Our findings show that, in human obesity, plasma visfatin is reduced, whereas visfatin mRNA is differentially regulated in SAT and VAT. Visfatin is not related to insulin resistance either as assessed by homeostasis model assessment or during lipid infusion.

Insulin resistance and obesity are associated with a reduction of mitochondrial content in various tissues of mammals. Moreover, a reduced nitric oxide (NO) bioavailability impairs several cellular functions, including mitochondrial biogenesis and insulin-stimulated glucose uptake, two important mechanisms of body adaptation in response to physical exercise. Although these mechanisms have been thoroughly investigated in skeletal muscle and heart, few studies have focused on the effects of exercise on mitochondria and glucose metabolism in adipose tissue. In this study, we compared the in vivo effects of chronic exercise in subcutaneous adipose tissue of wild-type (WT) and endothelial NO synthase (eNOS) knockout (eNOS 2/2 ) mice after a swim training period. We then investigated the in vitro effects of NO on mouse 3T3-L1 and human subcutaneous adipose tissue-derived adipocytes after a chronic treatment with an NO donor: diethylenetriamine-NO (DETA-NO). We observed that swim training increases mitochondrial biogenesis, mitochondrial DNA content, and glucose uptake in subcutaneous adipose tissue of WT but not eNOS 2/2 mice. Furthermore, we observed that DETA-NO promotes mitochondrial biogenesis and elongation, glucose uptake, and GLUT4 translocation in cultured murine and human adipocytes. These results point to the crucial role of the eNOS-derived NO in the metabolic adaptation of subcutaneous adipose tissue to exercise training.Reduced mitochondrial content and/or activity is associated with impaired cell function in several diseases (1,2). In particular, it has been hypothesized that mitochondrial impairment may be involved in the pathogenesis of obesity and insulin resistance and their progression toward type 2 diabetes (3,4), even though the role of mitochondria in health and disease is still under discussion (5,6). At the same time, metabolic disorders are also associated with a reduction of endothelial nitric oxide synthase (eNOS) enzymatic activity (7,8); in fact, mice lacking the eNOS gene are considered a useful murine model for metabolic syndrome because they display typical features, including hypertension, hypertriglyceridemia, endothelial dysfunction, insulin resistance, and visceral obesity (9). It is well known that physical exercise induces profound physiological adaptations in several tissues as a response to increased metabolic requirements. One of the major events induced by physical activity is the upregulation of eNOS gene expression and the consequent

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport.

Overactivity of the endocannabinoid system (ECS) has been linked to abdominal obesity and other risk factors for cardiovascular disease and type 2 diabetes. Conversely, administration of cannabinoid receptor type 1 (CB1) antagonists reduces adiposity in obese animals and humans. This effect is only in part secondary to the anorectic action of CB1 agonists. In order to assess the actions of CB1 antagonism on glucose homeostasis, diet‐induced obese (DIO) rats received the CB1 antagonist rimonabant (10 mg/kg, intraperitoneally (IP)) or its vehicle for 4 weeks, or were pair‐fed to the rimonabant‐treated group for the same length of time. Rimonabant treatment transiently reduced food intake, while inducing body weight loss throughout the study. Rats receiving rimonabant had significantly less body fat and circulating leptin compared to both vehicle and pair‐fed groups. Rimonabant, but not pair‐feeding, also significantly decreased circulating nonesterified fatty acid (NEFA) and triacylglycerol (TG) levels, and reduced TG content in oxidative skeletal muscle. Although no effects were observed during a glucose tolerance test (GTT), rimonabant restored insulin sensitivity to that of chow‐fed, lean controls during an insulin tolerance test (ITT). Conversely, a single dose of rimonabant to DIO rats had no acute effect on insulin sensitivity. These findings suggest that in diet‐induced obesity, chronic CB1 antagonism causes weight loss and improves insulin sensitivity by diverting lipids from storage toward utilization. These effects are independent of the anorectic action of the drug.

Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function. Methods Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.Results Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake. Conclusions/interpretation Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.