LE Magazine August 2002
Dietary L-carnitine supplementation in
obese cats alters carnitine metabolism and decreases ketosis
during fasting and induced hepatic lipidosis.
This study was designed to determine whether dietary
carnitine supplement could protect cats from ketosis and
improve carnitine and lipid metabolism in experimental feline
hepatic lipidosis (FHL). Lean spayed queens received a diet
containing 40 (CL group, n = 7) or 1000 (CH group, n = 4)
mg/kg of L-carnitine during obesity development. Plasma fatty
acid, beta-hydroxybutyrate and carnitine, and liver and muscle
carnitine concentrations were measured during experimental
induction of FHL and after treatment. In control cats (CL
group), fasting and FHL increased the plasma concentrations of
fatty acids two- to three-fold (P < 0.0001) and
beta-hydroxybutyrate > 10-fold (from a basal 0.22 +/- 0.03
to 1.70 +/- 0.73 after three-week fasting and 3.13 +/- 0.49
mmol/L during FHL). In carnitine-supplemented cats, these
variables increased significantly (P < 0.0001) only during
FHL (beta-hydroxybutyrate, 1.42 +/- 0.17 mmol/L). L-Carnitine
supplementation significantly increased plasma, muscle and
liver carnitine concentrations. Liver carnitine concentration
increased dramatically from the obese state to FHL in
nonsupplemented cats, but not in supplemented cats, which
suggests de novo synthesis of carnitine from endogenous amino
acids in control cats and reversible storage in supplemented
cats. These results demonstrate the protective effect of a
dietary L-carnitine supplement against fasting ketosis during
obesity induction. Increasing the L-carnitine level of diets
in cats with low energy requirements, such as after neutering,
and a high risk of obesity could therefore be recommended.
J Nutr 2002 Feb;132(2):204-10
Regulation of carnitine
acyltransferase synthesis in lean and obese Zucker rats by
dehydroepiandrosterone and clofibrate.
The effects of dehydroepiandrosterone (DHEA) and clofibrate
on mitochondrial and peroxisomal proliferation and carnitine
acyltransferases [mitochondrial carnitine palmitoyltransferase
(CPT) and peroxisomal carnitine octanoyltransferase (COT)]
were measured in lean and obese female Zucker rats. DHEA
increased total hepatic mitochondrial protein two-fold;
clofibrate increased total hepatic peroxisomal protein more
than five-fold. Both DHEA and clofibrate administration
increased enzyme activities, immunoreactive protein, messenger
RNA levels and transcription rates for the carnitine
acyltransferases. Transcription rates and messenger RNA
concentration for both carnitine acyltransferases correlated
with the increases in activity. These data suggest that the
hepatic CPT and COT in female Zucker rats are regulated
primarily at the transcriptional level by DHEA and
clofibrate.
J Nutr 1991 Apr;121(4):525-31
The clinical and metabolic effects of
rapid weight loss in obese pet cats and the influence of
supplemental oral L-carnitine.
The efficacy, safety, and metabolic consequences of rapid
weight loss in privately owned obese cats by means of a canned
weight-reduction diet and the influence of orally administered
L-carnitine on rate of weight loss, routine clinical
evaluations, hepatic ultrasonography, plasma amino acid
profiles, and carnitine analytes were evaluated. A
double-blinded placebo-controlled design was used with cats
randomly divided into 2 groups: Group 1 (n = 14) received
L-carnitine (250 mg PO q24h) in aqueous solution and group 2
(n = 10) received an identical-appearing water placebo. Median
obesity (body condition scores and percentage ideal body
weight) in each group was 25%. Caloric intake was restricted
to 60% of maintenance energy requirements (60 kcal/kg) for
targeted ideal weight. The reducing formula was readily
accepted by all cats. Significant weight loss was achieved by
week 18 in each group without adverse effects (group 1 =
23.7%, group 2 = 19.6%). Cats receiving carnitine lost weight
at a significantly faster rate (P < .05). Significant
increases in carnitine values developed in each group (P <
.02). However, significantly higher concentrations of all
carnitine moieties and a greater percentage of acetylcarnitine
developed in cats of group 1 (P < .01). The dietary formula
and described reducing strategy can safely achieve a 20%
weight reduction within 18 weeks in obese cats. An aqueous
solution of L-carnitine (250 mg PO q12h) was at least
partially absorbed, was nontoxic, and significantly increased
plasma carnitine analyte concentrations as well as rate of
weight loss.
J Vet Intern Med 2000
Nov-Dec;14(6):598-608
Effect of dehydroepiandrosterone
sulfate on carnitine acetyl transferase activity and
L-carnitine levels in oophorectomized rats.
Alteration in energy metabolism of postmenopausal women
might be related to the reduction of dehydroepiandrosterone
sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at
their nadir near menopause. DHEA and DHEAS modulate fatty acid
metabolism by regulating carnitine acyltransferases and CoA.
