Biomedical subjects

M Guerre-Millo

Publications and source records attributed to M Guerre-Millo.

At least 19 recordsLinked to original sources

PubMed2002

Hypoxia increases leptin expression in human PAZ6 adipose cells.

AIMS/HYPOTHESIS: Leptin, an adipose tissue-derived cytokine involved in the control of body weight, also participates in a variety of biological functions, including angiogenesis. Because reduced oxygen availability is a major inducer of angiogenesis, we hypothesized that low cellular oxygen tension could regulate leptin expression in adipose cells. METHODS: Differentiated PAZ6 adipocytes were cultured for 48 h in the presence of chemical inducers of cellular hypoxia (cobalt chloride or desferrioxamine) or in an atmosphere containing only 6% oxygen. The effect of hypoxia on the expression of leptin and several adipose genes was assessed by semi-quantitative RT-PCR. The effect of hypoxia on leptin promoter activity was tested in PAZ6 cells transiently transfected with a luciferase reporter construct, containing 1.87 kb of the human leptin promoter. Leptin secretion in the culture medium was determined by radioimmunoassay. RESULTS: Hypoxia increased leptin mRNA expression, leptin promoter activity and leptin secretion in the culture medium by two- to threefold ( p<0.05). The expression of the glucose transporter isoform 1 (GLUT-1) mRNA, a well known hypoxia inducible gene, was also increased. In contrast, glucose transporter isoform 4 (GLUT-4), hormone sensitive lipase (HSL), fatty acid binding protein (aP2) and uncoupling protein 2 (UCP2) mRNAs were markedly reduced by hypoxia. In addition, a similar hypoxia-induced increase in leptin mRNA and secretion was observed in primary rat adipose cells. CONCLUSION/INTERPRETATION: Hypoxia markedly and specifically increased leptin gene expression through activation of the leptin gene promoter, and this resulted in an increased leptin production by human PAZ6 adipocytes.

Adipose Tissue↗

PubMed2002

Adipose tissue hormones.

It is now widely accepted that white adipose tissue (WAT) secretes a number of peptide hormones, including leptin, several cytokines, adipsin and acylation-stimulating protein (ASP), angiotensinogen, plasminogen activator inhibitor-1 (PAI-1), adiponectin, resistin etc., and also produces steroids hormones. This newly discovered secretory function has shifted our view of WAT, which is no longer considered only an energy storage tissue but a major endocrine organ, at the heart of a complex network influencing energy homeostasis, glucose and lipid metabolism, vascular homeostasis, immune response and even reproduction. Virtually all known adipose secreted proteins are dysregulated when the WAT mass is markedly altered, either increased in the obese state or decreased in lipoatrophy. This strongly implicates adipose-secreted products in the ethiopathology and/or complications of both obesity and cachexia. This review discusses the physiological relevance of adipose secretion by focusing on protein and steroid hormones. Regulation of WAT secretion by the major regulatory factors impinging on the adipocytes, i.e. insulin, glucocorticoids, catecholamines and thiazolidinediones (TZD) will be addressed. The rationale for therapeutic strategies aimed at compensating adverse effects resulting from overproduction or lack of a specific adipose secretory product will be discussed.

Adipose Tissue↗

PubMed2002

Regulation of glucose transport and transporter 4 (GLUT-4) in muscle and adipocytes of sucrose-fed rats: effects of N-3 poly- and monounsaturated fatty acids.

