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Original Studies |
Endocrinology and Metabolism Unit and Surgery Unit (R.D.), University of Louvain, Faculty of Medicine, UCL 5530, B-1200 Brussels, Belgium
Address all correspondence and requests for reprints to: S. M. Brichard, Unité d’Endocrinologie et Métabolisme, UCL 5530, avenue Hippocrate 55, B-1200 Brussels, Belgium.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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10 nmol/L). Although the maximal
response was higher in obese than in lean subjects, the
EC50 values were roughly similar in both groups. Unlike
dexamethasone, insulin had no direct stimulatory effect on
ob gene expression and leptin secretion. Singularly,
insulin even inhibited the dexamethasone-induced rise in
ob mRNA and leptin release. This inhibition was observed
in both lean and obese subjects, whereas the expected stimulation of
insulin on glucose metabolism and the accumulation of mRNA species for
the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate
dehydrogenase occurred in lean patients only. This inhibitory effect
was already detectable at 10 nmol/L insulin and was also observed in
subcutaneous fat. Although a lowering of intracellular cAMP
concentrations is involved in some of the effects of insulin on adipose
tissue, this cannot account for the present finding, because the
addition of cAMP to the medium also decreased ob mRNA
and leptin secretion (regardless of whether dexamethasone was present).
In conclusion, glucocorticoids, at physiological concentrations,
stimulated leptin secretion by enhancing the pretranslational machinery
in human visceral fat. This effect was more pronounced in obese
subjects due to a greater responsiveness of the ob gene
and could contribute to the metabolic abnormalities associated with
central obesity by para/endocrine actions of hyperleptinemia on
adipocytes and liver. Unlike dexamethasone, insulin had no direct
stimulatory effect on ob gene expression and leptin
secretion, and even prevented the positive response to dexamethasone by
a cAMP-independent mechanism that remained functional despite insulin
resistance. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The hormonal regulation of the ob gene and leptin secretion
in humans is still unclear. cAMP and ß-adrenoceptor agonists inhibit
leptin expression and levels in rodents (1, 2, 3), but this
down-regulatory effect has not yet been studied in man. Glucocorticoids
and insulin have been proposed as potential up-regulators.
Glucocorticoids increased ob messenger ribonucleic acid
(mRNA) and leptin production in vivo when administered at
pharmacological doses in man (4, 5) and in vitro in
subcutaneous adipocytes (6, 7). However, the role of physiological
concentrations of glucocorticoids is as yet unsettled, especially as
there is an inverse relationship between fluctuations in plasma levels
of leptin and those of cortisol (8). The effects of insulin are more
controversial. Although acute (
3 h) insulin has no stimulatory effect
(9, 10, 11, 12), longer hyperinsulinemic clamps resulted in increased leptin
concentrations in some (13, 14), but not all (15, 16, 17), studies.
Experiments in vitro have not solved the controversy over
the potential direct effects of insulin on leptin synthesis, as both an
increase (6) and no change (7) have been reported. When insulin was
combined with dexamethasone, both synergism and antagonism were found
(6, 7). These discrepancies may be due to the use of different culture
models.
To assess the direct role of hormones on the expression of fat genes and synthesis of their products, cultured explants of adipose tissue have decisive advantages over clonal cell lines or stromal cells differentiated by long term exposure to pharmacological doses of adipogenic cocktails. The approach is more physiological, and the model is highly responsive to insulin (18); moreover, interactions between cells are preserved. These interactions as well as preadipocyte differentiation into an in vivo context may be a prerequisite for optimal ob gene expression and responsiveness to hormones (19).
Although critical for weight maintenance, the hormonal control of leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this regulation has never been addressed in human visceral fat. This adipose site, however, plays a causative role in a cluster of obesity-related metabolic abnormalities (including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis) whose high prevalence in western countries reaches epidemic proportions (20).
In the present study, we therefore investigated the multihormonal regulation of ob gene expression and leptin production in cultured explants of visceral fat from lean and obese subjects. We particularly focused on the interactions between glucocorticoids and insulin and briefly tackled the role of cAMP.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Adipose tissue was obtained from eight obese [three men and five women; age, 43 ± 5 yr; body mass index (BMI), 40.6 ± 1.6 kg/m2] and nine nonobese (four men and five women; age, 50 ± 4 yr; BMI, 23.7 ± 1 kg/m2) patients undergoing abdominal surgery after an overnight fast. Obesity was defined as a BMI of 30 kg/m2 or more. All cases were elective procedures to correct benign conditions (peptic ulceration, hernia repair, gastroesophageal reflux, and overweight status treated by vertical banded gastroplasty) or malignant disease (carcinoma of colon). Cancer cases had no evidence of disseminated disease, and the operation was curative. No patients had a history of diabetes, and none had undergone any significant weight change. Patients receiving endocrine therapy (e.g. steroids) or taking medications known to influence adipose tissue mass or metabolism were excluded. The study had the approval of the local ethical committee.
