BACKGROUND: Obesity in hypertensive patients is associated with dyslipidemia and insulin resistance, both of which are improved by weight control. n-3 Fatty acids have diverse effects on mechanisms underlying atherosclerosis, including a decrease in serum triacylglycerols and an increase in HDL(2) cholesterol. OBJECTIVE: The objective was to examine whether dietary fish enhances the effects of weight loss on serum lipids, glucose, and insulin in 69 overweight, treated hypertensive patients. DESIGN: Overweight patients being treated for hypertension were randomly assigned to either a daily fish meal (3.65 g n-3 fatty acids), a weight-loss regimen, the 2 regimens combined, or a control group for 16 wk. RESULTS: Sixty-three subjects completed the study. Weight decreased by a mean (+/-SEM) of 5.6 +/- 0.8 kg with energy restriction. Weight loss decreased fasting insulin (P = 0.003) and the area under the curve for insulin (P = 0.003) and glucose (P = 0.047) during an oral-glucose-tolerance test. The greatest decrease occurred in the fish + weight-loss group. There was no independent effect of fish on glucose or insulin. Fish increased HDL(2) cholesterol (P = 0.004) and decreased HDL(3) cholesterol (P = 0.026) without altering total, LDL, or HDL cholesterol. Weight loss had no effect on these variables. Fasting triacylglycerols fell significantly with fish consumption (29%) and weight loss (26%). The fish + weight-loss group showed the greatest improvement in lipids: triacylglycerols decreased by 38% (P < 0.001) and HDL(2) cholesterol increased by 24% (P = "0.04)" compared with the control group. CONCLUSIONS: Incorporating a daily fish meal into a weight-loss regimen was more effective than either measure alone at improving glucose-insulin metabolism and dyslipidemia. Cardiovascular risk is likely to be substantially reduced in overweight hypertensive patients with a weight-loss program incorporating fish meals rich in n-3 fatty acids

Glycemic index, cardiovascular disease, and obesity.

Morris KL, Zemel MB.

Nutr Rev. 1999 Sep; 57(9 Pt 1):273-6.

Although Americans have decreased the percent of energy they consume from fat, obesity and obesity-related comorbidities have progressively increased. Less attention has been paid to the role of carbohydrates, especially carbohydrate source, in these metabolic diseases. However, recent epidemiologic studies demonstrate consistently higher rates of cardiovascular disease and type II diabetes in individuals deriving a greater percentage of energy from refined grains and simple carbohydrates than from whole grains. Differences in the metabolic response to carbohydrates can be classified by glycemic index (GI), the blood glucose response to a given food compared with a standard (typically white bread or glucose). Classification of carbohydrates as "simple" or "complex" is of little use in predicting GI, because GI is influenced by starch structure (amylose versus amylopectin), fiber content, food processing, physical structure of the food, and other macronutrients in the meal. Low-GI diets have been reported to lower postprandial glucose and insulin responses, improve lipid profiles, and increase insulin sensitivity. Moreover, high-GI diets stimulate de novo lipogenesis and result in increased adipocyte size, whereas low-GI diets have been reported to inhibit these responses. Thus, the GI of dietary carbohydrates appears to play an important role in the metabolic fate of carbohydrates and, consequently, may significantly affect the risk of cardiovascular disease, diabetes, and obesity

Magnesium deficiency produces insulin resistance and increased thromboxane synthesis.

Nadler JL, Buchanan T, Natarajan R, et al.

Hypertension. 1993 Jun; 21(6 Pt 2):1024-9.

Evidence suggests that magnesium deficiency may play an important role in cardiovascular disease. In this study, we evaluated the effects of a magnesium infusion and dietary-induced isolated magnesium deficiency on the production of thromboxane and on angiotensin II-mediated aldosterone synthesis in normal human subjects. Because insulin resistance may be associated with altered blood pressure, we also measured insulin sensitivity using an intravenous glucose tolerance test with minimal model analysis in six subjects. The magnesium infusion reduced urinary thromboxane concentration and angiotensin II-induced plasma aldosterone levels. The low magnesium diet reduced both serum magnesium and intracellular free magnesium in red blood cells as determined by nuclear magnetic resonance (186 +/- 10 [SEM] to 127 +/- 9 mM, p < 0.01). Urinary thromboxane concentration measured by radioimmunoassay increased after magnesium deficiency. Similarly, angiotensin II-induced plasma aldosterone concentration increased after magnesium deficiency. Analysis showed that all subjects studied had a decrease in insulin sensitivity after magnesium deficiency (3.69 +/- 0.6 to 2.75 +/- 0.5 min-1 per microunit per milliliter x 10(-4), p < 0.03). We conclude that dietary-induced magnesium deficiency 1) increases thromboxane urinary concentration and 2) enhances angiotensin-induced aldosterone synthesis. These effects are associated with a decrease in insulin action, suggesting that magnesium deficiency may be a common factor associated with insulin resistance and vascular disease

Disorders of magnesium metabolism.

Nadler JL, Rude RK.

Endocrinol Metab Clin North Am. 1995 Sep; 24(3):623-41.

Magnesium depletion is more common than previously thought. It seems to be especially prevalent in patients with diabetes mellitus. It is usually caused by losses from the kidney or gastrointestinal tract. A patient with magnesium depletion may present with neuromuscular symptoms, hypokalemia, hypocalcemia, or cardiovascular complication. Physicians should maintain a high index of suspicion for magnesium depletion in patients at high risk and should implement therapy early

Health Implications of Obesity.

NIH.

1985;1985 Feb 11-13 5(9):1-7.

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.

NIH.

1998;1998 Jun

Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs.

Ostrowska E, Muralitharan M, Cross RF, et al.

J Nutr. 1999 Nov; 129(11):2037-42.

Conjugated linoleic acids (CLA) decrease the body fat content of rodents; the aim of this study was to determine whether dietary CLA altered carcass composition of pigs. Female Large White x Landrace pigs (n = 66) were used in this study. To obtain initial body composition, six pigs were slaughtered at 57 kg live weight, whereas the remaining pigs were allocated to one of six dietary treatments (0, 1.25, 2.5, 5.0, 7.5 and 10.0 g/kg CLA, containing 55% of CLA isomers). The diets, containing 14.3 MJ digestible energy (DE) and 9. 3 g available lysine per kg, were fed ad libitum for 8 wk. Dietary CLA had no significant effect on average daily gain (861 vs. 911 g/d for pigs fed diets with and without CLA, P = 0.15) or feed intake (2. 83 vs. 2.80 kg/d, P = 0.74). The gain to feed ratio was increased by dietary CLA by 6.3% (0.328 vs. 0.348, P = 0.009). Fat deposition decreased linearly (-8.2 +/- 2.09 g/d for each gram per kilogram increase in CLA concentration; P < 0.001) with increasing inclusion of CLA. At the highest level of CLA inclusion, fat deposition was decreased by 88 g/d (-31%). Similarly, the ratio of fat to lean tissue deposition decreased linearly (-0.093 +/- 0.0216 for each gram per kilogram increase in CLA concentration; P < 0.001) with increasing dietary CLA. The carcass lean tissue deposition response to dietary CLA was quadratic in nature and was maximized (+25%) at 5. 0 g/kg dietary CLA. Overall, dietary CLA increased the gain to feed ratio and lean tissue deposition and decreased fat deposition in finisher pigs

Effects of total energy withdrawal (fasting) on thelevels of growth hormone, thyrotropin, cortisol, adrenaline, noradrenaline, T4, T3, and rT3 in healthy males.

Palmblad J, Levi L, Burger A, et al.

Acta Med Scand. 1977 Jan; 201(1-2):15-22.

