© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Leptin, Peroxisome Proliferator-Activated Receptor-
, and CCAAT/Enhancer Binding Protein-
mRNA Expression in Adipose Tissue of Humans and Their Relation to Cardiovascular Risk Factors
From the Departments of Internal Medicine (F.K.) and Surgery (E.H.), Krankenhaus Hallein; and the Departments of Laboratory Medicine (D.B., H.O., H.E., W.P.) and Internal Medicine (B.P.), Landeskrankenanstalten, Salzburg, Austria.
Correspondence to Franz Krempler, MD, Department of Internal Medicine, Krankenhaus Hallein, Bürgermeisterstraße 34, A-5400 Hallein, Austria. E-mail w.patsch{at}lkasbg.gv.at
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Abstract |
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Abstract—Obesity is a prevalent disorder that increases the risk for premature cardiovascular disease. The adipose tissue itself plays an active role in the regulation of fuel metabolism and energy homeostasis by expressing a number of regulatory genes, such as leptin, peroxisome proliferator–activated receptor-
(PPAR), and CCAAT/enhancer binding protein-
(C/EBP). To study
the in vivo relationships among these genes and their associations with
cardiovascular risk factors, plasma levels of leptin,
lipids, apolipoproteins (apo), insulin, and glucose were measured in
216 obese, 165 nonobese, and 36 weight-losing postobese subjects. mRNA
expression of leptin, PPAR, and C/EBP in the extraperitoneal and
intraperitoneal adipose tissue was quantified in
subsets of subjects. In obese individuals, plasma leptin was associated
with apoA-I (r=0.2346, P<0.001) and
insulin (r=0.2125, P<0.002). Leptin and
C/EBP mRNA expression in extraperitoneal and
intraperitoneal adipose tissue of obese patients
was higher than in the respective tissues of nonobese or postobese
subjects. No significant differences among the study groups were found
for PPAR mRNA expression. Leptin, PPAR, and C/EBP mRNA levels
correlated with each other in the intraperitoneal
and extraperitoneal fat of obese subjects, but
multivariate analysis revealed that only
C/EBP was a predictor of leptin expression in extraperitoneal tissue
(partial r=0.6096, P<0.001).
Intraperitoneal PPAR expression was inversely
related to fasting insulin (r=-0.2888,
P<0.017) and a fasting insulin resistance index
(r=-0.2814, P<0.021) in obese subjects.
In postobese patients, intraperitoneal PPAR
expression was associated with plasma HDL cholesterol
(r=0.5695, P<0.018) and apoA-I
(r=0.6216, P<0.008) but was inversely
related to LDL cholesterol (r=-0.5101,
P<0.03) and apoB (r=-0.6331,
P<0.007). These findings suggest a relationship between
plasma leptin and HDL metabolism as well as adipose-tissue
site–dependent associations among leptin, C/EBP-, and PPAR- mRNA
expression. Furthermore, our results suggest that C/EBP- enhances
leptin expression in vivo and that PPAR mRNA expression is inversely
associated with cardiovascular risk factors.
Key Words: leptin • peroxisome proliferator–activated receptor- • CCAAT • enhancer binding protein- • obesity • cardiovascular risk
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Introduction |
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Obesity is the most prevalent nutritional disorder in western societies and is a major risk factor for premature cardiovascular disease.1 2 The disorder results from an imbalance in food intake and energy expenditure. Adipose tissue itself is actively involved in the regulation of energy homeostasis.3 Among the proteins secreted by adipose tissue, leptin plays a pivotal role in energy metabolism by signaling adipose tissue mass to hypothalamic centers that control food intake and influence energy usage.4 5
The metabolic signals that alter adipocyte function,
including leptin synthesis and secretion, are incompletely understood.
Peroxisome proliferator–activated receptor- (PPAR) and
CCAAT/enhancer binding protein- (C/EBP) are principal regulators
of adipocyte differentiation and function.6 7 C/EBP
mediates transactivation of leptin transcription in
vitro.8 9 10 Other in vitro studies suggested a functional
antagonism of C/EBP and PPAR in leptin expression,11
but little information is available about the in vivo relationship
among leptin, C/EBP, and PPAR mRNA expression in human
subjects.