The purpose of this study was to determine whether dietary
supplementation with DHEAS would also increase tissue
L-carnitine levels, carnitine acetyltransferase (CAT) activity
and mitochondrial respiration in oophorectomized rats. Plasma
L-carnitine levels rose following oophorectomy in all groups
(P < 0.0001). Supplementation with DHEAS was not associated
with further elevation of plasma L-carnitine levels, but with
increased hepatic total and free L-carnitine (P = 0.021 and P
< 0.0001, respectively) and cardiac total L-carnitine
concentrations (P = 0.045). In addition, DHEAS supplementation
increased both hepatic and cardiac CAT activities (P <
0.0001 and P = 0.05 respectively). CAT activity positively
correlated with the total and free carnitine levels in both
liver and heart (r = 0.764, r = 0.785 and r = 0.700, r =
0.519, respectively). Liver mitochondrial respiratory control
ratio, ADP:O ratio and oxygen uptake were similar in both
control and supplemented groups. These results demonstrate
that in oophorectomized rats, dietary DHEAS supplementation
increases the liver and heart L-carnitine levels and CAT
activities. In conclusion, DHEAS may modulate L-carnitine
level and CAT activity in estrogen deficient rats. The
potential role of DHEAS in the regulation of fatty acid
oxidation in postmenopausal women is worthy of
investigation.
Biochim Biophys Acta 1997 Feb
18;1344(3):201-9
Carnitine and dehydroepiandrosterone
sulfate induce protein synthesis in porcine primary
osteoblast-like cells.
Age-related bone loss eventually leads to osteopenia in men
and women. The etiology of age-related bone loss is currently
unknown; however, decreased osteoblast activity contributes to
this phenomenon. In turn, osteoblast proliferation and
function is dependent on energy production, thus the loss of
energy production that occurs with age may account for the
deficient osteoblast activity. Carnitine and
dehydroepiandrosterone-sulfate (DHEAS), both of which decline
with age, promote energy production through fatty acid
metabolism. Thus, we hypothesized that carnitine and DHEAS
would increase osteoblast activity in vitro. Accordingly, we
measured the effect of carnitine and DHEAS on palmitic acid
oxidation as a measure of energy production, and alkaline
phosphatase (ALP) activity and collagen type I (COL) as
indices of osteoblast function in primary porcine
osteoblast-like cell cultures. Carnitine (10(-3) and 10(-1) M)
but not DHEAS (10(-9), 10(-8), and 10(-7) M) increased
carnitine levels within the cells. Carnitine alone and in
combination with DHEAS increased palmitic acid oxidation. Both
carnitine and DHEAS alone and in an additive fashion increased
ALP activity and COL levels. These results demonstrate that in
osteoblast-like cells in vitro, energy production can be
increased by carnitine and osteoblast protein production can
be increased by both carnitine and DHEAS. These data suggest
that carnitine and DHEAS supplementation in the elderly may
stimulate osteoblast activity and decrease age-related bone
loss.
Calcif Tissue Int 1999
Jun;64(6):527-33
Correlation of serum L-carnitine and
dehydro-epiandrosterone sulphate levels with age and sex in
healthy adults.
OBJECTIVES: L-carnitine and dehydroepiandrosterone (DHEA)
independently promote mitochondrial energy metabolism. We
therefore wondered if an age-related deficiency of L-carnitine
or DHEA may account for the declining energy metabolism
associated with age. METHODS: we evaluated serum levels of
L-carnitine and the sulphated derivative of DHEA (DHEAS) in a
cross-sectional study of 216 healthy adults, aged 20 to 95.
RESULTS: serum DHEAS levels declined, while total carnitine
levels increased with age (P < 0.0001). Total and free
carnitine and DHEAS levels were lower in women than men (P
< 0.0001). Esterified/free (E/F) carnitine (inversely
related to carnitine availability) increased with age in both
sexes (P=0.012). CONCLUSION: reduced carnitine availability
correlates with the age-related decline of DHEAS levels. These
results are consistent with the hypothesis that decreased
energy metabolism with age relates to DHEAS levels and
carnitine availability.
Age Ageing 1999 Mar;28(2):211-6
Therapeutic effects of
dehydroepiandrosterone (DHEA) in diabetic mice.
Dehydroepiandrosterone (DHEA), a major adrenal secretory
steroid in humans, was therapeutic when fed in a concentration
of 0.4% to C57BL/KsJ mice with either non-insulin-dependent or
insulin-dependent diabetes. Genetically diabetic (db/db) mice
of both sexes develop obesity and a glucose intolerance and
hyperglycemia associated with insulin resistance by 2 mo of
age, and exhibit beta-cell necrosis and islet atrophy by 4 mo.