The goal of this study was to compare the short-term effects of dietary n-3 polyunsaturated (fish oil) and monounsaturated (olive oil) fatty acids on glucose transport, plasma glucose and lipid controls in a dietary insulin resistance model using sucrose-fed rats. The underlying cellular and molecular mechanisms were also determined in the muscle and adipose tissue. Male Sprague-Dawley rats (5 weeks old) were randomized for diets containing 57.5 % (w/w) sucrose and 14 % lipids as either fish oil (SF), olive oil (SO) or a mixture of standard oils (SC) for 3 weeks. A fourth control group (C) was fed a diet containing 57.5 % starch and 14 % standard oils. After three weeks on the diet, body weight was comparable in the four groups. The sucrose-fed rats were hyperglycemic and hyperinsulinemic in response to glucose load. The presence of fish oil in the sucrose diet prevented sucrose-induced hyperinsulinemia and hypertriglyceridemia, but had no effect on plasma glucose levels. Insulin-stimulated glucose transport in adipocytes increased after feeding with fish oil (p < 0.005). These modifications were associated with increased Glut-4 protein (p < 0.05) and mRNA levels in adipocytes. In the muscle, no effect was found on Glut-4 protein levels. Olive oil, however, could not bring about any improvement in plasma insulin, plasma lipids or Glut-4 protein levels. We therefore conclude that the presence of fish oil, in contrast to olive oil, prevents insulin resistance and hypertriglyceridemia in rats on a sucrose diet, and restores Glut-4 protein quantity in adipocytes but not in muscle at basal levels. Dietary regulation of Glut-4 proteins appears to be tissue specific and might depend on insulin stimulation and/or duration of dietary interventions.

Adipocytes↗

PubMed2001

Transcriptional effect of hypoxia on placental leptin.

We observed recentlyl that placental leptin is markedly increased in preeclampsia. Since this disorder is associated with vascular disorders, we have tested the hypothesis that hypoxia regulates leptin expression. We show that hypoxia increased leptin mRNA and secretion in trophoblast-derived BeWo cells. This effect was mediated through leptin promoter activation. 5' deletion analysis allowed us to delineate two regions containing 1.87 kb and 1.20 kb of the promoter which conferred respectively high and low responsiveness to hypoxia. These data indicate that leptin is up-regulated by hypoxia through a transcriptional mechanism likely to involve distinct hypoxia-responsive cis-acting sequences on the promoter.

Adipose Tissue↗

PubMed2001

Molecular and cellular mechanisms of adipose secretion: comparison of leptin and angiotensinogen.

Besides their function of lipid storage, the adipose cells secrete a number of proteins of physiopathological importance. To get further insights into this function, which remains poorly characterized, we sought to compare the mechanisms and regulation of secretion of two individual proteins in the same cells. Leptin and angiotensinogen were chosen and assessed by radioimmunoassay and quantitative immunoblotting, respectively, in primary culture of epididymal adipose cells from young obese Zucker rats. Leptin was secreted at a steady rate of 4 ng/10(6) cells/h over 2-6 h. Despite secretion, leptin cellular content remained stable at 3 ng/10(6) cells. In contrast, the rate of angiotensinogen secretion decreased regularly from 45 arbitrary units/10(6) cells/h at 2 h, to half this value at 6 h, although cell content remained constant at 100 arbitrary units/10(6) cells. Inhibition of protein synthesis by cycloheximide depleted the cells from leptin, but not from angiotensinogen for up to 6 h. Insulin increased leptin secretion (+75%) and cell content (+70 %), without affecting angiotensinogen. Secretion of both proteins was inhibited by Golgi-disturbing agents, brefeldin A and monensin. The presence of brefeldin A led to a specific rise in leptin cell content, an effect inhibited by cycloheximide and enhanced by insulin (+80%). These data show that leptin and angiotensinogen are both secreted through Golgi-dependent pathways and that their respective intracellular pool exhibit distinct turn-over rate and insulin sensitivity. These characteristics might account for the differential response of these adipose proteins to variations in the systemic environment.

Adipocytes↗

PubMed2001

Prenatal leptin production: evidence that fetal adipose tissue produces leptin.