Disturbances in lipid transport and carbohydrate
metabolism contribute substantially to the increased
cardiovascular risk in overweight
subjects.12 13 C/EBP and PPAR are integrated in the
control of lipid and carbohydrate
metabolism.7 14 15 16 17 Obesity-associated risk of
cardiovascular disease is modulated by the type of fat
distribution in that intra-abdominal obesity is associated with a
higher risk than subcutaneous obesity,13 18 and
biochemical evidence suggests differences in metabolic
properties of intraperitoneal and subcutaneous
adipose tissue.19 20 21
In the present study, we quantified mRNA levels of leptin,
C/EBP, and PPAR in intraperitoneal and
extraperitoneal adipose tissue of lean, obese, and postobese subjects
to gain insight into the in vivo control of leptin gene expression and
to determine associations of mRNA expression levels with established
cardiovascular risk factors.
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Methods |
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Study Population
This study included unrelated white subjects; 216 subjects were obese patients referred consecutively for weight reduction surgery who underwent a gastric banding procedure. Thirty-six different individuals referred to as postobese subjects underwent an elective procedure, such as adjustment or removal of the gastric tape or cholecystectomy. This group had lost 32.8±17.7 kg after a gastric banding operation. One hundred sixty-five subjects were lean individuals without a major illness. This control group included 20 lean subjects who underwent an elective surgical procedure, such as cholecystectomy or repair of hernias. Among diabetic subjects, only 3 obese patients received hypoglycemic drugs, and none received insulin or a thiazolidinedione. No subject of the entire study group was on lipid-lowering medication. Study subjects provided informed consent, and the study was approved by the institutional review board. After an overnight fast, general anesthesia was induced, and fat biopsies were taken from the abdominal subcutaneous fat, referred to as extraperitoneal adipose tissue, and/or the omental fat, referred to as intraperitoneal adipose tissue, at the beginning of the surgical procedure. Adipose tissue specimens were submerged in ice-cold saline and immediately transported to the laboratory, where they were divided into aliquots and frozen at -70°C, as described previously.22 23 Body mass index (BMI; kilograms per meter squared) was calculated from measurements of weight and height.
Biochemical Measurements
After an overnight fast, blood was collected into tubes
containing EDTA. Plasma glucose was measured by a
hexokinase/glucose-6-phosphate dehydrogenase method. Plasma insulin was
measured by immunoassay (MEIA, Abbott Laboratories). Fasting insulin
resistance index (FIRI) was calculated from fasting glucose and insulin
concentrations (mmolxµU/25) as described by Duncan et
al.24 Cholesterol and triglyceride
were measured by enzymatic procedures (catalogue Nos. 1489437 and
1058550, Boehringer Mannheim Diagnostics). HDL
cholesterol was determined in supernatants after
precipitation of plasma with phosphotungstic acid/magnesium chloride,
and LDL cholesterol was calculated by the formula of
Friedewald et al.25 Apolipoprotein (apo) B and A-I levels
were determined by nephelometric procedures (Array 360, Beckman).
Plasma leptin was measured by radioimmunoassay (Linco Inc).
Isolation of RNA From Adipose Tissues and Northern Blot
Analysis
Total RNA was isolated from 2 g of adipose tissue according
to the method of Chomczynski and Sacchi.26 The integrity
of RNA was ascertained by electrophoresis in formaldehyde gels. RNA
concentrations were determined by absorbance measurements at 260 nm.
Total adipose tissue RNA (30 µg) was denatured with 1 mol/L glyoxal,
50% DMSO and separated by electrophoresis in 1.2% agarose. The RNA
was transferred to S&S Nytran membranes (Schleicher & Schüll) by
capillary blotting and hybridized to a nearly full-length
32P-labeled leptin cDNA probe labeled by the
random priming method using [32P]dCTP (3000
Ci/mmol, Amersham). The relative abundance of leptin mRNA was
determined from the intensities of bands that were quantified on the
autoradiographs by densitometry with Molecular Analyst software
(Bio-Rad). After the leptin probe had been stripped according to the
manufacturer’s recommendations, membranes were subsequently hybridized
with human 32P-labeled PPAR and C/EBP cDNA
probes. The PPAR cDNA probe was obtained by reverse
transcription–polymerase chain reaction amplification of adipose
tissue RNA using 5'-CCAGCATTTCTACTCCACATT-3' (+300 to +320) and
5'-GCGGTTGTCGAAGAGGAAGAG-3' (+757 to +737) as upstream and downstream
primers, respectively (GenBank accession No. L40904). The nearly
full-length C/EBP cDNA probe was kindly provided by Per Antonson,
Stockholm, Sweden. Relative abundance levels of leptin, PPAR, and
C/EBP mRNA were corrected by use of the relative abundance of GAPDH
(GenBank Accession No. M33197) and ß-actin mRNA (GenBank Accession
No. M10278) abundance levels as described previously.22 23
mRNA signals were normalized by use of overlapping RNA samples in
Northern blots.