Ten days of total energy deprivation evoked the following endocrine changes in 12 healthy, normal-weight males: early and marked reductions and increments in the blood levels of T3 and reverse T3, respectively, with rapid returns to pre-starvation levels after refeeding; a slight and late decrease in the blood levels of T4; a minute reduction of the blood levels of TSH; a pronounced increase in the blood levels of growth hormone, but a return towards pre-exposure levels even before discontinuation of starving; a minor and gradual enhancement of the blood levels of cortisol, and an increase in nocturnal urinary adrenaline excretion. It is assumed that these changes reflect a complex regulatory mechanism, the purpose of which is to secure adequate energy supply to vital organs

Skeletal muscle membrane lipid composition is related to adiposity and insulin action.

Pan DA, Lillioja S, Milner MR, et al.

J Clin Invest. 1995 Dec; 96(6):2802-8.

The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= "-0.369," P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= "0.451," P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= "-0.610," P < 0.0001). Indices of elongase activity (r= "-0.467," P < 0.001), and delta9 desaturase activity (r= "0.332," P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."

Magnesium and glucose homeostasis.

Paolisso G, Scheen A, D'Onofrio F, et al.

Diabetologia. 1990 Sep; 33(9):511-4.

Magnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects

Effect of conjugated linoleic acid on body composition in mice.

Park Y, Albright KJ, Liu W, et al.

Lipids. 1997 Aug; 32(8):853-8.

The effects of conjugated linoleic acid (CLA) on body composition were investigated. ICR mice were fed a control diet containing 5.5% corn oil or a CLA-supplemented diet (5.0% corn oil plus 0.5% CLA). Mice fed CLA-supplemented diet exhibited 57% and 60% lower body fat and 5% and 14% increased lean body mass relative to controls (P < 0.05). Total carnitine palmitoyltransferase activity was increased by dietary CLA supplementation in both fat pad and skeletal muscle; the differences were significant for fat pad of fed mice and skeletal muscle of fasted mice. In cultured 3T3-L1 adipocytes CLA treatment (1 x 10(-4)M) significantly reduced heparin-releasable lipoprotein lipase activity (-66%) and the intracellular concentrations of triacylglyceride (-8%) and glycerol (-15%), but significantly increased free glycerol in the culture medium (+22%) compared to control (P < 0.05). The effects of CLA on body composition appear to be due in part to reduced fat deposition and increased lipolysis in adipocytes, possibly coupled with enhanced fatty acid oxidation in both muscle cells and adipocytes

Changes in body composition in mice during feeding and withdrawal of conjugated linoleic acid.

Park Y, Albright KJ, Storkson JM, et al.

Lipids. 1999 Mar; 34(3):243-8.

Two experiments were conducted. In Experiment 1, 8-wk-old mice were fed control diet or diet supplemented with 0.5% conjugated linoleic acid (CLA) to study the effect of CLA on body composition (CLA: 40.8-41.1% c-9,t-11 isomer, 43.5-44.9% t-10,c-12 isomer). The data for CLA-fed mice vs. controls described parallel but significantly distinct responses for both absolute and relative changes in body fat mass (reduced in CLA-fed mice) and for relative changes in whole body protein and whole body water (both of which were increased in CLA-fed mice). In the CLA-fed mice, the effect on whole body protein appeared to precede the reduction in body fat mass. In Experiment 2, weanling mice were fed control diet or diet supplemented with 0.5% CLA for 4 wk (test group), at which time all mice were fed control diet devoid of added CLA. The test group exhibited significantly reduced body fat and significantly enhanced whole body water relative to controls at the time of diet change. Time trends for changes in relative body composition were described by parallel lines where the test group exhibited significantly less body fat but significantly more whole body protein, whole body water, and whole body ash than controls. Tissue CLA levels declined following the withdrawal of CLA from the diet. In skeletal muscle of mice fed CLA-supplemented diet, the t-10,c-12 isomer was cleared significantly faster than the c-9,t-11 CLA isomer

Mannoheptulose and insulin inhibition.

Paulsen EP.

Ann N Y Acad Sci. 1968 Apr 11; 150(2):455-6.

In search of a lifestyle prescription to control body weight.

Pereira MA, Ebbeling CB, Pawlak DB, et al.

Am J Clin Nutr. 2002 Nov; 76(5):1140-1.

Glycemic index and disease.

Pi-Sunyer FX.

Am J Clin Nutr. 2002 Jul; 76(1):290S-8S.

It has been suggested that foods with a high glycemic index are detrimental to health and that healthy people should be told to avoid these foods. This paper takes the position that not enough valid scientific data are available to launch a public health campaign to disseminate such a recommendation. This paper explores the glycemic index and its validity and discusses the effect of postprandial glucose and insulin responses on food intake, obesity, type 1 diabetes, and cardiovascular disease. Presented herein are the reasons why it is premature to recommend that the general population avoid foods with a high glycemic index

Genetic versus environmental aetiology of the metabolic syndrome among male and female twins.

Poulsen P, Vaag A, Kyvik K, et al.

Diabetologia. 2001 May; 44(5):537-43.

AIMS/HYPOTHESIS: The aetiology of the metabolic syndrome including hyperinsulinaemia, glucose intolerance, dyslipidaemia, hypertension and obesity is not known. We studied the relative impact of genetic versus environmental factors for the development of the components in the syndrome among male and female twins. METHODS: A total of 303 elderly twin pairs participated in the study. We report concordances and heritability estimates of the components by classic twin analysis to assess the proportion of variation attributed to genetic factors. RESULTS: All components correlated significantly. The concordance rates for glucose intolerance, overall obesity and low HDL-cholesterol were significantly higher among monozygotic than dizygotic twins indicating a genetic influence on the development of these phenotypes. The heritability estimates for glucose concentration, BMI and HDL-cholesterol among monozygotic twins confirmed these findings. The heritability estimates for waist-to-hip ratio, fasting insulin and triglycerides, however, were low, indicating a major environmental influence. We found a higher genetic influence on glucose intolerance and systolic blood pressure and a lower genetic influence on low HDL-cholesterol and diastolic blood pressure among male twins compared to female twins. CONCLUSION/INTERPRETATION: Based on the correlations between the components in the syndrome, we propose a core complex including hyperinsulinaemia, obesity, hypertriglyceridaemia and low HDL-cholesterol with only weak associations to glucose concentrations and blood pressure levels. The study confirms the notion of a multifactorial aetiology of the components including genetic and non-genetic factors. The differences in aetiology between male and female twins indicate an influence of sex on several of the components in the metabolic syndrome

Aerobic exercise training improves insulin sensitivity independent of plasma tumor necrosis factor-alpha levels in older female hypertensives.

Reynolds TH, Brown MD, Supiano MA, et al.

Metabolism. 2002 Nov; 51(11):1402-6.

The purpose of the present study was to determine if the improvement in insulin sensitivity following aerobic exercise training (AEX) is associated with a decline in plasma tumor necrosis factor-alpha (TNF-alpha) levels. Fourteen older hypertensive females (age, 62 +/- 2 years) participated in a 6-month AEX program. Following AEX there was a significant increase in maximal aerobic capacity (VO(2)max) (P =.0001), and a significant decline in systolic (P =.01) and diastolic (P =.006) blood pressure. In addition, following AEX there was a significant decline in total body fat mass (P =.005), abdominal fat mass (P =.048), and percent body fat (P =.006). Insulin sensitivity, as assessed by the insulin-assisted frequently sampled intravenous glucose tolerance test (FSIVGTT), increased significantly following AEX (P =.007). Despite the increase in insulin sensitivity and the decline in body fat, plasma TNF-alpha levels were not altered by AEX (P =.223). No significant relationship existed among the changes in TNF-alpha levels and the changes insulin sensitivity or any measure of body composition following AEX. In conclusion, in this population of older hypertensive females, AEX improved insulin sensitivity and lowered blood pressure without a reduction in plasma TNF-alpha levels

Conjugated linoleic acid (CLA) reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial.

Riserus U, Berglund L, Vessby B.

Int J Obes Relat Metab Disord. 2001 Aug; 25(8):1129-35.