In the adult, circulating leptin is highly correlated to adipose tissue mass. Whether such a relationship exists prenatally is unknown, because the actual source of fetal leptin has not been determined. In the present study, we have assessed the placental contribution to fetal and maternal circulating leptin concentrations and determined whether fetal adipose tissue produces leptin. The rate of leptin production in dually perfused human placenta was 0.036 ng/min.g. Ninety-five percent of the leptin released was delivered into the maternal circulation, vs. only 5% on the fetal side. Leptin messenger RNA and protein were detected in adipose tissue biopsies of 20-38 week human fetuses. However, leptin concentration was twice lower in fetal (0.22 +/- 0.11 ng/mg protein, n = 6) than in adult (0.49 +/- 0.12 ng/mg protein, n = 8) adipose tissue. Umbilical leptin levels closely reflected ponderal index at birth over a wide range of birth weights (1.6--4.1 kg). In sharp contrast, maternal and placental leptin concentrations were increased in pregnancies associated with fetal growth retardation. We conclude that umbilical leptin levels are independent of placental leptin production and can be taken as a marker of fat mass in human fetuses. By contrast, placental leptin production makes a substantial contribution to maternal circulating leptin levels during pregnancy.

Adipose Tissue↗

PubMed2001

PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance.

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-alpha-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-alpha-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wild-type mice, whereas it remained unchanged in PPAR-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-alpha genotype. These data suggest that PPAR-alpha plays a role for the development of IR in response to a Western-type high-fat diet.

1-Methyl-3-isobutylxanthine↗

PubMed2000

Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.

Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPARalpha. To determine whether PPARalpha activators also improve insulin sensitivity, we measured the capacity of three PPARalpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPARalpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPARalpha activation in vivo was demonstrated by marked alterations in the expression of PPARalpha target genes, whereas PPARgamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARalpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.

Adipose Tissue↗

PubMed2000

Negative regulation of leptin by chronic high-glycemic index starch diet.

The response of plasma leptin to a high-glycemic index (high-GI) starch diet after a short (3 weeks) and prolonged (12 weeks) period was determined in Sprague-Dawley rats. Age-matched rats were fed an identical isocaloric diet except that the carbohydrates were from either mung bean starch (low-GI) or waxy cornstarch (high-GI). After a single test meal of the high-GI starch diet, postprandial plasma glucose (P < .05) and insulin (P < .01) peaks and plasma glucose (P < .014) and insulin (P < .05) areas were higher versus the low-GI starch diet (n = 8 per group). Other age-matched control rats were fed the same diets for a longer period. After 3 weeks, ob mRNA levels were decreased by 50% (P < .005) in the epididymal adipose tissue of high-GI-fed rats versus low-GI-fed rats, without a significant decrease in plasma leptin. After 12 weeks of the high-GI starch diet, both plasma leptin and ob mRNA were decreased by 34% (P < .005) and 41% (P < .05), respectively, compared with the low-GI diet. Both relative epididymal adipose tissue weight (adjusted per 100 g body weight) and total fat mass, as measured by dual-energy x-ray absorptiometry (DEXA), were unchanged by the high-GI starch diet. Basal nonfasting plasma insulin, glucose, and triglycerides were not altered by the high-GI starch diet, whereas free fatty acids were significantly elevated and associated with a trend (P < .13) for increased plasma free glycerol. Plasma leptin levels were negatively correlated with free fatty acid levels (r = .56, P < .05). Despite low leptin, rats fed on the high-GI diet did not increase their food intake, suggesting increased leptin sensitivity. These findings might precede weight gain and the increase in fat mass. Chronic nutritional factors might alter plasma leptin via several overlapping factors independently of energy intake.

Adipose Tissue↗

PubMed1998

The stomach is a source of leptin.

The circulating peptide leptin, which is the product of the ob gene, provides feedback information on the size of fat stores to central Ob receptors that control food intake and body-weight homeostasis. Leptin has so far been reported to be secreted only by adipocytes and the placenta. Here we show that leptin messenger RNA and leptin protein are present in rat gastric epithelium, and that cells in the glands of the gastric fundic mucosa are immunoreactive for leptin. The physiological function of this previously unsuspected source of leptin is unknown. However, both feeding and administration of CCK-8 (the biologically active carboxy-terminal end of cholecystokinin) result in a rapid and large decrease in both leptin cell immunoreactivity and the leptin content of the fundic epithelium, with a concomitant increase in the concentration of leptin in the plasma. These results indicate that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety.

