Reversing adipocyte differentiation: implications for treatment of obesity.
(9/5124)
Conventional treatment of obesity reduces fat in mature adipocytes but leaves them with lipogenic enzymes capable of rapid resynthesis of fat, a likely factor in treatment failure. Adenovirus-induced hyperleptinemia in normal rats results in rapid nonketotic fat loss that persists after hyperleptinemia disappears, whereas pair-fed controls regain their weight in 2 weeks. We report here that the hyperleptinemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma in epididymal fat; enzymes of fatty acid oxidation and their transcription factor, PPARalpha, normally low in adipocytes, are up-regulated, as are uncoupling proteins 1 and 2. This transformation of adipocytes from cells that store triglycerides to fatty acid-oxidizing cells is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, tumor necrosis factor alpha, and leptin, and by the appearance of the preadipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype. (+info)
Leptin in CAPD patients: serum concentrations and peritoneal loss.
(10/5124)
BACKGROUND: To determine whether serum leptin concentrations in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are influenced by peritoneal loss of leptin and to compare serum leptin levels of normal subjects with those of patients receiving renal replacement therapy such as haemodialysis (HD), CAPD, or kidney transplantation. SUBJECTS AND METHODS: Eighty-four individuals were investigated: six females and 14 males on standard CAPD; 13 females and 13 males on chronic HD; 10 female and eight male kidney transplant recipients, and 10 female and 10 male subjects as controls. Morning serum, 8-h and 24-h samples of peritoneal fluid concentrated to 6-20-fold by Centricon 3 (cutoff 3000 daltons), and 24-h urinary concentrations of leptin were measured with commercial RIA (Linco Research, Inc., USA). Venous blood and peritoneal fluid samples of albumin, beta2-microglobulin, glucose, urea, and creatinine were determined by standard laboratory techniques. Serum insulin levels were measured by radioimmunoassay. RESULTS: Patients (men and women) on CAPD and after kidney transplantation exhibited significantly higher serum concentrations of leptin and leptin/BMI ratios than control subjects. These increased values did not reach statistical significance in HD patients. Serum leptin concentrations were correlated very significantly with BMI in all cases (r=0.380, P<0.001). Moreover, in CAPD patients (r=0.630, P<0.007) and in HD patients (r=0.668, P<0.005), but not in kidney transplant recipients or control subjects, significant correlations were observed between serum leptin and insulin concentrations. Residual renal function (RRF) in the range 0-12.8 ml/min and serum beta2-microglobulin levels in the range 7.9-47.1 mg/l did not influence serum leptin levels in CAPD and HD patients. As expected, leptin was detected in the peritoneal fluid of CAPD patients. Twenty-four-hour peritoneal loss (30.95+/-21.05 ng/min) and 24-h peritoneal clearance (0.01+/-0.01 ml/kg/min) of leptin account for only 3.9% of estimated whole-body leptin production rate and 0.7% of leptin clearance from plasma respectively. Twenty-four-hour urinary losses of leptin in CAPD patients were negligible, accounting for 5.6+/-1.8% (range 0.3-15.2%) of total (peritoneal and urinary) loss of this hormone. CONCLUSIONS: These findings suggest that serum leptin levels are not affected by continuous peritoneal loss of leptin during CAPD and that insulin resistance and hyperinsulinaemia contribute to elevated serum leptin concentrations in CAPD and HD patients. The aetiology of increased serum leptin levels in kidney transplant recipients is probably different from that in dialysis patients. (+info)
Analysis of the relationship between fasting serum leptin levels and estimates of beta-cell function and insulin sensitivity in a population sample of 380 healthy young Caucasians.
(11/5124)
OBJECTIVE: Circulating leptin levels correlate positively with the degree of obesity and prolonged hyperinsulinaemia increases serum leptin levels. Moreover, insulin secreting beta-cells express functional leptin receptors indicating a functional relationship between leptin and insulin. The aim of this study was to examine the relationship between fasting serum leptin levels and measures of insulin sensitivity and beta-cell function in a population-based sample of 380 young healthy Caucasians. DESIGN AND METHODS: Multiple regression analysis was employed to analyse the relationship between fasting serum leptin levels and levels of fasting serum insulin, insulin sensitivity index and acute insulin response (AIR) in a population-based study of 380 young healthy Caucasians who underwent a combined intravenous glucose and tolbutamide tolerance test. RESULTS AND CONCLUSION: Serum leptin levels were positively correlated to measures of adiposity and were 3.2 times higher in women than in men (P<0.00001). In multiple regression analyses adjusting for age, percentage body fat, waist circumference and maximal aerobic capacity, a significant positive correlation was observed between the fasting serum leptin concentrations and both fasting serum insulin levels (P<0.0001) and AIR (P = 0.014) for women. No significant interrelation of these variables was found in men. However, for both genders a significant negative correlation was observed between fasting serum leptin levels and measures of insulin sensitivity index (P = 0.007). (+info)
Effect of leptin deficiency on metabolic rate in ob/ob mice.