In contrast, DHEA feeding initiated between 1 and 4 mo of age,
while only moderately effective in preventing obesity, did
prevent the other pathogenic changes and effected a rapid
remission of hyperglycemia, a preservation of beta-cell
structure and function, and an increased insulin sensitivity
as measured by glucose tolerance tests. DHEA feeding was also
therapeutic to normal C57BL/KsJ male mice made diabetic by
multiple low doses of streptozotocin (SZ). While DHEA
treatments did not block either the direct cytotoxic action of
SZ on beta-cells or the development of insulitis, the steroid
significantly moderated the severity of the ensuing diabetes
(reduced hyperglycemia and water consumption, and increased
plasma insulin and numbers of residual, granulated
beta-cells).
Diabetes 1982 Sep;31(9):830-3
Molecular Differences Caused by
Differentiation of 3T3-L1 Preadipocytes in the Presence of
either Dehydroepiandrosterone (DHEA) or 7-Oxo-DHEA.
The effects of dehydroepiandrosterone (DHEA) and 7-oxo-DHEA
on the cell size, adiposity, and fatty acid composition of
differentiating 3T3-L1 preadipocyte cells are correlated with
stearoyl-CoA desaturase (SCD) expression (mRNA and protein
levels) and enzyme activity. Fluorescence-activated cell
sorting shows that preadipocyte cells treated with
methylisobutylxanthine, dexamethasone, and insulin (MDI) plus
DHEA comprise a population distribution of predominantly large
cells with reduced adiposity. In contrast, cells treated with
MDI plus 7-oxo-DHEA comprise a population distribution of
almost equal proportions of small and large cells that have an
adiposity equivalent to cells differentiated with MDI alone.
The cells treated with MDI plus DHEA have significantly
reduced levels of total fatty acid, mainly due to a dramatic
reduction in the level of palmitoleic (Delta(9)-16:1) acid.
The cells treated with MDI plus 7-oxo-DHEA have a
significantly increased level of total fat, primarily due to
increased levels of Delta(9)-16:1 and palmitic (16:0) acids.
At the molecular level, the DHEA-treated cells contain lowered
amounts of SCD1 mRNA and antibody-detectable desaturase
protein, while 7-oxo-DHEA-treated cells contained elevated
levels of SCD1 mRNA and protein. Inhibition of differentiation
in DHEA-treated cells was also suggested by a reduction in the
mRNA level of the adipogenic gene aP2. At the level of
microsomal enzymatic activity, SCD activity was decreased in
DHEA-treated cells while the SCD activity was increased in
7-oxo-DHEA-treated cells. The changes in mRNA levels and
enzyme activity were concentration-dependent and appeared as
early as day 3 of the differentiation protocol. The results
show that DHEA and 7-oxo-DHEA have distinct modes of action
with respect to the complex transcriptional cascade required
for differentiation. Furthermore, differences in the
insulin-stimulated uptake of 2-deoxyglucose and in the
activity of carnitine palmitoyl transferase observed from
either DHEA- or 7-oxo-DHEA-treated cells support the ability
of DHEA to produce a thermogenic effect in differentiating
preadipocytes, while 7-oxo-DHEA promotes differentiation
without other changes typical of thermogenesis.
Biochemistry 2002 Apr
30;41(17):5473-82
Characteristics of dehydroepiandrosterone as a peroxisome
proliferator.
Treatment of rats with dehydroepiandrosterone (300 mg/kg body
weight, per os, 14 days) caused a remarkable increase in the
number of peroxisomes and peroxisomal beta-oxidation activity
in the liver. The activities of carnitine acetyltransferase,
microsomal laurate 12-hydroxylation, cytosolic palmitoyl-CoA
hydrolase, malic enzyme and some other enzymes were also
increased. The increases in these enzyme activities were all
greater in male rats than in female rats. Immunoblot analysis
revealed remarkable induction of acyl-CoA oxidase and
enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase
bifunctional enzyme in the liver and to a smaller extent in
the kidney, whereas no significant induction of these enzymes
was found in the heart. The increase in the hepatic
peroxisomal beta-oxidation activity reached a maximal level at
day five of the treatment of dehydroepiandrosterone and the
increased activity rapidly returned to the normal level on
discontinuation of the treatment. The increase in the activity
was also dose-dependent, which was saturable at a dose of more
than 200 mg/kg body weight. All these features in enzyme
induction caused by dehydroepiandrosterone correlate well with
those observed in the treatment of clofibric acid, a
peroxisome proliferator. Co-treatment of
dehydroepiandrosterone and clofibric acid showed no synergism
in the enhancement of peroxisomal beta-oxidation activity,
suggesting the involvement of a common process in the
mechanism by which these compounds induce the enzymes. These
results indicate that dehydroepiandrosterone is a typical
peroxisome proliferator. Since dehydroepiandrosterone is a
naturally occurring C19 steroid in mammals, the structure of
which is novel compared with those of peroxisome proliferators
known so far, this compound could provide particular
information in the understanding of the mechanisms underlying
the induction of peroxisome proliferation.
Biochim Biophys Acta 1991 Apr
17;1092(2):233-43
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