Statistical Analyses
Two-way ANOVA27 was used to test the equality of
such continuous variables as age and biochemical measurements among
obese, nonobese, and postobese subjects. A transformation was made on
the original variable if the equal variance and normality
assumptions of the 2-way ANOVA were rejected. For some
analyses, mRNA abundance levels were adjusted, by multiple
regression, for sex and/or age. To compare categorical variables, a
contingency 
2 test was used. Stepwise multiple
linear regression models were used to identify independent predictor
variables for plasma leptin, leptin mRNA expression, and PPAR
mRNA expression. Independent variables with a value of
P<0.05 (2-sided) were considered statistically
significant.
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Results |
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Approximately 4 times more female than male patients were admitted for bariatric surgery. Therefore, more female than male patients were recruited for the control group. According to the selection criteria for surgery, average BMI and leptin levels were considerably higher in obese than in nonobese subjects (Table 1
). Although the majority of
postobese subjects were still losing weight according to their own
weight measurements, accurate dietary and weight data were not
available in many postobese subjects. We therefore estimated the actual
calorie intake status of postobese subjects by comparing their plasma
leptin values with those predicted from multivariate
analysis using BMI and sex as predictor variables in the
population of obese and nonobese subjects. According to these
calculations, the average leptin level in postobese subjects was
62.24% (CI 50.51% to 73.98%) of the level predicted. Hence,
postobese subjects were most likely on a hypocaloric diet at the time
of the study.
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Compared with nonobese control subjects, average values for plasma
insulin, leptin, triglyceride, and apoB were significantly
higher in obese subjects, whereas average values for HDL
cholesterol and apoA-I were significantly lower. Blood
pressure readings, as well as the prevalence of non–insulin-dependent
diabetes, were also higher in obese subjects than in control subjects.
Systolic blood pressure readings, plasma insulin, leptin, and
apoB levels were significantly lower in postobese than in obese
patients. Exclusion of diabetic subjects reduced plasma glucose in the
obese study group to 85±18 mg/dL (P<0.024) but had no
considerable effect on the average values of the other variables
shown in Table 1
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Relation of Plasma Leptin With Sex, BMI, and
Cardiovascular Risk Factors
In all 3 study groups, plasma leptin was significantly higher in
women than in men (obese: 40.9 versus 27.6 ng/mL, P<0.001;
nonobese: 10.5 versus 3.8 ng/mL, P<0.001; postobese: 14.2
versus 4.4 ng/mL, P<0.04). Sex-adjusted plasma
leptin correlated with BMI in obese (r=0.3297), nonobese
(r=0.5809), and postobese subjects (r=0.6548)
(all P<0.001). In obese patients, sex-adjusted leptin
correlated with apoA-I (r=0.2346, P<0.001) and
insulin (r=0.2125, P<0.002). No such
associations were found in nonobese or postobese subjects. Exclusion of
diabetic patients, whether they were receiving hypoglycemic drugs or
not, did not alter the associations found in obese subjects.
Multivariate analysis in obese subjects
demonstrated that BMI, sex, apoA-I, and insulin were independent
predictors of plasma leptin (Table 2,
obese subjects). This model explained 26% of the variance in plasma
leptin. In multivariate analyses of nonobese or
postobese subjects, only sex and BMI were retained as independent
variables, and these models explained 50% or 48% of the variance
in plasma leptin (Table 2, nonobese and postobese subjects).
Again, exclusion of diabetic subjects did not alter the relationships
in the obese and control groups.
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Leptin, PPAR, and C/EBP mRNA Expression
Relative mRNA abundance levels of leptin, PPAR, and C/EBP in
intraperitoneal and extraperitoneal adipose tissues
of obese, nonobese, and postobese subjects are shown in Table 3. No sex-associated differences were
found in the mRNA expression levels of these genes (not shown). In
obese subjects, leptin mRNA expression in extraperitoneal adipose
tissue correlated with plasma leptin (r=0.3411,
P<0.002). Adjustment for sex did not substantially alter
the association in obese patients (P<0.003). Moreover, in
obese and nonobese subjects, Spearman rank order correlations showed
associations of intraperitoneal leptin mRNA
abundance with BMI (R=0.1988, P<0.037 and
R=0.6294, P<0.009).
