Obesity-induced endoplasmatic reticulum (ER) stress has been demonstrated to underlie the induction of obesity-induced JNK and NF-κB activation inflammatory responses, and generation of peripheral insulin resistance. On the other hand, exercise has been used as a crucial tool in obese and diabetic patients, and may reduce inflammatory pathway stimulation. However, the ability of exercise training to reverse endoplasmatic reticulum stress in adipose and hepatic tissue in obesity has not been investigated in the literature. Here, we demonstrate that exercise training ameliorates ER stress and insulin resistance in DIO-induced rats. Rats were fed with standard rodent chow (3,948 kcal kg(-1)) or high-fat diet (5,358 kcal kg(-1)) for 2 months. After that rats were submitted to swimming training (1 h per day, 5 days for week with 5% overload of the body weight for 8 weeks). Samples from epididymal fat and liver were obtained and western blot analysis was performed. Our results showed that swimming protocol reduces pro-inflammatory molecules (JNK, IκB and NF-κB) in adipose and hepatic tissues. In addition, exercise leads to reduction in ER stress, by reducing PERK and eIF2α phosphorylation in these tissues. In parallel, an increase in insulin pathway signaling was observed, as confirmed by increases in IR, IRSs and Akt phosphorylation following exercise training in DIO rats. Thus, results suggest that exercise can reduce ER stress, improving insulin resistance in adipose and hepatic tissue.

UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy.

Obesity and insulin resistance are rapidly expanding public health problems. These disturbances are related to many diseases, including heart pathology. Acting through the Akt/mTOR pathway, insulin has numerous and important physiological functions, such as the induction of growth and survival of many cell types and cardiac hypertrophy. However, obesity and insulin resistance can alter mTOR/p70S6k. Exercise training is known to induce this pathway, but never in the heart of diet-induced obesity subjects. To evaluate the effect of exercise training on mTOR/p70S6k in the heart of obese Wistar rats, we analyzed the effects of 12 weeks of swimming on obese rats, induced by a high-fat diet. Exercise training reduced epididymal fat, fasting serum insulin and plasma glucose disappearance. Western blot analyses showed that exercise training increased the ability of insulin to phosphorylate intracellular molecules such as Akt (2.3-fold) and Foxo1 (1.7-fold). Moreover, reduced activities and expressions of proteins, induced by the high-fat diet in rats, such as phospho-JNK (1.9-fold), NF-kB (1.6-fold) and PTP-1B (1.5-fold), were observed. Finally, exercise training increased the activities of the transduction pathways of insulin-dependent protein synthesis, as shown by increases in Raptor phosphorylation (1.7-fold), p70S6k phosphorylation (1.9-fold), and 4E-BP1 phosphorylation (1.4-fold) and a reduction in atrogin-1 expression (2.1-fold). Results demonstrate a pivotal regulatory role of exercise training on the Akt/mTOR pathway, in turn, promoting protein synthesis and antagonizing protein degradation.

PGC-1α expression is a tissue-specific regulatory feature that is extremely relevant to diabetes. Several studies have shown that PGC-1α activity is atypically activated in the liver of diabetic rodents and contributes to hepatic glucose production. PGC-1α and Foxo1 can physically interact with one another and represent an important signal transduction pathway that governs the synthesis of glucose in the liver. However, the effect of physical activity on PGC-1α/Foxo1 association is unknown. Here we investigate the expression of PGC-1α and the association of PGC-1α/Foxo1 in the liver of diet-induced obese rats after acute exercise. Wistar rats swam for two 3 h-long bouts, separated by a 45 min rest period. Eight hours after the acute exercise protocol, the rats were submitted to an insulin tolerance test (ITT) and biochemical and molecular analysis. Results demonstrate that acute exercise improved insulin signalling, increasing insulin-stimulated Akt and Foxo1 phosphorylation and decreasing PGC-1α expression and PGC-1α/Foxo1 interaction in the liver of diet-induced obesity rats under fasting conditions. These phenomena are accompanied by a reduction in the expression of gluconeogenesis genes, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphate (G6Pase). Thus, these results provide new insights into the mechanism by which exercise could improve fasting hyperglycaemia.