BACKGROUND: Abdominal obesity is strongly related to metabolic disorders. Recent research suggests that dietary conjugated linoleic acid (CLA) reduces body fat and may improve metabolic variables in animals. The metabolic effects of CLA in abdominally obese humans have not yet been tested. OBJECTIVE: To investigate the short-term effect of CLA on abdominal fat and cardiovascular risk factors in middle-aged men with metabolic disorders. METHODS: Twenty-five abdominally obese men (waist-to-hip ratio (WHR), 1.05+/-0.05; body mass index (BMI), 32+/-2.7 kg/m(2) (mean+/-s.d.)) who were between 39 and 64-y-old participated in a double-blind randomised controlled trial for 4 weeks. Fourteen men received 4.2 g CLA/day and 10 men received a placebo. The main endpoints were differences between the two groups in sagittal abdominal diameter (SAD), serum cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, free fatty acids, glucose and insulin. RESULTS: At baseline, there were no significant differences between groups in anthropometric or metabolic variables. After 4 weeks there was a significant decrease in SAD (cm) in the CLA group compared to placebo (P=0.04, 95% CI; -1.12, -0.02). Other measurements of anthropometry or metabolism showed no significant differences between the groups. CONCLUSIONS: These results indicate that CLA supplementation for 4 weeks in obese men with the metabolic syndrome may decrease abdominal fat, without concomitant effects on overall obesity or other cardiovascular risk factors. Because of the limited sample size, the effects of CLA in abdominal obesity need to be further investigated in larger trials with longer duration

Subclinical thyroid disease in the elderly.

Samuels MH.

Thyroid. 1998 Sep; 8(9):803-13.

The development of sensitive assays for thyrotropin (TSH) has led to the discovery that many older patients have abnormal TSH levels without other alterations in serum thyroid hormone levels, conditions termed subclinical hypothyroidism (isolated elevation of TSH levels) and subclinical hyperthyroidism (isolated suppression of TSH levels). Subclinical hypothyroidism occurs in 5% to 10% of elderly subjects, and is especially prevalent in elderly women. Subclinical hyperthyroidism is less common, affecting less than 2% of the elderly population. The causes of subclinical thyroid disease in the elderly are similar to those of thyroid disease in the general population, although medications and iodine-containing compounds may play an increased role. Potential risks of subclinical hypothyroidism in the elderly include progression to overt hypothyroidism, cardiovascular effects, hyperlipidemia, and neurological and neuropsychiatric effects. Potential risks of subclinical hyperthyroidism in the elderly include progression to overt hyperthyroidism, cardiovascular effects (especially atrial fibrillation), and osteoporosis. Decisions to treat elderly subjects with subclinical thyroid disease should be based on a careful assessment of these risks in the individual patient

Increased estrogen production in obese men.

Schneider G, Kirschner MA, Berkowitz R, et al.

J Clin Endocrinol Metab. 1979 Apr; 48(4):633-8.

Serum estrone (E1) and 17beta-estradiol (E2) were noted to be 2-fold elevated in a group of morbidly obese men. Urinary E1 and E2 production rates were elevated in proportion to the degree of obesity, with values as high as 127 and 157 micrograms/day, respectively. Although serum testosterone (T) concentrations were reduced in obese men, averaging 348 +/- 35 vs. 519 +/- 42 ng/dl in lean controls, the dialyzable T fractions were elevated and, hence, the calculated free T concentrations were normal in obese men. Further, the obese men exhibited normal serum LH, FSH, and T responses to clomiphene citrate, indicating intact hypothalamic-pituitary-Leydig cell axes. MCRs of T and peripheral conversion of T to E2 and androstenedione (delta) to E1 were all increased in obese men in proportion to the percentage above ideal weight. Although the obese mean exhibited increased blood levels and production rates of estrogens, there were no signs of feminization, increased T-estrogen-binding, globulin levels, or suppressed basal gonadotropin levels, suggesting a lack of biological effect. We postulate that obese men exhibit defective estrogen receptors, leading to decreased T-estrogen-binding globulin, increased clearance of androgenic hormones, and elevated estrogen production rates

Toxicological evaluation of dietary conjugated linoleic acid in male Fischer 344 rats.

Scimeca JA.

Food Chem Toxicol. 1998 May; 36(5):391-5.

To assess the toxicity of conjugated linoleic acid (CLA) after an extended feeding period, 40 male Fischer 344 rats were given either a basal diet (control) or the same diet supplemented with 1.5% CLA. During the 36-wk study, food disappearance, body weights, and cageside examinations were determined weekly and were found to be unaffected by CLA treatment. On termination, 15 major organs from 10 animals in each treatment group were excised, weighed, and prepared for histopathological evaluation. Results indicated no treatment-related effects. Likewise, haematological analysis of collected cardiac blood did not reveal any significant difference. The average daily intake of CLA by rats in this study was 80-fold and 50-fold greater than the estimated 50th and 90th percentile daily intakes, respectively, for teenage boys. Hence, results from this study indicate a lack of toxicity and support the potential determination for the GRAS status of CLA

Prevalence of attempting weight loss and strategies for controlling weight.

Serdula MK, Mokdad AH, Williamson DF, et al.

JAMA. 1999 Oct 13; 282(14):1353-8.

CONTEXT: Overweight and obesity are increasing in the United States. Changes in diet and physical activity are important for weight control. OBJECTIVES: To examine the prevalence of attempting to lose or to maintain weight and to describe weight control strategies among US adults. DESIGN: The Behavioral Risk Factor Surveillance System, a random-digit telephone survey conducted in 1996 by state health departments. Setting The 49 states (and the District of Columbia) that participated in the survey. PARTICIPANTS: Adults aged 18 years and older (N = 107 804). MAIN OUTCOME MEASURES: Reported current weights and goal weights, prevalence of weight loss or maintenance attempts, and strategies used to control weight (eating fewer calories, eating less fat, or using physical activity) by population subgroup. RESULTS: The prevalence of attempting to lose and maintain weight was 28.8% and 35.1 % among men and 43.6% and 34.4% among women, respectively. Among those attempting to lose weight, a common strategy was to consume less fat but not fewer calories (34.9% of men and 40.0% of women); only 21.5% of men and 19.4% of women reported using the recommended combination of eating fewer calories and engaging in at least 150 minutes of leisure-time physical activity per week. Among men trying to lose weight, the median weight was 90.4 kg with a goal weight of 81.4 kg. Among women, the median weight was 70.3 kg with a goal weight of 59.0 kg. CONCLUSIONS: Weight loss and weight maintenance are common concerns for US men and women. Most persons trying to lose weight are not using the recommended combination of reducing calorie intake and engaging in leisure-time physical activity 150 minutes or more per week

Calorie restriction and aging: a life-history analysis.

Shanley DP, Kirkwood TB.

Evolution Int J Org Evolution. 2000 Jun; 54(3):740-50.

The disposable soma theory suggests that aging occurs because natural selection favors a strategy in which fewer resources are invested in somatic maintenance than are necessary for indefinite survival. However, laboratory rodents on calorie-restricted diets have extended life spans and retarded aging. One hypothesis is that this is an adaptive response involving a shift of resources during short periods of famine away from reproduction and toward increased somatic maintenance. The potential benefit is that the animal gains an increased chance of survival with a reduced intrinsic rate of senescence, thereby permitting reproductive value to be preserved for when the famine is over. We describe a mathematical life-history model of dynamic resource allocation that tests this idea. Senescence is modeled as a change in state that depends on the resources allocated to maintenance. Individuals are assumed to allocate the available resources to maximize the total number of descendants. The model shows that the evolutionary hypothesis is plausible and identifies two factors, both likely to exist, that favor this conclusion. These factors are that survival of juveniles is reduced during periods of famine and that the organism needs to pay an energetic "overhead" before any litter of offspring can be produced. If neither of these conditions holds, there is no evolutionary advantage to be gained from switching extra resources to maintenance. The model provides a basis to evaluate whether the life-extending effects of calorie-restriction might apply in other species, including humans

The Testosterone Syndrome.