Adipocytes↗

PubMed1998

[Hexose transporters in humans: their role in insulin sensitivity of peripheral tissues].

UNLABELLED: OBJECTIVES AND JUSTIFICATION: To describe facilitated diffusion glucose transporters (GLUT) in humans, and particularly the regulation of GLUT4 expression since it is predominantly responsible for insulin-mediated glucose transport in muscle and adipose tissue, and plays a crucial role in whole-body glucose homeostasis. MAIN POINTS: Numerous studies have shown abnormal expression of GLUT4 in insulin responsive tissues in diabetes mellitus and other insulin resistant states. The recent development of transgenic mice that overexpress GLUT4 in muscle, adipose tissue, or both has also emphasized the importance of GLUT4 in glucose homeostasis. PERSPECTIVES AND PROJECTS: The studies performed in transgenic mice suggest that strategies to increase GLUT4 transporters in insulin responsive tissues may lead to new therapeutic possibilities to improve insulin sensitivity in insulin resistant states such as non-insulin-dependent diabetes mellitus. CONCLUSIONS: Glucose transport is a crucial process in mammals, which needs specific transmembrane hexose transporters. Each transporter is important in the regulation of glucose homeostasis. Advances in the knowledge of both the action and the regulation of the glucose transport system may provide new insights for the development of therapeutic interventions in diseases such as obesity or diabetes mellitus.

Adipose Tissue↗

PubMed1998

Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation.

The tubby strain of mice exhibits maturity-onset obesity and sensory deficits in vision and hearing. The mutated gene, tub , responsible for this phenotype was identified recently, but the function of the TUB protein has not been deduced from its amino acid sequence. This prompted us to undertake expression mapping studies with the hope that they might help to elucidate the biological role of the TUB protein. We report the tub gene expression pattern in embryonic, fetal and adult mice tissues as determined by northern blots and in situ hybridization, using antisense oligonucleotidic probes. In mouse embryos, tub is expressed selectively in differentiating neurons of the ensemble of central and peripheral nervous systems, starting at 9.5 days after conception. In adult mice, tub is transcribed in several major brain areas, including cerebral cortex, hippocampus, several nuclei of the hypothalamus controlling feeding behavior, in the spiral ganglion of the inner ear and in the photoreceptor cells of the retina. These structures contain potential cellular targets of the tubby mutation-induced pathogenesis. The neuronal-specific tub gene distribution allows the establishment of a genotype-phenotype correlation in the tubby mice. This correlation is reminiscent of that observed in fat/fat mice, whose phenotype, also characterized by obesity, is caused by a null mutation in the carboxypeptidase E (CPE) gene. Our observations highlight similarities between CPE, prohormone convertases, several neuropeptides and tub gene expression patterns during embryogenesis, and may narrow down the avenues to explore in order to determine ultimately the function of the TUB protein.

Adaptor Proteins, Signal Transducing↗

PubMed1998

A high glycemic index starch diet affects lipid storage-related enzymes in normal and to a lesser extent in diabetic rats.