Adipose tissue culture
One to 60 g wet weight of omental and subcutaneous biopsies
were placed in Krebs buffer containing 2% (wt/vol) BSA and immediately
transported to the laboratory. All visible vessels and coagulation
particles were removed. Fat tissue was cut with scissors into small
pieces (3–4 mm3) and agitated for 30 min in MEM with
Earle’s salts supplemented with 1% BSA, as previously described (18, 21). The pieces of adipose tissue were then rinsed in
phosphate-buffered saline and incubated in 100-mm petri dishes
containing 9 mL MEM supplemented with 1 mL FCS, 100 IU/mL penicillin,
100 µg/mL streptomycin, and 0.25 µg/mL amphotericin B.
Approximately 700-1000 mg adipose tissue were cultured per dish; all
conditions were carried out in duplicate, then material was pooled.
Depending on the amount of tissue available, it was not always possible
to generate all data from the same patient. The dishes were cultured
for up to 48 h at 37 C in an air-CO2 (19:1)
atmosphere. The culture medium was changed every 24 h. The basal
concentration of glucose in fresh medium was 5 mmol/L. The basal
concentrations of cortisol and insulin were extremely low (0.5
nmol/L and 3 pmol/L, respectively). Different hormones or
pharmacological agents were added in various combinations in accordance
with the experimental protocols. Cell viability, as assessed by low
release of lactate dehydrogenase and triglycerides into the medium
(22), did not change over the course of culture (not shown). At the end
of the experiment, the pieces of adipose tissue were again rinsed in
phosphate-buffered saline, collected, frozen in liquid nitrogen, and
stored at -70 C for subsequent RNA extraction. Aliquots (1.5 mL) of
medium were also saved and stored at -20 C for measurement of leptin
and glucose concentrations.
RNA extraction and Northern blot analysis
Total RNA was isolated with an acid guanidinium thiocyanate-phenol-chloroform mixture as previously described (23). The concentration of RNA was determined by absorbance at 260 nm. For Northern blot analysis, 10 µg RNA were denatured in a solution containing 2.2 mmol/L formaldehyde and 50% (vol/vol) formamide by heating at 95 C for 2 min. RNA was then size-fractionated by 1% (wt/vol) agarose gel electophoresis, transferred to a Hybond-N membrane (Amersham, Little Chalfont, UK), and cross-linked by UV irradiation. The integrity and relative amounts of RNA were assessed by methylene blue staining of the blots.
The complementary DNA (cDNA) probes for human ob and insulin-sensitive glucose transporter GLUT4 were provided by Dr. R. Devos (Roche, Gent, Belgium) and Dr. A. Leturque (Paris, France), respectively. Human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA (a gift from Dr. B. Lethe, ICP, Brussels, Belgium) was amplified by PCR using commercially available primers (Clontech, Palo Alto, CA). The filters were then exposed to Kodak X-Omat AR films (Eastman Kodak, Rochester, NY) for 4–24 h (ob and GAPDH) or 2–6 days (GLUT4) at -70 C with intensifying screens. Hybridizations with the different radiolabeled probes and subsequent washing of the membranes were performed as previously reported (23). The same filters were hybridized successively with the different probes. To normalize the amount of total RNA loaded on each lane, the blots were also hybridized with an oligonucleotide specific for ribosomal 18S RNA (24). Optical densities of the mRNA or ribosomal RNA bands on the blots were quantified by scanning densitometry (Sharp Scanner JX 325 combined with Image Master Software, Pharmacia, Uppsala, Sweden), and levels of specific mRNAs were expressed relative to those of ribosomal 18S RNA. Internal standards (pooled RNA from two or three patients) were always loaded on each gel to allow direct comparisons between different blots.
Leptin secretion
Leptin levels were measured in the culture medium by RIA, using a commercially available kit (Human Leptin RIA kit, DRG, Germany). Samples (100 µL) were run in duplicate. The sensitivity of the test was 0.25 ng/mL, and the limit of linearity was 100 ng/mL. Unless otherwise indicated, as media were renewed every day, the secretion rate was expressed as nanograms of leptin released per µg tissue DNA/24 h (over 0–24 or 24–48 h).