Shippen E.

2001;

Oxidative stress, caloric restriction, and aging.

Sohal RS, Weindruch R.

Science. 1996 Jul 5; 273(5271):59-63.

Under normal physiological conditions, the use of oxygen by cells of aerobic organisms generates potentially deleterious reactive oxygen metabolites. A chronic state of oxidative stress exists in cells because of an imbalance between prooxidants and antioxidants. The amount of oxidative damage increases as an organism ages and is postulated to be a major causal factor of senescence. Support for this hypothesis includes the following observations: (i) Overexpression of antioxidative enzymes retards the age-related accrual of oxidative damage and extends the maximum life-span of transgenic Drosophila melanogaster. (ii) Variations in longevity among different species inversely correlate with the rates of mitochondrial generation of the superoxide anion radical (O2) and hydrogen peroxide. (iii) Restriction of caloric intake lowers steady-state levels of oxidative stress and damage, retards age-associated changes, and extends the maximum life-span in mammals

Obesity and mortality: a review of the epidemiologic data.

Solomon CG, Manson JE.

Am J Clin Nutr. 1997 Oct; 66(4 Suppl):1044S-50S.

At least one-third of Americans are obese, as defined by body mass indexes corresponding to body weight > or = 120% of ideal body weight, and this figure is rising steadily. Women and nonwhites have particularly high rates of obesity. Obesity greatly increases risks for many serious and morbid conditions, including diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, and some cancers. Obesity is clearly associated with increased risk for mortality, but there has been controversy regarding optimal weight with respect to mortality risk. We review the literature concerning obesity and mortality, with reference to body fat distribution and weight gain, and consider potential effects of sex, age, and race on this relation. We conclude that when appropriate adjustments are made for effects of smoking and underlying disease, optimal weights are below average in both men and women; this appears to be true throughout the adult life span. Central obesity, most commonly approximated by the waist-to-hip ratio, may be particularly detrimental, although this requires further study. Weight gain in adulthood is also associated with increased mortality. These observations support public health measures to reduce obesity and weight gain, including recent recommendations to limit weight gain in the adult years to 4.5 kg (10 lb)

The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing.

Sonntag WE, Lynch C, Thornton P, et al.

J Anat. 2000 Nov; 197 Pt 4:575-85.

Research studies clearly indicate that age-related changes in cellular and tissue function are linked to decreases in the anabolic hormones, growth hormone and insulin-like growth factor (IGF)-1. Although there has been extensive research on the effects of these hormones on bone and muscle mass, their effect on cerebrovascular and brain ageing has received little attention. We have also observed that in response to moderate calorie restriction (a treatment that increases mean and maximal lifespan by 30-40%), age-related decreases in growth hormone secretion are ameliorated (despite a decline in plasma levels of IGF-1) suggesting that some of the effects of calorie restriction are mediated by modifying the regulation of the growth hormone/IGF-1 axis. Recently, we have observed that microvascular density on the surface of the brain decreases with age and that these vascular changes are ameliorated by moderate calorie restriction. Analysis of cerebral blood flow paralleled the changes in vasculature in both groups. Administration of growth hormone for 28 d was also found to increase microvascular density in aged animals and further analysis indicated that the cerebral vasculature is an important paracrine source of IGF-1 for the brain. In subsequent studies, administration of GHRH (to increase endogenous release of growth hormone) or direct administration of IGF-I was shown to reverse the age-related decline in spatial working and reference memory. Similarly, antagonism of IGF-1 action in the brains of young animals impaired both learning and reference memory. Investigation of the mechanisms of action of IGF-1 suggested that this hormone regulates age-related alterations in NMDA receptor subtypes (e.g. NMDAR2A and R2B). The beneficial role of growth hormone and IGF-1 in ameliorating vascular and brain ageing are counterbalanced by their well-recognised roles in age-related pathogenesis. Although research in this area is still evolving, our results suggest that decreases in growth hormone and IGF-1 with age have both beneficial and deleterious effects. Furthermore, part of the actions of moderate calorie restriction on tissue function and lifespan may be mediated through alterations in the growth hormone/IGF-1 axis

Effect of caloric restriction and dietary composition of serum T3 and reverse T3 in man.

Spaulding SW, Chopra IJ, Sherwin RS, et al.

J Clin Endocrinol Metab. 1976 Jan; 42(1):197-200.

To evaluate the effect of caloric restriction and dietary composition on circulating T3 and rT3 obese subjects were studied after 7-18 days of total fasting and while on randomized hypocaloric diets (800 kcal) in which carbohydrate content was varied to provide from 0 to 100% calories. As anticipated, total fasting resulted in a 53% reduction in serum T3 in association with reciprocal 58% increase in rT3. Subjects receiving the no-carbohydrate hypocaloric diets for two weeks demonstrated a similar 47% decline in serum T3 but there was no significant change in rT3 with time. In contrast, the same subjects receiving isocaloric diets containing at least 50 g of carbohydrate showed no significant changes in either T3 or rT3 concentration. The decline in serum T3 during the no-carbohydrate diet correlated significantly with blood glucose and ketones but there was no correlation with insulin or glucagon. We conclude that dietary carbohydrate is an important regulatory factor in T3 production in man. In contrast, rT3 concentration is not significantly affected by changes in dietary carbohydrate. Our data suggest that the rise in serum rT3 during starvation may be related to more severe caloric restriction than that caused by the 800 kcal diet

Impact of age on associations between weight and mortality.

Stevens J.

Nutr Rev. 2000 May; 58(5):129-37.

The effect of age on the weight associated with the lowest mortality and the effect of age on the mortality risk associated with obesity are issues fraught with methodologic complexities. Current evidence supports the notion that the body mass index associated with the lowest mortality falls within the range of 18.5 to 24.9 in men and women between the ages of 30 and 74. The impact of age on the mortality risk associated with obesity changes with age, however, and the direction of the trend depends upon the measure used

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats.

Storlien LH, James DE, Burleigh KM, et al.

Am J Physiol. 1986 Nov; 251(5 Pt 1):E576-E583.

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil prevents insulin resistance induced by high-fat feeding in rats.

Storlien LH, Kraegen EW, Chisholm DJ, et al.

Science. 1987 Aug 21; 237(4817):885-8.

Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an omega-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic omega-6 fatty acids from safflower oil with long-chain polyunsaturated omega-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus

Dietary fats and insulin action.

Storlien LH, Baur LA, Kriketos AD, et al.

Diabetologia. 1996 Jun; 39(6):621-31.

The night-eating syndrome; a pattern of food intake among certain obese patients.

Stunkard AJ, GRACE WJ, WOLFF HG.

Am J Med. 1955 Jul; 19(1):78-86.

Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and pregnenolone sulfate concentrations in patients with hyperthyroidism and hypothyroidism.

Tagawa N, Tamanaka J, Fujinami A, et al.

Clin Chem. 2000 Apr; 46(4):523-8.