No abstract

Protein hepatocyte nuclear factor 4α (HNF-4α) is atypically activated in the liver of diabetic rodents and contributes to hepatic glucose production. HNF-4α and Foxo1 can physically interact with each other and represent an important signal transduction pathway that regulates the synthesis of glucose in the liver. Foxo1 and HNF-4α interact with their own binding sites in the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) promoters, and this binding is required for their effects on those promoters. However, the effect of physical activity on the HNF-4α/Foxo1 pathway is currently unknown. Here, we investigate the protein levels of HNF-4α and the HNF-4α/Foxo1 pathway in the liver of leptin-deficient (ob/ob) and diet-induced obese Swiss (DIO) mice after acute exercise. The ob/ob and DIO mice swam for four 30 min periods, with 5 min rest intervals for a total swimming time of 2 h. Eight hours after the acute exercise protocol, the mice were submitted to an insulin tolerance test (ITT) and determination of biochemical and molecular parameters. Acute exercise improved insulin signalling, increasing insulin-stimulated Akt and Foxo1 phosphorylation and decreasing HNF-4α protein levels in the liver of DIO and ob/ob mice under fasting conditions. These phenomena were accompanied by a reduction in the expression of gluconeogenesis genes, such as PEPCK and G6Pase. Importantly, the PI3K inhibitor LY292004 reversed the acute effect of exercise on fasting hyperglycaemia, confirming the involvement of the PI3K pathway. The present study shows that exercise acutely improves the action of insulin in the liver of animal models of obesity and diabetes, resulting in increased phosphorylation and nuclear exclusion of Foxo1, and a reduction in the Foxo1/HNF-4α pathway. Since nuclear localization and the association of these proteins is involved in the activation of PEPCK and G6Pase, we believe that the regulation of Foxo1 and HNF-4α activities are important mechanisms involved in exercise-induced improvement of glucose homeostasis in insulin resistant states.

Insulin signalling in the hypothalamus plays a role in maintaining body weight. The forkhead transcription factor Foxo1 is an important mediator of insulin signalling in the hypothalamus. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase/Akt signalling pathway, but the role of hypothalamic Foxo1 in insulin resistance and obesity remains unclear. Here, we identify that a high-fat diet impaired insulin-induced hypothalamic Foxo1 phosphorylation and degradation, increasing the nuclear Foxo1 activity and hyperphagic response in rats. Thus, we investigated the effects of the intracerebroventricular (i.c.v.) microinfusion of Foxo1-antisense oligonucleotide (Foxo1-ASO) and evaluated the food consumption and weight gain in normal and diet-induced obese (DIO) rats. Three days of Foxo1-ASO microinfusion reduced the hypothalamic Foxo1 expression by about 85%. i.c.v. infusion of Foxo1-ASO reduced the cumulative food intake (21%), body weight change (28%), epididymal fat pad weight (22%) and fasting serum insulin levels (19%) and increased the insulin sensitivity (34%) in DIO but not in control animals. Collectively, these data showed that the Foxo1-ASO treatment blocked the orexigenic effects of Foxo1 and prevented the hyperphagic response in obese rats. Thus, pharmacological manipulation of Foxo1 may be used to prevent or treat obesity.

TRB3 (a mammalian homolog of Drosophila) is emerging as an important player in the regulation of insulin signaling. TRB3 can directly bind to Ser/Thr protein kinase Akt, the major downstream kinase of insulin signaling. Conversely, physical exercise has been linked to improved glucose homeostasis and enhanced insulin sensitivity; however, the molecular mechanisms by which exercise improves glucose homeostasis, particularly in the hepatic tissue, are only partially known. Here, we demonstrate that acute exercise reduces fasting glucose in two models diabetic mice. Western blot analysis showed that 8 h after a swimming protocol, TRB3 expression was reduced in the hepatic tissue from diet-induced obesity (Swiss) and leptin-deficient (ob/ob) mice, when compared with respective control groups at rest. In parallel, there was an increase in insulin responsiveness in the canonical insulin-signaling pathway in hepatic tissue from DIO and ob/ob mice after exercise. In addition, the PEPCK expression was reduced in the liver after the exercise protocol, suggesting that acute exercise diminished hepatic glucose production through insulin-signaling restoration. Thus, these results provide new insights into the mechanism by which physical activity improves glucose homeostasis in type 2 diabetes.