Taken together, our data demonstrate that inhibition of peripheral CB1R action in adipocytes directly promotes transdifferentiation of white adipocytes into a mitochondria-rich, thermogenic brown fat phenotype. Enhanced thermogenesis and insulin sensitivity may represent a peripheral mechanism contributing to weight loss and improved glucose homeostasis in rimonabant-treated patients.

The melanocortin (MC) system is a pivotal component of the hypothalamo-pituitary-adrenal (HPA) stress axis and plays an important role in the pathogenesis of obesity and the metabolic syndrome. Adipose dysfunction is implicated in the pathogenesis of these disorders. We investigated direct ACTH effects on adipose functions in immortalised murine white and brown adipocytes. MC receptor types 2 and 5 were expressed at the mRNA and protein levels and were strongly up-regulated during differentiation. Chronic ACTH stimulation did not affect adipogenesis. Insulin-induced glucose uptake in white adipocytes was acutely and transiently reduced by 45% upon ACTH treatment. Visfatin and adiponectin gene expression was reduced by about 50% in response to ACTH, while interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were acutely up-regulated by 2100 and 60% respectively. Moreover, IL-6 secretion was increased by 1450% within 4 h of ACTH treatment. In brown adipocytes, stimulation with ACTH caused a 690% increase in uncoupling protein (UCP)-1 mRNA levels within 8 h, followed by a 470% increase in UCP-1 protein concentrations after 24 h. Consistently, p38 mitogen-activated protein kinase (MAPK) phosphorylation was acutely increased by 1800% in response to ACTH stimulation, and selective inhibition of p38 MAPK abolished the ACTH-mediated UCP-1 protein increase. Taken together, ACTH acutely promotes an insulinresistant, pro-inflammatory state and transiently enhances energy combustion. In conditions characterised by a dysregulation of the HPA stress axis such as the metabolic syndrome, direct MC interaction with adipocytes may contribute to dysregulated energy balance, insulin resistance and cardiometabolic complications.

Topiramate is an anticonvulsant agent effective in the prophylaxis of migraine, which also induces weight reduction by an unknown mechanism. We investigated the effect of topiramate on metabolic and endocrine parameters in patients with migraine independently of any intention to lose body weight. Six patients (26-61 years old, body mass indices [BMI] 20.9-32.1 kg/m(2)) with migraine were treated with an average dose of 100 mg topiramate/day over a period of 20 weeks. The following parameters were measured every 4-8 weeks: BMI, body fat proportion, waist and hip circumference, HOMA insulin resistance, fasting serum-/plasma concentrations of adiponectin, leptin, ghrelin, vascular endothelial growth factor (VEGF), cortisol, interleukin-6 and tumor necrosis factor (TNF)-alpha. Profound metabolic changes were observed for the whole treatment period. Compared with the baseline value, 20 weeks of treatment reduced the BMI by 7.2+/-1.4%, body fat proportion by 11.6+/-3.6%, waist circumference by 4.2+/-1.2%, leptin by 39.2+/-6.5% and HOMA insulin resistance by 37.3+/-5%, while adiponectin was increased by 69.9+/-17.3% (P<0.05, respectively). VEGF concentrations increased during the week 2-4 by 177.4+/-39.4% (P<0.05) followed by a continuous decrease. There were trends for a reduction in ghrelin concentration, whereas cortisol, interleukin-6 and TNF-alpha values were unchanged. In summary, in this small sample of migraine patients topiramate treatment was associated with increased insulin sensitivity, increased adiponectin concentration and a reduction of body fat in all treated patients. The role of increased VEGF concentrations prior to these metabolic changes is not clear and might, hypothetically, involve a centrally mediated effect of topiramate on body weight regulation.

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Objective:The endocannabinoid system is a major component in the control of energy metabolism. Cannabinoid 1 (CB1)-receptor blockade induces weight loss and reduces the risk to develop the metabolic syndrome with its associated cardiovascular complications. These effects are mediated by central and peripheral pathways. Interestingly, weight loss is mainly achieved by a reduction of visceral fat mass. We analyzed fat depot-specific differences on adipocyte differentiation, inflammation and oxidative metabolism in CB1-receptor knockout cells.Materials and methods:We used newly generated epididymal/inguinal adipose cell lines from CB1-receptor knockout mice. Differences in differentiation were measured by fat-specific Oil Red O staining and quantitative analysis of key differentiation markers. Induction of apoptosis was evaluated by cell death detection and investigation of p53 phosphorylation. Inflammation markers were quantified by real-time PCR. For analyzing the process of transdifferentiation we measured oxygen consumption and mitochondrial biogenesis.Results:Differentiation was reduced in visceral adipocytes from CB1-receptor knockout mice as compared with wild-type controls. Moreover, we found an induction of apoptosis in these cells. In contrast, subcutaneous adipocytes from CB1-receptor knockout mice showed an accelerated differentiation and a reduced rate of apoptosis. Inflammation was increased in visceral fat cells, as analyzed by the expression pattern of interleukin-6, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α, whereas in subcutaneous adipocytes these markers were decreased. Furthermore, subcutaneous CB1-receptor knockout cells were more sensitive toward a conversion into a brown fat phenotype. Uncoupling protein-1 as well as PGC-1α expression was significantly elevated. This was accompanied by an increase in mitochondrial biogenesis and oxygen consumption.Conclusion:In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells. Thus, CB1-receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other.