BACKGROUND: Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to have protective effects against cardiovascular disease, cancer, immune-modulated diseases, and aging. We examined serum concentrations of DHEA, DHEA-S, and pregnenolone sulfate (PREG-S) in patients with thyroid dysfunction. METHODS: Steroids extracted with methanol from serum sample were separated into an unconjugated fraction (DHEA) and a monosulfate fraction (DHEA-S and PREG-S), using a solid-phase extraction and an ion-exchange column. After separation of unconjugated steroids by HPLC, the DHEA concentration was measured by enzyme immunoassay. The monosulfate fraction was treated with arylsulfatase, and the freed steroids were separated by HPLC. The DHEA and PREG fractions were determined by gas chromatography-mass spectrometry, and the concentrations were converted into those of DHEA-S and PREG-S. RESULTS: Serum concentrations of DHEA, DHEA-S, and PREG-S were all significantly lower in patients with hypothyroidism (n = 24) than in age- and sex-matched healthy controls (n = 43). By contrast, in patients with hyperthyroidism (n = 22), serum DHEA-S and PREG-S concentrations were significantly higher, but the serum DHEA concentration was within the reference interval. Serum concentrations of these three steroids correlated with serum concentrations of thyroid hormones in these patients. Serum albumin and sex hormone-binding globulin concentrations were not related to these changes in the concentration of steroids. CONCLUSIONS: Serum concentrations of DHEA, DHEA-S, and PREG-S were decreased in hypothyroidism, whereas serum DHEA-S and PREG-S concentrations were increased but DHEA was normal in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these steroids, and DHEA sulfotransferase might be increased in hyperthyroidism

Serum concentration of androstenediol and androstenediol sulfate in patients with hyperthyroidism and hypothyroidism.

Tagawa N, Takano T, Fukata S, et al.

Endocr J. 2001 Jun; 48(3):345-54.

Androstenediol (5-androsten-3beta, 17beta-diol, ADIOL) and androstenediol 3-sulfate (ADIOLS) are active metabolites of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), respectively, and have estrogenic activity and immunoregulatory function. We examined serum concentrations of ADIOL, ADIOLS, DHEA, DHEAS and pregnenolone sulfate (5-pregnen-3beta-ol-20-one sulfate, PREGS) in patients with Graves' thyrotoxicosis (male/female 9/14), hypothyroidism (11/20) and in normal controls (14/29). In hypothyroidism serum levels of all these steroids were significantly decreased in both genders. In hyperthyroidism, in contrast, serum levels of ADIOLS (male 1.49 +/- 0.69, female 0.64 +/- 0.31 micromol/l), DHEAS (male 7.43 +/- 3.91, female 5.13 +/- 2.03 micromol/l), and PREGS (male 1.13 +/- 0.58, female 1.07 +/- 0.85 micromol/l) were markedly increased, but serum concentrations of ADIOL and DEHA were not significantly different from controls (ADIOLS male 0.36 +/- 0.33, female 0.14 +/- 0.09 micromol/l; DHEAS male 2.88 +/- 1.70, female 1.86 +/- l1.03pmol/l; PREGS male 0.18 +/- 0.12, female 0.11 +/- 0.08 micromol/l; ADIOL male 3.76 +/- 1.35, female 1.91 +/- 1.17 nmol/l; DHEA male 9.23 +/- 3.49, female 13.5 +/- 10.8nmol/l). Serum concentrations of all these steroids correlated with the serum concentration of the thyroid hormones in these patients. Serum albumin and sex hormone-binding globulin concentrations were not related to these changes in the concentrations of steroids. These findings indicate that serum concentrations of ADIOLS, ADIOL, DHEAS, DHEA and PREGS were decreased in hypothyroidism, whereas serum ADIOLS, DHEAS and PREGS concentrations were increased but ADIOL and DHEA were normal in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these steroids and sulfotransferase is speculated to be increased in hyperthyroidism. Increased ADIOLS might contribute to menstrual disturbances and gynecomastia in hyperthyroidism

Impact of binge eating on metabolic and leptin dynamics in normal young women.

Taylor AE, Hubbard J, Anderson EJ.

J Clin Endocrinol Metab. 1999 Feb; 84(2):428-34.

Well defined eating disorders such as anorexia nervosa and bulimia are associated with significant known health risks. Although binge eating behavior is increased in unsuccessfully dieting obese women, other health implications of this common eating pattern are unknown. We hypothesized that ingestion of an entire day's calories at one time in the evening, a common eating practice among Americans, would lead to disruptions in glucose, insulin, and leptin metabolism and in menstrual cyclicity, even in healthy young women. Seven lean women without a history of eating disorders were studied on two occasions separated by one or two menstrual cycles. During one admission, they ate three regular meals plus a snack on each of 3 days. On the other admission, they ate the same number of calories, macronutrient matched to the normal diet, in a single evening meal. Glucose, insulin, and leptin were measured frequently for 12-14 h beginning at 0800 h on the third day of each diet, and an insulin tolerance test was performed while the subjects were fasting on the fourth day. Daily blood samples were obtained until ovulation was documented to assess any impact on menstrual function. Ingestion of an entire day's calories at dinner resulted in a significant increase in fasting glucose levels and a dramatic increase in insulin responses to the evening meal. The diurnal pattern of leptin secretion was altered, such that the gradual rise in leptin from 0800 h observed during the normal diet was abolished, and leptin did not begin to rise during the binge diet until at least 2 h after the evening meal. No changes were demonstrated in insulin sensitivity, follicular growth, or ovulation between the two diets. We conclude that 1) ingestion of a large number of calories at one time (binge eating) impacts metabolic parameters even when total calories and macronutrients are appropriate for weight; 2) the timing of energy intake is an independent determinant of the diurnal rhythm of leptin secretion, indicating a relatively acute affect of energy balance on leptin dynamics; 3) the mechanism of exaggerated insulin secretion after a binge meal remains to be determined, but may be related to the altered diurnal pattern of leptin secretion; and 4) as most binge eating episodes in the population are associated with the ingestion of excess calories, it is hypothesized that binge eating behavior is associated with even greater metabolic dysfunction than that described herein

Effects of testosterone supplementation in the aging male.

Tenover JS.

J Clin Endocrinol Metab. 1992 Oct; 75(4):1092-8.

Serum androgen levels decline with aging in normal males, such that a significant number of men over 60 yr of age will have a mean serum total testosterone (T) level near the low end of the normal adult range. It is not known whether lower T levels in older men have an effect on androgen-responsive organ systems, such as muscle, bone, bone marrow, and prostate, nor are there data to evaluate the relative benefits and risks of T supplementation in older men. We assessed the physiological and biochemical effects of T therapy in 13 healthy men, 57-76 yr old, who had low or borderline low serum T levels (< or = "13.9" nmol/L). Intramuscular testosterone enanthate (TE; 100 mg weekly) and placebo injections were given for 3 months each. Before treatment and at the end of both 3-month treatment regimens, lean body mass, body fat, biochemical parameters of bone turnover, hematological parameters, lipoprotein profiles, and prostate parameters [such as prostate-specific antigen (PSA)] were evaluated. Serum T levels rose in all subjects with TE treatment, such that the lowest level of T during a week's period was 19.7 +/- 0.7 nmol/L (mean +/- SE). After 3 months of TE treatment, lean body mass was significantly increased, and urinary hydroxyproline excretion was significantly depressed. With TE treatment, there was a significant increase in hematocrit, a decline in total cholesterol and low density lipoprotein cholesterol, and a sustained increase in serum PSA levels. Placebo treatment led to no significant changes in any of these parameters. We conclude that short term (3 months) TE supplementation to healthy older men who have serum T levels near or below the lower limit of normal for young adult men results in an increase in lean body mass and possibly a decline in bone resorption, as assessed by urinary hydroxyproline excretion, with some effect on serum lipoproteins, hematological parameters, and PSA. The sustained stimulation of PSA and the increase in hematocrit that occur with physiological TE supplementation suggest that older men should be screened carefully and followed periodically throughout T therapy

The decrease in body fat in mice fed conjugated linoleic acid is due to increases in energy expenditure and energy loss in the excreta.

Terpstra AH, Beynen AC, Everts H, et al.

J Nutr. 2002 May; 132(5):940-5.