Analytical procedures
Glucose concentrations were measured in media, before and after culture, using a glucose oxidase method (glucose analyzer, Beckman, Fullerton, CA). The glucose consumption rate by explants was expressed as milligrams per µg tissue DNA/24 h. DNA was measured in fresh adipose tissue samples (50–100 mg) using a spectrofluorimetric method (25).
Presentation of the results
Results are the mean ± SEM for the indicated numbers of patients. Data that were not normally distributed (ob mRNA, leptin secretion, and GLUT4 mRNA) were first log transformed before statistical processing (26). Comparisons between groups (lean/obese) were carried out using unpaired Student’s t test, and comparisons between different conditions within a same group were made using paired Student’s t test or ANOVA followed by the Newman-Keuls test for multiple comparisons when appropriate. The correlation analysis was performed using Pearson’s test. Differences were considered statistically significant at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Before the culture, ob mRNA levels tended to be higher
in obese than in lean subjects (P = 0.07), in
agreement with previous reports (27, 28). Within the first 24 h of
culture, ob mRNA levels declined spontaneously in the
absence of dexamethasone. In contrast, in the presence of 50 nmol/L
dexamethasone, these levels increased in a time-dependent manner, and
the values reached after 24 and 48 h were greater in obese than in
lean patients (P < 0.05 or less). The cumulative
integrated ob mRNA responses [area under the curve and
above respective basal (i.e. without dexamethasone) levels]
were elevated about 5-fold in the obese group compared with those in
the lean subjects at both time points. In agreement with the results
with short term incubations (28), after 24 h of culture in the
absence of dexamethasone, the leptin secretion rate was faster in obese
than in lean subjects (P < 0.05), but this difference
disappeared after 48 h. With dexamethasone, the leptin secretion
accelerated in both groups from 24 h onward, with values again
higher (P < 0.05) in obese subjects at 24 and 48
h. The cumulative integrated leptin responses (stimulated minus basal
values) were thus about 2.5- and 4-fold greater in obese than in lean
patients at 24 and 48 h, respectively. Because of the lower
cellularity of obese fat [DNA in nanograms per g tissue: 204 ±
22 (n = 8) vs. 403 ± 81 (n = 9);
P < 0.05], which is probably due to an approximately
2-fold increase in fat cell size (28), when data were expressed per g
tissue, the difference in leptin responses between the two groups was
attenuated, but still remained significant at 48 h [cumulative
integrated leptin responses in nanograms per g: 248 ± 49 (n
= 8) in obese vs. 130 ± 25 (n = 9) in lean
subjects; P < 0.05].
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, there were
positive relationships between the BMI and the cumulative integrated
ob mRNA and leptin responses to 48-h dexamethasone treatment
(r = 0.77; P < 0.0005 and r = 0.57;
P < 0.05, respectively). Gender did not influence the
responses to glucocorticoids (not shown).
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). The
glucocorticoid was effective at concentrations above 1 nmol/L. The
maximal effect was obtained at about 50–100 nmol/L, and 50% of this
effect was observed at approximately 10 nmol/L. Compared to lean
subjects, absolute levels of ob mRNA and leptin were higher
in obese subjects for concentrations of 50 and 10 nmol/L dexamethasone
or greater, respectively. Although the absolute maximal response to
glucocorticoids was increased in obese subjects, the EC50
was roughly similar in both groups. Thus, the greater stimulation of
ob gene expression and leptin secretion produced by
dexamethasone in obesity has to be due to a greater responsiveness to
the hormone rather than to a change in sensitivity.
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Unlike dexamethasone, insulin did not affect ob mRNA and
leptin secretion from human visceral fat. Because similar results were
obtained in lean and obese subjects, the values of the groups were
pooled (Fig. 4).
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and 6). This inhibition was observed in both
lean and obese subjects, in whom it corresponded to 80–40% and
60–40% of respective values with 50 nmol/L dexamethasone alone. This
effect was already detectable at 10 nmol/L insulin (n = 4; not
shown).
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). After 48 h of culture, basal
levels of ob mRNA in subcutaneous fat exceeded those in
visceral fat, in agreement with data obtained in freshly isolated
tissue (29) (Fig. 7, upper panels). In the presence of
dexamethasone, ob mRNA levels increased and reached similar
values at both adipose tissue sites. However, the net stimulation
produced by the hormone (after subtraction of basal levels) tended to
be higher in visceral (maximum change in ob mRNA optical
density, 32 ± 14) than in subcutaneous (21 ± 6) fat. The
inhibitory effect of insulin on dexamethasone action was comparable in
both adipose regions. Changes in leptin levels paralleled those in
ob mRNA (Fig. 7, lower panels). Because of the
lower cellularity of subcutaneous fat compared to visceral fat
(107 ± 9 vs. 177 ± 18 ng DNA/g tissue;
P < 0.01; eight subjects, two lean and six obese),
leptin secretion rates were also expressed as nanograms per g tissue.