The of this study was to evaluate the chronic effects of a high (waxy corn) vs. a low (mung beans) glycemic index starch diet on the lipogenic enzymes, fatty acid synthase (FAS) and lipoprotein lipase (LPL). Normal and diabetic (streptozotocin-injected on d 2 of life) male Sprague-Dawley rats consumed a diet containing 575 g/kg carbohydrates either as waxy cornstarch (WCS) or as mung bean starch (MBS). After 3 wk, neither body weights nor relative epididymal fat pad weights differed. In diabetic rats, the WCS diet induced high basal plasma insulin levels. Plasma triglycerides were not significantly affected by diet in either normal or diabetic rats. Adipose tissue and liver LPL activities were not modified by the type of starch in the diet. In normal rats, FAS activity and gene expression in epididymal adipose tissue but not in liver were greater in rats consuming the WCS diet than in those consuming MBS. To evaluate the implication of insulin in this regulation, two genes regulated by insulin [GLUT4 and phosphoenolpyruvate carboxykinase (PEPCK)] were also studied. The high glycemic index WCS diet compared with the low glycemic index MBS diet resulted in lower hepatic PEPCK mRNA in both normal and diabetic rats. Normal, but not diabetic rats fed WCS had greater GLUT4 gene expression in adipocytes than did those fed MBS. We conclude that the total replacement of 575 g/kg low glycemic index starch by a high glycemic index starch for 3 wk caused the following in normal rats: 1) high FAS activity and mRNA in adipose tissue but not in liver and 2) high GLUT4 gene expression in adipose tissue. In both normal and diabetic rats this same diet resulted in lower hepatic PEPCK mRNA. Therefore, high glycemic index starch diet is implicated in stimulating FAS activity and lipogenesis and might have undesirable long-term metabolic effects.

Adipose Tissue↗

PubMed1998

Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans.

The recently discovered adipose cell-specific hormone called leptin decreases food intake and increases energy expenditure in rodents through a pathway involving hypothalamic leptin receptors, OB-R. In addition, leptin decreases insulin circulating levels independent of the reduction in food intake. Whether or not the hormone has a direct effect on pancreatic beta-cells is not clear, because previous in vitro studies have led to controversial results depending on the animal model used. The present study was designed to investigate the effects of leptin in islets of Langerhans isolated from normal rodents. Three isoforms of the leptin receptor, OB-Ra, b, and f, were detected by RT-PCR analysis of total RNA from rat islets. In static incubations, leptin (10 ng/ml) did not alter basal insulin secretion nor insulin secretion stimulated by glucose alone, potassium chloride, or ketoisocaproic acid. In contrast, insulin secretion stimulated by glucose + 3-isobutyl 1-methylxanthine (IBMX) was inhibited by 34 +/- 15% (n = 4, P < 0.05). This was further substantiated in perifusion experiments, in which leptin decreased by 31 +/- 3% (n = 5, P < 0.01) glucose + IBMX-stimulated insulin release. Similarly, in mouse islets a significant inhibitory effect of leptin (-31 +/- 4%, n = 6, P < 0.05) was observed only on glucose + IBMX-stimulated insulin secretion, with no effect of the hormone on basal nor glucose-stimulated secretion. Finally, leptin was totally inefficient in islets isolated from obese fa/fa rats, which bear a mutation in OB-R. These results suggest that, in normal rodent islets, leptin specifically inhibits IBMX-potentiated glucose-induced insulin secretion, through a direct effect involving at least one of the three isoforms of OB-R expressed in islets.

1-Methyl-3-isobutylxanthine↗

PubMed1998

Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Results of a controlled study.

OBJECTIVE: To evaluate the effect of a moderate dose of fish oil on glycemic control and in vivo insulin action in type 2 diabetic men with elevated plasma triacylglycerols and to determine the effect of the same treatment on gene expression of GLUT4, lipoprotein lipase (LPL), and hormone-sensitive lipase (HSL) in the abdominal adipose tissue. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic men were randomly allocated to 2 months of 6 g daily of either fish oil or sunflower oil, separated by a 2-month washout interval, in a double-blind crossover design. RESULTS: For glucose metabolism, 2 months of fish oil supplementation compared with sunflower oil led to similar fasting plasma insulin, glucose, and HbA1c. Basal hepatic glucose production did not increase after fish oil. There was no difference in insulin suppression of hepatic glucose production nor in insulin stimulation of whole-body glucose disposal measured by the euglycemic-hyperinsulinemic clamp. Fish oil did not ameliorate the low mRNA level of GLUT4 in adipose tissue of these patients. For lipid profile, fish oil lowered plasma triacylglycerol more than sunflower oil (P < 0.05) and tended to increase the amount of mRNA of both LPL and HSL in adipose tissue. CONCLUSIONS: A moderate dose of fish oil did not lead to deleterious effects on glycemic control or whole-body insulin sensitivity in type 2 diabetic men, with preserved triacylglycerol-lowering capacities.

