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Early evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance. Here, we investigated whether this insulin resistance, mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway, could be reversed by acute physical exercise. Rats on a high-fat diet were subjected to swimming for two 3 h-long bouts, separated by a 45 min rest period. Two or 16 h after the exercise protocol the rats were killed and proteins from the insulin signalling pathway were analysed by immunoprecipitation and immunoblotting. We demonstrated that a high-fat diet led to an increase in the iNOS protein level and S-nitrosation of insulin receptor β (IRβ), insulin receptor substrate 1 (IRS1) and Akt. Interestingly, an acute bout of exercise reduced iNOS expression and S-nitrosation of proteins involved in the early steps of insulin action, and improved insulin sensitivity in diet-induced obesity rats. Furthermore, administration of GSNO (NO donor) prevents this improvement in insulin action and the use of an inhibitor of iNOS (L-N 6 -(1-iminoethyl)lysine; L-NIL) simulates the effects of exercise on insulin action, insulin signalling and S-nitrosation of IRβ, IRS1 and Akt. In summary, a single bout of exercise reverses insulin sensitivity in diet-induced obese rats by improving the insulin signalling pathway, in parallel with a decrease in iNOS expression and in the S-nitrosation of IR/IRS1/Akt. The decrease in iNOS protein expression in the muscle of diet-induced obese rats after an acute bout of exercise was accompanied by an increase in AMP-activated protein kinase (AMPK) activity. These results provide new insights into the mechanism by which exercise restores insulin sensitivity.

OBJECTIVEIn obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action.RESEARCH DESIGN AND METHODSThe effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-κB activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice.RESULTSPD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF-α and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-α, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser307 phosphorylation in JNK and inhibitor of NF-κB kinase (IKKβ) activation in these tissues.CONCLUSIONSTreatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.

The peel of the native Brazilian fruit jaboticaba is rich in anthocyanins, which are known for their anti-obesity effects in animal models. The aim of the present study was to evaluate the effects of freeze-dried jaboticaba peel powder (FDJPP) on a number of metabolic parameters in a model of diet-induced obesity. Mice (n 8 per group) were initially fed on a high-fat diet (HFD, 35 % w/w) for 4 weeks and then switched to a HFD supplemented with FDJPP (1, 2 or 4 % w/w) for an additional 6 weeks. Energy intake, weight loss, glucose tolerance, insulin resistance and lipid profile were determined, and the results were evaluated using ANOVA and Tukey's tests. The FDJPP exerted no protective effect on HFD-induced weight gain, hyperleptinaemia and glucose intolerance. However, the supplementation was effective to reduce insulin resistance, as evidenced in the insulin tolerance test, and subsequently confirmed by improved signal transduction through the insulin receptor/insulin receptor substrate-1/Akt/forkhead box protein pathway and by the attenuation of HFD-induced inflammation in the liver, verified by lower expressions of IL-1b and IL-6 and decreased phosphorylated IkB-a protein levels in all jaboticaba-treated mice. These results suggest that FDJPP may exert a protective role against obesity-associated insulin resistance.Key words: Jaboticaba: Obesity: Insulin resistance Obesity has reached epidemic proportions in the world, with substantial adverse consequences for human health (1) . A number of life-threatening diseases, such as type 2 diabetes mellitus, dyslipidaemia, CVD, hypertension and certain types of cancer, are associated with this condition (2) .Nutritional factors are known to play an important role in the development of a number of diseases. The recent changes in human lifestyle, with the introduction of high-fat/simple carbohydrate-rich diets, are amongst the most important factors leading to the increased prevalence of obesity. Conversely, epidemiological data suggest that increased consumption of fruits and vegetables are positively associated with the prevention of metabolic disorders, including obesity (3,4) . The ability of some vegetable-derived nutrients to reduce the risk of chronic diseases has been associated, at least in part, with the occurrence of bioactive non-nutrient compounds that are known to exert a wide range of biological activities (5,6) .Anthocyanins, which belong to the flavonoid class, are an example of such bioactive compounds. They constitute the largest and probably the most important group of watersoluble natural pigments responsible for the vivid blue, purple and red colour of many vegetables and fruits (7) . Many reports have shown that anthocyanin exhibits an array of pharmacological properties, such as anti-inflammatory and anticarcinogenic activities, as well as preventive effects on CVD and degenerative disease. The majority of research has focused on the antioxidant properties of these dietary polyphenols (8) . Furthermore, it has been shown that phenolic co...

Our study allows concluding that the reduction in SREBP-1c protein levels is associated with steatosis reversion induced by exercise training.