In this case, basal differences between regions disappeared (25 ng/g
tissue·24 h at both sites), but hormonal changes remained
qualitatively unmodified (not shown). Importantly, the secretion rates
obtained in subcutaneous fat on the second day of culture (25–125 ng/g
tissue·24 h; basal and dexamethasone-stimulated values) were close to
those found in man in vivo by a standard method of
arterio-venous balance in the same adipose region (30), an observation
that supports the validity of our model.
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). Thus,
insulin accelerated glucose consumption by cultured human fat, as
previously described (31), and increased the expression of GLUT4 and
GAPDH mRNA, in agreement with results obtained in primary cultured rat
adipocytes or clonal adipose cell lines (21, 32, 33). These stimulatory
effects were observed in lean patients only (Table 1 and Fig. 6
). In
obese insulin-resistant subjects, GLUT4 mRNA was so strikingly
decreased that the signal was not readily detectable even after long
term exposure of the blots (Table 1 and Fig. 6). This pretranslational
suppression of GLUT4 is consonant with data obtained in fresh tissue
from obese subjects (34).
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). As described in rats (21), cAMP
prevented the stimulatory effect of the glucocorticoid on ob
mRNA and leptin release (Table 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We confirm the stimulatory effect of glucocorticoids on ob gene and leptin secretion previously described in cultures of human subcutaneous adipocytes (6, 7). We extend these data to visceral fat, which plays a key role in obesity-linked metabolic abnormalities. In this fat depot, the net increment of ob mRNA and leptin induced by 50 nmol/L dexamethasone tended to be higher than that in subcutaneous fat. Moreover, dexamethasone was already effective at concentrations 1 or 2 orders of magnitude lower than those reported in mature subcutaneous adipocytes (7). These differences may be explained by the greater number of glucocorticoid receptors in visceral fat (35). Importantly, the EC50 for dexamethasone in this adipose region was about 10 nmol/L, a concentration that can be considered within a physiological range (if dexamethasone concentrations are converted into cortisol concentrations on the basis of their respective glucocorticoid potencies of 30:1). This finding strongly supports the concept of an interplay between glucocorticoids and leptin in human physiology. Low concentrations of glucocorticoids may stimulate the expression of the human ob gene. The increased secretion of leptin may, in turn, directly (36) or indirectly (via the central nervous system) (37, 38) inhibit the release of glucocorticoids. Thus, leptin would ultimately exert a negative feedback on its own expression by diminishing cortisol levels. This model could reconcile the hypothesis of a physiological role for glucocorticoids in leptin secretion with the inverse relationship found between plasma levels of the two hormones in man (8).
Repeated measurements of ob mRNA and leptin were performed in the present study. We show that qualitative changes in leptin secretion reflect the time- and dose-dependent increases in ob mRNA induced by dexamethasone. This unambiguously indicates that the glucocorticoid acts at the pretranslational level. This stimulation of ob gene expression was prevented by actinomycin D and thus could be mediated by enhanced transcription, probably through binding of the steroid-receptor complex to the glucocorticoid response element that has recently been identified in the regulatory region of the human ob gene (39). The stimulation was also blocked by cycloheximide and thus could require ongoing protein synthesis, an event possibly dependent on an actinomycin-sensitive step. As the inhibition by actinomycin was only partial whereas that by cycloheximide was complete, we cannot rule out the possibility that both actinomycin-sensitive and -insensitive mechanisms are ultimately involved in the glucocorticoid action. The lack of a cycloheximide effect on dexamethasone-induced accumulation of ob mRNA in the rat (21) emphasizes species differences in ob regulation.
Glucocorticoids more potently increase leptin secretion in obese than in lean individuals due to a greater responsiveness of the ob gene. Leptin seems to play a dual role in human physiology and to be subjected to dual control. Under chronic conditions of steady state energy balance, leptin is a static index of the amount of triglyceride stored in adipose tissue. Under nonsteady state energy balance situations, leptin may be acutely regulated by hormonal or nutritional changes (i.e. glucocorticoid administration, fasting, etc.) independently of the available adipose tissue triglyceride stores and may serve as a sensor of energy balance (40). We extend in vivo data from a small group of healthy women (4) and show that the dual regulation of leptin production operates not only alternately, but also simultaneously. Thus, dexamethasone induced a rapid rise in ob mRNA levels before any changes could have occurred in fat stores. However, this stimulation was amplified by already elevated amounts of energy reserves, as ob mRNA accumulation closely correlates with BMI and, hence, lipid content in fat cells. This is the first in vitro demonstration that factors both extrinsic and intrinsic to the adipocyte may operate in concert to ultimately modulate ob gene expression. The intrinsic factors that contribute to the overexpression of the ob gene in adipocytes from obese individuals in the presence of positive stimulus remain unknown. One may only speculate about the potential synergistic role of mechanical forces applied to the cell or of altered intracellular lipid metabolism as cell stretching or lipids may act as signaling intermediates (41).