We carried out energy balance studies in four groups of young, growing, 5-wk-old Balb-C mice (n = 12/group) that were either food restricted or nonrestricted and fed high fat diets (38 energy%) with or without 0.93 g/100 g conjugated linoleic acid (CLA) for 39 d. The energy in carcasses, excreta and food was measured in a bomb calorimeter. CLA lowered the percentage of the energy intake that was stored in the body from 1.9 +/- 0.8 to -2.3 +/- 0.7% (mean +/- SD, P < 0.05) in the nonrestricted mice and from 1.4 +/- 1.3 to -2.9 +/- 0.7% (P < 0.05) in the restricted mice. Thus, the CLA-treated mice had a net loss of body energy. The percentage of the energy intake eliminated in the excreta increased from 7.6 +/- 0.9% in controls to 8.7 +/- 1.0% (P < 0.05) in the CLA-treated mice that were nonrestricted and from 7.3 +/- 0.8 to 8.4 +/- 0.6 (P < 0.05) in the restricted mice. The amount of energy ingested minus the amount retained in carcasses and excreta equals the energy expenditure. The percentage of the energy intake that was expended as heat increased from 90.5 +/- 1.2 in controls to 93.6 +/- 1.5% (P < 0.05) in the CLA-treated nonrestricted mice and from 91.3 +/- 1.5 to 94.5 +/- 1.0% (P < 0.05) in the restricted mice. The lower energy storage in the CLA-fed mice was accounted for by an increase in the energy expenditure (74%) and by an increase in energy lost in the excreta (26%). Feeding CLA also increased liver weight, which may warrant further studies on the safety of CLA

Clinical Guide to Laboratory Tests.

Tietz NW.

1995; Third Edition

[A randomized comparison of two weight-reducing diets. Calorie counting versus low-fat carbohydrate-rich ad libitum diet].

Toubro S, Astrup AV.

Ugeskr Laeger. 1998 Feb 2; 160(6):816-20.

We compared the importance of rate of initial weight loss for long term outcome in obese patients and the efficacy of two different dietary weight maintenance programmes. An initial weight loss of 12.6 kg was achieved either by eight weeks low energy diet (2 MJ/day) (n = 21) or 17 weeks conventional hypocaloric, high protein diet (5 MJ/day) (n = 22) both supported by an anorectic compound (ephedrine 20 mg and caffeine 200 mg thrice daily). Weight loss rate had no effect on long-term weight maintenance. Randomisation to one year weight maintenance of either an ad lib, low fat, high carbohydrate diet or a fixed energy diet ( 5 kg

Effect of starvation on the production and metabolism of thyroxine and triiodothyronine in euthyroid obese patients.

Vagenakis AG, Portnay GI, O'Brian JT, et al.

J Clin Endocrinol Metab. 1977 Dec; 45(6):1305-9.

The metabolic clearance and production rates of thyroxine (T4) and triiodothyronine (T3) were measured in 9 obese euthyroid patients prior to and during prolonged starvation. The metabolic clearance rates (MCR) and serum concentrations of T4, and, therefore, the metabolic degradation or production rates of T4 were undecreased strikingly during starvation, from 145 +/- 7 ng/dl (mean +/- SE) to 66 +/- 9 ng/dl (P less than 0.001), while the mean MCR of T3 was unchanged, with the result that T3 degradation or production rates were markedly decreased (36.4 +/- 4.5 microgram/d vs. 11.2 +/- 0.7 microgram/d; P less than 0.001). These findings suggest that the decrease in serum T3 concentration observed during starvation results from a decrease in the peripheral conversion of T4 to 53

The anti-ageing action of dietary restriction.

Van Remmen H, Guo Z, Richardson A.

Novartis Found Symp. 2001; 235:221-30.

Over 60 years ago, McCay's laboratory showed that dietary or calorie-restriction dramatically increased the lifespan of rats. Since then, numerous laboratories with a variety of strains of rats and mice have confirmed this initial observation and have shown that reducing calorie intake (without malnutrition) significantly increases both the mean and maximum survival of rodents. Currently, dietary restriction is the only experimental manipulation that has been shown to retard ageing of mammals. Although mechanism whereby dietary restriction retards ageing is currently unknown, much of the emerging data suggest that the calorie-restricted rodents live longer and age more slowly because they are more resistant to stress and have an enhanced ability to protect cells against damaging agents

Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men.

Vessby B, Tengblad S, Lithell H.

Diabetologia. 1994 Oct; 37(10):1044-50.

Recent data indicate that peripheral insulin sensitivity may be influenced by dietary fat quality and skeletal muscle phospholipid fatty acid composition. During a health survey of 70-year-old men insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique and the fatty acid composition of the serum cholesterol esters was determined (n = 215) by gas liquid chromatography. In a subsample the fatty acids of the skeletal muscle phospholipids and triglycerides were determined after fine needle biopsy from m. vastus lateralis (n = 39). The peripheral insulin sensitivity was significantly and negatively correlated to the proportion of palmitic (r = -0.31, p < 0.001), palmitoleic (r = "-0.25," p < 0.001) and di-homo-gamma-linolenic (r = "-0.33," p < 0.001) acids and positively to the content of linoleic (r = "0.28," p < 0.001) acid in the serum cholesterol esters. There was an even stronger negative relationship to the proportion of palmitic acid in the skeletal muscle phospholipds (r = "-0.45," p < 0.004). The fatty acid composition was also significantly related to insulin sensitivity in a stepwise multiple regression analysis in the presence of other clinical variables, which were associated with insulin action in univariate analysis. Thus, more than 51% of the variation of the insulin sensitivity was explained by an equation containing body mass index, serum triglyceride concentration and the content of palmitic acid in the skeletal muscle phospholipids. It is concluded that the fatty acid composition in serum and of the phospholipids of skeletal muscle may influence insulin action in elderly men

Effect of ingested mannoheptulose in animals and man.

Viktora JK, Johnson BF, Penhos JC, et al.

Metabolism. 1969 Feb; 18(2):87-102.

Effects of a very low calorie diet on weight, thyroid hormones and mood.

Wadden TA, Mason G, Foster GD, et al.

Int J Obes. 1990 Mar; 14(3):249-58.

Changes in weight, thyroid hormones and mood were examined in 15 obese (113 kg) women over an 18-week period. After 4 weeks of a 1200 kcal/day diet, patients were randomly assigned to one of two dietary conditions: very low calorie diet (VLCD) (n = 8) or balanced deficit diet (BDD) (n = 7). VLCD patients consumed 400 kcal/day for 8 weeks and then gradually returned to a 1200 kcal/day diet. BDD patients consumed 1200 kcal/day for the entire 18 weeks. Differences in weight losses between the conditions were statistically significant only during the consumption of the VLCD. Serum T3 decreased by as much as 66 percent in VLCD patients during consumption of the 400 kcal/day diet, whereas rT3 increased by as much as 27 percent. T3 increased when patients were realimented with a 1000 kcal/day balanced diet but remained a significant 22 percent below baseline at the end of the study. BDD patients also showed marked reductions in T3, as great as 40 percent, so that the differences between the two conditions were not statistically significant. Multiple regression analyses, collapsing across conditions (n = 15), indicated that weight loss at week 12 and baseline T3 accounted for 63 percent of the variance in the change in T3 at week 12. Patients in both conditions showed improvements in mood. Changes in depression were not associated with changes in serum T3

Physiologic changes in humans subjected to severe, selective calorie restriction for two years in biosphere 2: health, aging, and toxicological perspectives.

Walford RL, Mock D, MacCallum T, et al.

Toxicol Sci. 1999 Dec; 52(2 Suppl):61-5.