(12/5124)
Reduced metabolic rate may contribute to weight gain in leptin-deficient (ob/ob) mice; however, available studies have been criticized for referencing O2 consumption (VO2) to estimated rather than true lean body mass. To evaluate whether leptin deficiency reduces energy expenditure, four separate experiments were performed: 1) NMR spectroscopy was used to measure fat and nonfat mass, permitting VO2 to be referenced to true nonfat mass; 2) dietary manipulation was used in an attempt to eliminate differences in body weight and composition between ob/ob and C57BL/6J mice; 3) short-term effects of exogenous leptin (0.3 mg. kg-1. day-1) on VO2 were examined; and 4) body weight and composition were compared in leptin-repleted and pair-fed ob/ob animals. ob/ob animals had greater mass, less lean body mass, and a 10% higher metabolic rate when VO2 was referenced to lean mass. Dietary manipulation achieved identical body weight in ob/ob and C57BL/6J animals; however, despite weight gain in C57BL/6J animals, percent fat mass remained higher in ob/ob animals (55 vs. 30%). Exogenous leptin increased VO2 in ob/ob but not control animals. Weight loss in leptin-repleted ob/ob mice was greater than in pair-fed animals (45 vs. 17%). We conclude, on the basis of the observed increase in VO2 and accelerated weight loss seen with leptin repletion, that leptin deficiency causes a reduction in metabolic rate in ob/ob mice. In contrast, these physiological studies suggest that comparison of VO2 in obese and lean animals does not produce useful information on the contribution of leptin to metabolism. (+info)
Plasma leptin concentrations in obese children: changes during 4-mo periods with and without physical training.
(13/5124)
BACKGROUND: Little is known about the effects of physical training on plasma leptin concentrations in children. OBJECTIVE: We sought to determine the effects of 4-mo periods with and without physical training on leptin in obese children and to explore the determinants of leptin at baseline and in response to physical training. DESIGN: Participants were 34 obese 7-11-y-old children randomly assigned to engage in physical training during either the first or second 4 mo of the 8-mo study. RESULTS: Total body composition, visceral adiposity, and insulin were all positively correlated with leptin at baseline (P < or = 0.05); however, only fat mass was retained in the final stepwise regression (P = 0.0001, R2 = 0.57). Leptin decreased during the 4-mo periods of physical training and increased in the 4 mo after cessation of physical training (P < 0.001 for the time by group interaction). Decreases in leptin were greatest in children with higher pretraining leptin concentrations, those whose total mass increased least, and those whose insulin concentrations decreased most (P < or = 0.05); only pretraining leptin concentration (P = 0.009) and change in total mass (P = 0.0002) were retained in the final regression (R2 = 0.53). CONCLUSIONS: In obese children, leptin concentration decreased during 4 mo of physical training and increased during a subsequent 4-mo period without physical training, fat mass was highly correlated with baseline leptin, and greater reductions in leptin during 4 mo of physical training were seen in children with higher pretraining leptin and in those whose total mass increased least. (+info)
Dihydrotestosterone, stanozolol, androstenedione and dehydroepiandrosterone sulphate inhibit leptin secretion in female but not in male samples of omental adipose tissue in vitro: lack of effect of testosterone.