The pathophysiological significance of increased responsiveness of ob gene expression to glucocorticoids in obesity is as yet unsettled. However, this phenomenon could contribute to the metabolic abnormalities associated with abdominal obesity. Omental fat cells can generate active cortisol, and central obesity may reflect Cushing’s disease of the omentum (42). In visceral fat from ob obese individuals, constant exposure and increased responsiveness of ob gene to corticoids may result in local and portal hyperleptinemia. This may, in turn, lead to perturbations of glucose homeostasis by para/endocrine mechanisms on adipocytes (in particular, through increased lipolysis) (22) and liver (through increased phosphoenolpyruvate carboxykinase expression) (43). In both cases, gluconeogenesis would be directly or indirectly stimulated. If hyperresponsiveness of ob gene to glucocorticoids also turned out to be true in subcutaneous fat, hyperleptinemia in obesity would reflect not only a resistance to central receptors, but also a primary alteration of adipocytes (i.e. abnormal steroid response).
Unlike dexamethasone, insulin added for up to 48 h to the medium had no stimulatory effect on human ob gene and leptin production in visceral fat, in agreement with a report on mature subcutaneous adipocytes (7). Thus, the increase in plasma leptin concentrations observed in some in vivo studies, after 4- to 8-h euglycemic-hyperinsulinemic clamps may be mediated indirectly. However, chronic (3- to 4-day) exposure to insulin (an experimental situation of massive overfeeding) was found to stimulate the leptin secretion rate in vivo and in vitro (16). Yet, this chronic effect of insulin was considered a consequence of the trophic action of the hormone on adipocytes rather than one of its classical metabolic responses. It may perhaps explain why insulin was found to be stimulatory in human stromal cells differentiated by chronic previous exposure to the hormone (6).
In cultured explants, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin while having its expected stimulatory effects on glucose utilization, GLUT4, and GAPDH mRNA species. This is consonant with data obtained in mature rat and human adipocytes (7, 21), but again contrasts with those in human adipocytes differentiated by chronic exposure to adipogenic cocktails containing high doses of these two hormones (6).
The hormonal regulation of the ob gene is the first example of a dominant inhibitory role of insulin over a stimulation induced by glucocorticoids in adipose tissue. However, this type of regulation is not uncommon in liver, as insulin inhibits the glucocorticoid-induced transcriptional stimulation of at least four genes: those for insulin-like growth factor-binding protein-1, phosphoenolpyruvate carboxykinase, PKF 2/FBPase-2, and peroxisomal acyl-coenzyme A oxidase (reviewed in Refs. 21 and 44). The mechanisms that could contribute to this singular inhibitory effect of insulin in fat tissue remain unknown. A lowering of the intracellular cAMP concentration is known to be involved in some of the effects of insulin in adipose tissue (45). This cannot account for the present findings, because increasing the cAMP concentrations in human fat cells also decreases ob expression and leptin production (in the absence or presence of corticoids). The inhibition by insulin was observed in both lean and obese subjects, whereas the stimulation of glucose metabolism occurred in lean patients only. This suggests that this inhibition is mediated via pathways that remain operative despite insulin resistance.
In conclusion, glucocorticoids stimulate leptin secretion from human visceral fat at the pretranslational level. This effect is more pronounced in obese subjects and could contribute to the metabolic abnormalities associated with central obesity.
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Acknowledgments |
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Footnotes |
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2 Chercheur Qualifié from the Fonds National de la Recherche
Scientifique.
Received September 19, 1997.
Revised November 5, 1997.
Accepted December 1, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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G. Van den Berghe, P. Wouters, F. Weekers, S. Mohan, R. C. Baxter, J. D. Veldhuis, C. Y. Bowers, and R. Bouillon Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1311 - 1323. [Abstract] [Full Text]
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and 
) and obese (O; 
and •) subjects cultured in MEM with (
-reductase type I and type II activities in
primary and cocultured fibroblast and epithelial cells derived from
human BPH.