Biosphere 2 is a closed ecological space of 7-million cubic feet near Tucson, AZ, containing 7 biomes: rain forest, Savannah, ocean, marsh, desert, agricultural station, and habitat for humans and domestic animals. Sealed inside, 4 men and 4 women maintained themselves and the various systems for 2 years. All organic material, all water, and nearly all air was recycled, and virtually all food was grown inside. On the low calorie but nutrient-dense diet available, the men sustained 18% and the women 10% weight loss, mostly within the first 6 to 9 months. The nature of the diet duplicated rodent diets that had been shown to enhance health, lower disease incidence, and retard aging. Using blood specimens frozen at different points during and after the 2 years, determinations were made of a number of biochemical parameters judged to be pertinent based on past studies of rodents and monkeys on similar diets. These included blood lipids, glucose, insulin, glycosylated hemoglobin, renin, and others. The results clearly suggest that humans react to such a nutritional regime similarly to other vertebrates. In addition to these studies, and because this was a tightly closed, isolated environment, the levels of insecticides or pollutants or their derivatives were determined in the sera of 2 crew members. It was found that levels of the lipophilic toxicant DDE and the "total PCB" load increased with the loss of body fat during the first 12-18 months inside Biosphere 2, then decreased

Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice.

Weindruch R, Kayo T, Lee CK, et al.

J Nutr. 2001 Mar; 131(3):918S-23S.

An active research area in biological gerontology concerns the mechanisms by which caloric restriction (CR) retards the aging process in laboratory rodents. We used high density oligonucleotide arrays representing 6347 genes to determine the gene expression profile of the aging process in gastrocnemius muscle of male C57BL/6 mice. Aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were completely or partially prevented by CR. Transcriptional patterns of muscle from calorie-restricted animals suggest that CR retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage. The use of high density oligonucleotide microarrays provides a new tool to measure biological age on a tissue-specific basis and to evaluate at the molecular level the efficacy of nutritional interventions designed to retard the aging process

Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse.

West DB, Delany JP, Camet PM, et al.

Am J Physiol. 1998 Sep; 275(3 Pt 2):R667-R672.

Conjugated linoleic acid (CLA) is a naturally occurring group of dienoic derivatives of linoleic acid found in the fat of beef and other ruminants. CLA is reported to have effects on both tumor development and body fat in animal models. To further characterize the metabolic effects of CLA, male AKR/J mice were fed a high-fat (45 kcal%) or low-fat (15 kcal%) diet with or without CLA (2.46 mg/kcal; 1.2 and 1.0% by weight in high- and low-fat diets, respectively) for 6 wk. CLA significantly reduced energy intake, growth rate, adipose depot weight, and carcass lipid and protein content independent of diet composition. Overall, the reduction of adipose depot weight ranged from 43 to 88%, with the retroperitoneal depot most sensitive to CLA. CLA significantly increased metabolic rate and decreased the nighttime respiratory quotient. These findings demonstrate that CLA reduces body fat by several mechanisms, including a reduced energy intake, increased metabolic rate, and a shift in the nocturnal fuel mix

Resting metabolic rate and diet-induced thermogenesis: a methodological reappraisal.

Weststrate JA.

Am J Clin Nutr. 1993 Nov; 58(5):592-601.

The variability in resting metabolic rate (RMR), diet-induced thermogenesis (DIT), and fuel utilization rates as well as the impact of several factors on RMR and DIT were assessed in several studies with a total of 103 males and females. The intraindividual CV of RMR and respiratory quotients was 5-6%. The intraindividual variability in DIT and fuel utilization rates was substantially higher. RMR did not change from morning to afternoon. The menstrual cycle phase did not affect RMR and DIT. DIT after mixed meals of 1.3-2.6 MJ could be assessed with good accuracy in 3 h. It is concluded that the low reproducibility of DIT implies that sample sizes of < 10 individuals with one measurement per subject and per treatment have power levels < 80% of assessing true, relatively large (50%) treatment effects or between-group differences in DIT

A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia.

Weyer C, Hanson RL, Tataranni PA, et al.

Diabetes. 2000 Dec; 49(12):2094-101.

Fasting hyperinsulinemia is a widely used surrogate measure of insulin resistance and predicts type 2 diabetes in various populations. Whether fasting hyperinsulinemia predicts diabetes independent of insulin resistance is unknown. In 319 Pima Indians with normal glucose tolerance, fasting plasma insulin concentration and insulin-stimulated glucose disposal (M) (hyperinsulinemic clamp) were inversely related, but at any given M, there was substantial variation, with some subjects being hyperinsulinemic and others being hypoinsulinemic relative to their degree of insulin sensitivity. In 262 of the 319 subjects followed prospectively over 6.4 +/- 3.9 years, a high fasting plasma insulin concentration was a significant independent predictor of diabetes, in addition to low M and low acute insulin response (AIR) (intravenous glucose challenge). In 161 of the 319 subjects with follow-up measurements of M and AIR (5.1 +/- 3.9 years), a high relative fasting plasma insulin concentration predicted a decline in AIR but not in M before the onset of diabetes. The adjusted fasting plasma insulin concentration was a familial trait (heritability of 0.52) and in a genome-wide scan, there was suggestive evidence of linkage (logarithm of odds score 1.77) to a region on chromosome 3q, which harbors the gene encoding GLUT2. These results provide the first prospective evidence in humans that fasting hyperinsulinemia itself has a primary role in the pathogenesis of diabetes, independent of insulin resistance. Whether amelioration of basal insulin hypersecretion will prevent diabetes remains to be elucidated

Obesity: Preventing and Managing the Global Epidemic. WHO Consultation on Obesity.

WHO.

1998;June 3-5, 1997

Triiodothyronine, T.S.H., and prolactin in obese women.

Wilcox RG.

Lancet. 1977 May 14; 1(8020):1027-9.

Basal levels of thyroid-stimulating hormone and prolactin and their response to thyrotrophin-releasing hormone are normal in obese women. Serum thyroxine and triiodothyronine are also normal and do not correlate with body-weight in healthy non-dieting women. After jejunoileal bypass, serum-triio-dothyronine levels fall, and this fall appears to depend more on the reduction in calorie intake after the operation than on the reduction in body-weight per se

Current estimates of the economic cost of obesity in the United States.

Wolf AM, Colditz GA.

Obes Res. 1998 Mar; 6(2):97-106.

This study was undertaken to update and revise the estimate of the economic impact of obesity in the United States. A prevalence-based approach to the cost of illness was used to estimate the economic costs in 1995 dollars attributable to obesity for type 2 diabetes mellitus, coronary heart disease (CHD), hypertension, gallbladder disease, breast, endometrial and colon cancer, and osteoarthritis. Additionally and independently, excess physician visits, work-lost days, restricted activity, and bed-days attributable to obesity were analyzed cross-sectionally using the 1988 and 1994 National Health Interview Survey (NHIS). Direct (personal health care, hospital care, physician services, allied health services, and medications) and indirect costs (lost output as a result of a reduction or cessation of productivity due to morbidity or mortality) are from published reports and inflated to 1995 dollars using the medical component of the consumer price index (CPI) for direct cost and the all-items CPI for indirect cost. Population-attributable risk percents (PAR%) are estimated from large prospective studies. Excess work-lost days, restricted activity, bed-days, and physician visits are estimated from 88,262 U.S. citizens who participated in the 1988 NHIS and 80,261 who participated in the 1994 NHIS. Sample weights have been incorporated into the NHIS analyses, making these data generalizable to the U.S. population. The total cost attributable to obesity amounted to $99.2 billion dollars in 1995. Approximately $51.64 billion of those dollars were direct medical costs. Using the 1994 NHIS data, cost of lost productivity attributed to obesity (BMI> or =30) was $3.9 billion and reflected 39.2 million days of lost work. In addition, 239 million restricted-activity days, 89.5 million bed-days, and 62.6 million physician visits were attributable to obesity in 1994. Compared with 1988 NHIS data, in 1994 the number of restricted-activity days (36%), bed-days (28%), and work-lost days (50%) increased substantially. The number of physician visits attributed to obesity increased 88% from 1988 to 1994. The economic and personal health costs of overweight and obesity are enormous and compromise the health of the United States. The direct costs associated with obesity represent 5.7% of our National Health Expenditure in the United States

Energy balance in rats given chronic hormone treatment. 1. Effects of long-acting insulin.

Woodward CJ, Emery PW.