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In obese patients, leptin and C/EBP but not PPAR mRNA abundance
levels were significantly higher in the extraperitoneal than in the
intraperitoneal adipose tissue, whereas no such
differences were observed in nonobese and postobese subjects (Table 3). Compared with nonobese and postobese subjects, obese
patients exhibited higher extraperitoneal and
intraperitoneal expression levels of leptin and
C/EBP mRNA. No significant differences among the 3 study groups were
found in PPAR mRNA levels. Results were not substantially altered
when diabetic patients and/or subjects receiving any type of medication
were excluded from the analyses.
The relationships among leptin, PPAR, and C/EBP mRNA expression
in adipose tissue deposits of obese patients are shown in Table 4. Significant associations of
intraperitoneal with extraperitoneal tissue
expression were observed for C/EBP and PPAR but not leptin mRNA
in univariate analyses.
Multivariate analysis, adjusted for age, sex,
BMI, and insulin (all forced into the model) demonstrated that C/EBP
but not PPAR mRNA expression was a predictor of leptin mRNA
abundance in the extraperitoneal adipose tissue (partial
r=0.6096, P<0.001). This model accounted for
40% of the variance of leptin mRNA expression. In
intraperitoneal adipose tissue, neither C/EBP
nor PPAR mRNA abundance was maintained as an independent predictor
of leptin mRNA expression on multivariate
analysis. These associations remained similar after exclusion
of diabetic subjects.
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In nonobese and postobese patients, only C/EBP mRNA abundance
exhibited significant correlations between the 2 tissue sites
(P<0.01 for both study groups). Furthermore, no
associations among the expression levels of the 3 mRNA species were
noted in any tissue.
PPAR mRNA Expression and Cardiovascular
Risk Factors
In obese nondiabetic patients, intraperitoneal
PPAR mRNA was inversely related with fasting insulin and FIRI in
univariate analyses (r=-0.2888,
P<0.017 and r=-0.2814, P<0.021,
respectively) and in multivariate analyses
after adjustment for age and sex (r=-0.2926,
P<0.017 and r=-0.2998, P<0.015,
respectively).
Striking relationships were observed in postobese subjects.
Univariate analyses showed correlations of
intraperitoneal PPAR mRNA with HDL
cholesterol (r=0.5695, P<0.018) and
apoA-I (r=0.6216, P<0.008) and inverse
relationships with LDL cholesterol (r=-0.5101,
P<0.031) and apoB (r=-0.6331,
P<0.007). In multivariate models with
intraperitoneal PPAR mRNA as the dependent
variable, both HDL cholesterol and LDL
cholesterol were retained as independent variables
after adjustment for age and sex (Table 5, HDL and LDL Cholesterol).
HDL cholesterol and LDL cholesterol could be
replaced by apoA-I and apoB without diminishing the predictive value of
the model (Table 5, ApoA-I and ApoB). The proportion of the
PPAR mRNA variance explained by lipoprotein lipids or
apolipoproteins was 57% and 61%, respectively, providing internal
consistency for the relationship of lipid transport with
intraperitoneal PPAR mRNA expression in
postobese subjects.
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Discussion |
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The main findings of our study are that (1) plasma leptin correlated with apoA-I and insulin in obese subjects; (2) associations among leptin, C/EBP
, and PPAR mRNA expression were adipose-tissue
site–dependent; (3) C/EBP but not PPAR mRNA abundance was an
independent predictor of leptin mRNA expression in extraperitoneal
adipose tissue of obese subjects; and (4) PPAR mRNA expression was
inversely associated with CAD risk factors in obese and postobese
patients.