(14/5124)
Leptin, the product of the Ob gene, is a polypeptide hormone expressed in adipocytes which acts as a signalling factor from the adipose tissue to the central nervous system, regulating food intake and energy expenditure. It has been reported that circulating leptin levels are higher in women than in men, even after correction for body fat. This gender-based difference may be conditioned by differences in the levels of androgenic hormones. To explore this possibility, a systematic in vitro study with organ cultures from human omental adipose tissue, either stimulated or not with androgens (1 microM), was undertaken in samples obtained from surgery on 44 non-obese donors (21 women and 23 men). The assay was standardized in periods of 24 h, ending at 96 h, with no apparent tissue damage. Leptin results are expressed as the mean+/-s.e.m. of the integrated secretion into the medium, expressed as ng leptin/g tissue per 48 h. Spontaneous leptin secretion in samples from female donors (4149+/-301) was significantly higher (P<0.01) than that from male donors (2456+/-428). Testosterone did not exert any significant effect on in vitro leptin secretion in either gender (4856+/-366 in women, 3322+/-505 in men). Coincubation of adipose tissue with dihydrotestosterone (DHT) induced a significant (P<0.05) leptin decrease in samples taken from women (3119+/-322) but not in those taken from men (2042+/-430). Stanozolol, a non-aromatizable androgen, decreased (P<0.05) leptin secretion in female samples (2809+/-383) but not in male (1553+/-671). Dehydroepiandrosterone sulphate (DHEA-S) induced a significant (P<0.01) leptin decrease in female samples (2996+/-473), with no modifications in samples derived from males (1596+/-528). Exposure to androstenedione also resulted in a significant reduction (P<0.01) of leptin secretion in samples taken from women (2231+/-264), with no effect on male adipose tissue (1605+/-544). In conclusion, DHT, stanozolol, DHEA-S and androstenedione induced a significant inhibition of in vitro leptin secretion in samples from female donors, without affecting the secretion in samples from men. Testosterone was devoid of activity in either gender. (+info)
Serum leptin is associated with the perception of palatability during a standardized high-carbohydrate breakfast test.
(15/5124)
Leptin is an adipocyte-derived signalling molecule which plays a key role in the regulation of body weight and energy expenditure. Since its involvement in human eating behaviour is still poorly understood, we investigated whether the perception of palatability of food was related to fasting serum leptin levels. Twenty-six non-diabetic subjects, six men and twenty women of widely ranging age and body mass index, performed a standardized high-carbohydrate breakfast test. Palatability was evaluated with a visual analogue scale, body composition by bioelectrical impedance, serum leptin and plasma insulin by radioimmunoassay. Palatability was correlated to fasting serum leptin levels independently of body mass index, body fat mass and percentage of body fat (P<0.01). No significant relation was observed with peaks of insulinaemia, integrated concentrations of insulin or insulin resistance indices. A stepwise regression analysis indicated that serum leptin gave the strongest predictive association with palatability. These results suggest that the leptin system may be involved in the regulation of human eating behaviour in relation to the perception of palatability of food. (+info)
Transcriptional regulation of fatty acid synthase gene by insulin/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats.
(16/5124)
Transcriptional regulation of the fatty acid synthase (FAS) gene by insulin/glucose, polyunsaturated fatty acids and leptin was investigated in hepatocytes and adipocytes of Wistar fatty rats and their lean littermates. The sequence spanning nucleotides -57 to -35 of FAS gene, which is responsive to insulin/glucose stimulation [Fukuda, H., Iritani, N. & Noguchi, T. (1997) FEBS Lett. 406, 243-248], was linked to a reporter gene containing a heterologous promoter and transfected into rat hepatocytes or adipocytes. The activity of the reporter, chloramphenicol acetyltransferase, in the presence of glucose alone was similar in the primary cultured cells from the lean and obese rats. In the presence of insulin/glucose, however, chloramphenicol acetyltransferase activity was markedly increased in hepatocytes of lean rats, but was not significantly increased in those of obese rats. The stimulation by insulin/glucose was reduced in arachidonic acid-treated cells of lean rats. Similarly, the stimulation by insulin/glucose was reduced in leptin-treated cells and in cells from lean rats containing an expression vector encoding leptin. However, neither polyunsaturated fatty acids nor leptin-treated cells from obese rats responded to insulin-stimulation. The same effects were observed at endogenous FAS mRNA and enzyme levels. Similar results were seen in adipocytes, although the stimulation and suppression were much smaller than in hepatocytes. The insulin-binding capacities of the receptors of liver and adipose tissue were reduced in the presence of leptin or polyunsaturated fatty acids. Leptin and polyunsaturated fatty acids appeared to suppress the insulin stimulation of FAS transcription by reducing the insulin-binding capacities of receptors. Leptin converged on the insulin/glucose response element of FAS gene and suppressed the transcription. (+info)