Br J Nutr. 1989 May; 61(3):437-44.

1. Sprague-Dawley rats were injected for 16 d with long-acting insulin, and energy balance was calculated using the comparative carcass technique. Two experiments were carried out with females (starting weights 150 and 90 g respectively), and one with males (starting weight 150 g). In a fourth experiment, cytochrome c oxidase (EC 1.9.3.1) activity was measured as an indicator of the capacity for substrate oxidation. 2. Insulin increased weight gain by up to 57% (P less than 0.01 for all studies). Metabolizable energy intake (kJ/d) was also consistently higher in the treated groups, by up to 34% (P less than 0.01 for all studies). The excess weight gained by the insulin-treated rats was predominantly due to fat deposition. 3. Energy expenditure, calculated as the difference between metabolizable intake and carcass energy gain, was expressed on a whole-body basis, or relative to either metabolic body size (kg body-weight0.75) or fat-free mass. Insulin consistently raised energy expenditure, regardless of the method of expression, but this change reached statistical significance in only two of the nine comparisons. 4. Cytochrome c oxidase activity was not affected by insulin treatment in either interscapular brown adipose tissue or gastrocnemius muscle. In liver, total enzyme activity (U/tissue) was increased from 2928 (SE 162) in the controls to 3940 (SE 294) in the treated group (P less than 0.02), but specific activity (U/mg protein) was unchanged. 5. It is concluded that, despite causing substantial hyperphagia, insulin treatment only slightly increases energy expenditure in rats. The costs of increased tissue deposition may account for this change

The role of viscous soluble fiber in the metabolic control of diabetes. A review with special emphasis on cereals rich in beta-glucan.

Wursch P, Pi-Sunyer FX.

Diabetes Care. 1997 Nov; 20(11):1774-80.

Recent recommendations for the dietary management of diabetes mellitus state that diet needs to be individualized so that there is improved glucose and lipid control in the patient. In a majority of individuals with diabetes, this is best done with a diet that is low in fat and high in carbohydrate, particularly that of cereal origin. However, symptoms of hyper- and hypoglycemia must be averted. Most cereal products, however, tend to have a high glycemic index Cereals such as Prowashonupana barley or fractions of oat bran are particularly high in the soluble fiber beta-glucan, which when taken with a meal increases the viscosity of the meal bolus once it has reached the small intestine, where the absorption of nutrients occurs. This high viscosity delays absorption. A 50% reduction in glycemic peak can be achieved with a concentration of 10% beta-glucan in a cereal food. A significant lowering of plasma LDL cholesterol concentrations can also be anticipated with the daily consumption of > or = 3 g of beta-glucan. Diabetic individuals can benefit from diets that are high in beta-glucan, which, as a component of oats and barley, can be incorporated into breakfast cereals and other products

Comparison of weight in middle age, weight at 18 years, and weight change between, in predicting subsequent 14 year mortality and coronary events: Caerphilly Prospective Study.

Yarnell JW, Patterson CC, Thomas HF, et al.

J Epidemiol Community Health. 2000 May; 54(5):344-8.

OBJECTIVE: The prevalence of obesity is increasing in many European countries and in the United States. This report examines the mortality and morbidity associated with being overweight and obese in the Caerphilly Prospective Study and the relative effects of weight in middle age and self reported weight at 18 years. DESIGN: All men aged 45 to 59 years from the town of Caerphilly, South Wales and outlying villages were identified and 2512 men were examined for the first time between 1979 and 1983. Men were asked to recall their weight at 18 years of age (when the majority had been examined for National Service) so that weight then, weight at screening, and the difference could be related to their 14 year follow up from screening. A total of 2335 men could recall their weight at 18 years. By 14 years of follow up from screening 465 men had died and 382 had had coronary events. RESULTS: Mean body mass index in men who reported their weight at 18 years was 22.3 (SD 2.8) kg/m(2) and only 41 of these men (1.8%) were classified as obese (index >/= 30 kg/m(2)). The index did not predict all cause mortality when examined by quintile. For major ischaemic heart disease (non-fatal or fatal ischaemic heart disease) the relative odds was 1.73 (95% CI 1.21, 2.48) in the top fifth of the distribution (body mass index >/= 24.2 kg/m(2)) compared with the bottom fifth (body mass index /= 30 kg/m(2) however, the relative odds were 2.03 (95% CI, 1.03, 4.01) for all cause mortality and 2.17 (95% CI, 1.08, 4.34) for major ischaemic heart disease, adjusted for age, smoking habit and social class. When men were recruited to the study, from 1979 to 1983; the mean body mass index had increased to 26.2 (SD 3.6), a mean increase of 3.9 kg/m(2) or 11. 2 kg; 299 men (12.1%) were classified as obese and showed significantly increased relative odds of both all cause mortality (1. 53 (95% CI 1.14, 2.06) and major ischaemic heart disease (1.55 (95% CI 1.13, 2.11)), adjusted for age, smoking habit and social class relative to the non-obese men. The effect of gain in weight from 18 years to recruitment was also examined; all cause mortality showed highest mortality in the fifth of the distribution who experienced weight loss or minimal weight gain. For major ischaemic heart disease an inconsistent, weak trend was shown, the relative odds rising to a maximum of 1.26 (0.89, 1.80) in the top fifth of weight gain compared with the bottom fifth. Weight gain showed strong associations with potential cardiovascular risk factors measured at recruitment; insulin, triglyceride, glucose, diastolic and systolic blood pressure and high density lipoprotein-cholesterol. CONCLUSIONS: Body mass at 18 years of age of 30 kg/m(2) or more conferred increased risk for all cause mortality and major ischaemic heart disease during 14 years of follow up of men aged 45 to 59 years. By the baseline examination the prevalence of obesity (body mass index >/=30) had increased from 1.8% to 12.1%; obese men also showed an excess risk of major ischaemic heart disease and overall mortality, but these risks were lower than those predicted from 18 years of age. Weight gain was strongly associated with smoking habit, the greatest weight gain being among ex-smokers and the least among light smokers. Weight gain from 18 years of age to baseline examination showed little relation with subsequent mortality and risk of major ischaemic heart disease when adjusted for age, smoking habit and social class. The lowest mortality rate occurred in the "fifth" of men who gained a mean weight of 16.1 kg. Weight gain is closely associated with some adverse cardiovascular risk factors; in particular with insulin, triglyceride, glucose and diastolic blood pressure

Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle.

Zainal TA, Oberley TD, Allison DB, et al.

FASEB J. 2000 Sep; 14(12):1825-36.

In laboratory rodents, caloric restriction (CR) retards several age-dependent physiological and biochemical changes in skeletal muscle, including increased steady-state levels of oxidative damage to lipids, DNA, and proteins. We used immunogold electron microscopic (EM) techniques with antibodies raised against 4-hydroxy-2-nonenal (HNE) -modified proteins, dinitrophenol, and nitrotyrosine to quantify and localize the age-dependent accrual of oxidative damage in rhesus monkey vastus lateralis skeletal muscle. Using immunogold EM analysis of muscle from rhesus monkeys ranging in age from 2 to 34 years old, a fourfold maximal increase in levels of HNE-modified proteins was observed. Likewise, carbonyl levels increased approximately twofold with aging. Comparing 17- to 23-year-old normally fed to age-matched monkeys subjected to CR for 10 years, levels of HNE-modified proteins, carbonyls, and nitrotyrosine in skeletal muscle from the CR group were significantly less than control group values. Oxidative damage largely localized to myofibrils, with lesser labeling in other subcellular compartments. Accumulation of lipid peroxidation-derived aldehydes, such as malondialdehyde and 4-hydroxy-2-alkenals, and protein carbonyls were measured biochemically and confirmed the morphological data. Our study is the first to quantify morphologically and localize the age-dependent accrual of oxidative damage in mammalian skeletal muscle and to demonstrate that oxidative damage in primates is lowered by CR