As has been reported in numerous previous studies,28 29
plasma leptin levels correlated with BMI and were higher in women than
in men in all 3 study groups. Sex and BMI explained 
50% of the
variance of plasma leptin in nonobese and postobese subjects. In obese
patients, the predictive value of sex and BMI for plasma leptin was
considerably lower, suggesting that other factors gain importance in
the regulation of leptin or that the control of plasma leptin levels is
disturbed in obese subjects. Both univariate and
multivariate analyses revealed associations of
leptin with apoA-I and insulin in obese patients. A relationship
between leptin and apoA-I was reported recently in overweight
children.30 Although leptin synthesis, which depends on
fat cell size and total number of adipocytes, is the main determinant
of circulating leptin levels,31 different rates of
adipocyte leptin secretion may also influence plasma leptin
levels.32 We previously reported that a variable
fraction of leptin is associated with HDL after
ultracentrifugation.30 One may therefore
speculate that apoA-I, analogous to its function in reverse
cholesterol transport, is involved in the transport or
release of leptin from adipocytes. Conversely, leptin itself may
modulate apoA-I synthesis and/or metabolism, since it has
been shown to stimulate lipolysis and oxidation of fatty
acids.33
In obese patients, plasma leptin was associated with insulin, a relationship well known from previous studies.23 34 35 Although such an association may be explained, at least in part, by the relation of insulin resistance with BMI,36 growing evidence suggests that insulin stimulates leptin synthesis not only in rodents but also in humans. We have recently shown that obese subjects with impaired insulin signaling due to a variation in the IRS-1 gene displayed lower leptin mRNA and plasma levels than obese wild-type subjects.23 Consistent with a stimulatory role of insulin on leptin gene expression are increases of leptin mRNA and plasma levels in patients with insulin-secreting tumors.37 The result of the present study showing that insulin is a predictor of plasma leptin independent of BMI and sex lends further support to a role of insulin in the long-term regulation of leptin gene expression.
To fulfill its central role in energy homeostasis, adipose tissue
deposits must undergo continuous remodeling, which includes
differentiation of precursor cells into adipocytes.38
PPAR and C/EBP regulate adipocyte differentiation6 7
but must also play a role in mature adipose tissue function. In our
study, C/EBP expression was associated with obesity and was highest
in the extraperitoneal adipose tissue of obese subjects, which is known
to harbor larger and more fat-laden adipocytes.22 39
Hence, increased C/EBP synthesis may be required for maintaining
adipocyte function when fat cell size increases and obesity advances.
In contrast, PPAR expression was not related to BMI. This finding
must be qualified, however, because mRNA expression levels do not
necessarily predict protein concentrations or functional activities.
Moreover, several isoforms of PPAR have been
identified.40 41 PPAR1 mRNA was
much more abundant in human adipose tissue than
PPAR2 mRNA, which accounted for 13% of
total PPAR mRNA.42 Conflicting results regarding the
association of the 2 isoforms with obesity were reported.
PPAR2, but not PPAR1,
was increased in subcutaneous adipose tissue of obese humans in 1
study,43 whereas the expression ratios of the 2 mRNA
species were similar in various adipose tissue depots and independent
of the degree of obesity in another study.42
PPAR3, a third recently identified isoform, is
also expressed in adipose tissue,41 but data on a possible
relation of PPAR3 with obesity are not yet
available. Because we determined the abundance of total PPAR mRNA,
possible differences among adipose tissue sites and in relation to
obesity status of mRNA species encoding the PPAR- isoforms could not
be assessed.
PPAR and C/EBP mRNA levels were significantly correlated in the
extraperitoneal and intraperitoneal adipose tissue
of obese subjects. This result is consistent with a synergistic
function of the 2 genes in maintaining adipocyte
function,44 but the greater variance of C/EBP mRNA
abundance implicates differences in the regulation of C/EBP and
PPAR mRNA expression.
Signaling pathways operating through PPAR and C/EBP are central
to adipocyte function, because a number of adipocyte-specific genes
possess binding sites for PPAR and C/EBP, and overexpression of
these factors can induce adipocyte differentiation.6 7
C/EBP expression precedes the expression of leptin during adipocyte
differentiation.9 Studies of the leptin promoter
identified a C/EBP motif that mediated transactivation of leptin
transcription.8 9 In contrast, thiazolidinedione treatment
or PPAR/retinoid X receptor- cotransfection did not alter
transcription from the leptin promoter in transient transfection
studies.10 However, a putative binding site for PPAR
was localized in the leptin promoter, and transfection studies in
primary rat adipocytes and CV-1 cells suggested a functional antagonism
of C/EBP and PPAR in leptin expression. Interestingly, this
antagonism was observed with constructs containing the C/EBP but
devoid of the PPAR binding site.11 Moreover,
thiazolidinediones induced expression of both C/EBP mRNA and protein