Basal Metabolism↗

PubMed1998

Does leptin regulate insulin secretion?

The hormone leptin secreted by adipocytes plays a major role in body weight homeostasis. Its main target is the hypothalamus, but it also affects several peripheral tissues directly. The direct effect of leptin on insulin secretion by pancreatic beta cells has been investigated in several studies, though with controversial results. Interpretation of these data must take into account the animal model and the leptin concentrations used. Experiments carried out on islets from ob/ob mice harbouring a mutation in the leptin gene are not representative of the leptin effect in normal animals because ob/ob islets are very sensitive to the hormone and show altered regulation of insulin secretion. In normal rodent islets, physiological concentrations of leptin seem to inhibit insulin secretion only when the islets are maximally stimulated with high concentrations of glucose associated with secretion potentiators. Several isoforms of the leptin receptor are expressed in pancreatic beta cells. Indirect experimental evidence suggests that leptin signalling in islets requires the long isoform of the receptor. The molecular mechanisms underlying the effect of leptin on insulin secretion are unknown. Our hypothesis is that physiological concentrations of leptin in normal rodents do not affect the direct pathway (coupling a rise in glucose concentration to insulin secretion) but modulate a potentiation of glucose-induced insulin secretion involving cyclic AMP or phospholipase C/protein kinase C activation.

Adipocytes↗

PubMed1997

Rab 3D in rat adipose cells and its overexpression in genetic obesity (Zucker fatty rat).

Members of the Rab 3 subfamily of low-molecular-mass GTP-binding proteins have been functionally implicated in regulated exocytosis. The aim of the present study was to examine the subcellular distribution of a member of this family, Rab 3D, in rat adipose cells, given the hypothesis that this protein might be involved in insulin-stimulated GLUT4 exocytosis. We show that Rab 3D immunoreactivity is associated predominantly with the high-density microsomal fraction, where the signal intensity is 3- and 7-fold greater than that in plasma membranes and low-density microsomes respectively. Rab 3D does not co-localize with GLUT4 on immuno-isolated intracellular vesicles and, unlike GLUT4, it is not redistributed in response to insulin. Thus, if Rab 3D plays a role in GLUT4 trafficking, it relies on mechanisms independent of relocation. We observed that Rab 3D is overexpressed in adipose cells of obese (fa/fa) Zucker rats, in a tissue- and isoform-specific manner. The pathophysiological significance of this defect remains elusive. This could form the molecular basis for altered adipose secretory function in obesity.

Adipose Tissue↗

PubMed1997

Regulation of ob gene and overexpression in obesity.

The ob gene product, called leptin, is a recently discovered hormone secreted by the adipose cells. By acting as a satiety factor and increasing energy expenditure, leptin plays a major role in body weight homeostasis in mice. Ob gene and leptin production by the adipose cells are under the control of various hormonal and metabolic factors. Ob mRNA levels are markedly reduced by fasting and restored to normal by refeeding. High-fat feeding increases ob gene and plasma leptin, and induces a state of resistance to leptin. Two hormones, insulin and corticosterone, increase leptin production in rodent and human adipose cells. In contrast, the activity of the sympathetic nervous system exerts an opposite effect, mainly through activation of the adipose beta 3-adrenergic receptors. Leptin synthesis is also decreased by thiazolidinediones, a new class of antidiabetic drugs. The obese Zucker fa/fa rats bear a mutation in the leptin receptor gene (OB-R) and are leptin resistant. In these rats, ob mRNA levels are increased early in life and are not reduced by fasting. This suggests that functional OB-Rs are required for the generation of the signal(s) that downregulates ob gene expression in the adipose cell. The extent to which this is relevant to human obesities, which are characterized by increased leptin levels, remains to be determined.

Adipocytes↗