in fully differentiated 3T3-L1 adipocytes,45 and C/EBP
expression vectors were shown to activate transcription from
the PPAR promoter in UMR 106 cells.46 Thus, the
regulation of leptin expression by C/EBP and PPAR appears to be
complex in vitro. In our in vivo study, leptin mRNA abundance levels in
the intraperitoneal and extraperitoneal adipose
tissue correlated with the expression of PPAR and C/EBP in obese
patients and tended to correlate in nonobese and postobese subjects. In
a multivariate model, C/EBP, but not PPAR, was an
independent predictor of leptin mRNA abundance in the extraperitoneal
adipose tissue. Moreover, the decrease in C/EBP expression in going
from the obese to the postobese state was paralleled by a decrease
in leptin mRNA abundance (Table 3). These results support the
proposed role of C/EBP as a transcriptional activator of
the leptin gene. Reduced insulin sensitivity of the omental compared
with the subcutaneous adipose tissue has been implicated in the
differences of leptin mRNA expression between the 2 tissue
sites.47 Our results strongly suggest that
C/EBP-–mediated upregulation represents an additional
mechanism that contributes to the higher leptin expression in the
extraperitoneal adipose tissue. The repressor effect of PPAR on the
leptin gene that has been demonstrated in cell culture
experiments11 was not apparent at the mRNA level measured
in the present study. Because PPAR total mRNA expression does
not reflect the integrated activities of PPAR protein isoforms, an
inhibitory effect of PPAR on leptin expression may have
been concealed in our in vivo study. Supportive evidence for a role of
PPAR in leptin expression in vivo comes from a recent report
demonstrating that carriers of a PPAR2
polymorphism had higher plasma leptin levels than wild-type
subjects.48 Studies in rats suggested that leptin itself
may regulate PPAR, because leptin injection increased the expression
of PPAR protein in adipocytes.49 Our data showed no
correlations of plasma leptin with PPAR or C/EBP mRNA
expression.
C/EBP mRNA abundance levels in the extraperitoneal and
intraperitoneal adipose tissue deposits correlated
in all 3 study groups, indicating that common signaling mechanisms
regulate the expression of this gene in both tissue sites. PPAR mRNA
expression correlated only in the obese group. Leptin mRNA expression
levels in intraperitoneal and extraperitoneal
tissue sites exhibited no correlation in any of the study groups.
Hence, tissue site–specific factors contributed significantly to
leptin gene expression.
In obese subjects, intraperitoneal PPAR
expression was inversely related to fasting insulin and FIRI, both
indicators of insulin resistance. PPAR is a receptor for
thiazolidinediones, a new class of antidiabetic
compounds.14 15 Activation of PPAR is believed to be
central to the insulin-sensitizing effect of these drugs.3
Our findings are thus consistent with a role of PPAR in
glucose homeostasis and suggest that PPAR may be a key factor in
maintaining insulin sensitivity as obesity develops.
In postobese subjects, intraperitoneal PPAR
expression correlated with HDL cholesterol and apoA-I but
was inversely related to LDL cholesterol and apoB. No such
relationships were observed in obese or nonobese subjects. Postobese
subjects had lost a considerable amount of weight and were still losing
weight, judged by the relation of actual to predicted plasma leptin
values. After prolonged hypocaloric nutrition, energy stores are
reduced and several metabolic processes, including VLDL
synthesis by the liver as well as cellular lipid
metabolism, are altered. The associations of PPAR
expression with HDL and LDL components may relate to the sterol content
of adipocytes, because LDL and HDL would be expected to have opposing
effects on cellular cholesterol homeostasis. Sterol
depletion of cells induces a proteolytic release of sterol regulatory
element binding proteins (SREBPs) from the endoplasmic reticulum. After
translocation into the nucleus, SREBPs activate a number of
genes, thereby augmenting cellular cholesterol synthesis
and uptake.50 A SREBP motif has been identified in the
PPAR3 promoter,44 and
transactivation by SREBPs might contribute to the relationship of
PPAR mRNA with HDL and LDL in postobese subjects. Such a scenario
would be consistent with the interrelationship of lipid and
glucose metabolism originally proposed by Randle et
al.51 Because PPAR is involved in the remodeling of
adipose tissue,52 it is also possible that changes in
adipose tissue metabolism are the primary event that
secondarily affects plasma levels of HDL and LDL. Irrespective of the
mechanism, our findings further underline the central role of the
intraperitoneal adipose tissue for
metabolic processes that affect
cardiovascular risk.
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Acknowledgments |
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This study was supported by a grant from the Medizinische Forschungsgesellschaft Salzburg (to W.P.) and by the Jubilaeumsfondsprojekt Nr. 7228 of the Oesterreichische Nationalbank (to W.P.). The technical assistance of C. Winkler and the assistance of Dr C. Breban in the management of study patients are gratefully acknowledged.
Received January 19, 1999; accepted September 1, 1999.
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