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Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity. In the present study the cross-talk between insulin and leptin was evaluated in rat liver. Upon stimulation of JAK2 tyrosine phosphorylation, leptin induced JAK2 co-immunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin in stimulating IRS phosphorylation and their association with PI 3-kinase. Simultaneous treatment with both hormones yielded no change in maximal phosphorylation of STAT3, IRS-1, IRS-2 and Akt, but led to a marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. This indicates that there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver. [ABSTRACT FROM AUTHOR]

Several authors have shown that hematological parameters can be used to detect poor prognosis in patients with cancer. Thus, such features could be used in artificial intelligence (AI-based) models to predict mortality among these patients. This work aimed to develop and compare several AI-based models to predict the prognosis (death vs. survival) of cancer in patients using blood tests and patient data as inputs. At total, 908 cancer patients were assisted in a prospective study. Four artificial intelligence models were compared: artificial neural networks (ANN), supporting vector machines (SVM), decision trees and neuro-fuzzy networks. Also, four different input strategies were tested, considering the use of 49, 45, 22 and 14 inputs. The results of this study showed that the ANN and the SVM presented the best results, using 45 inputs. The ANN was the best model since it presented better statistical values for the positive (death) and negative (survival) classes. The use of blood parameters as inputs for AI-based models could be used to predict death in patients with cancer, and this methodology can be expanded to other diseases. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Birth Weight and Type 2 Diabetes in Adults: A Systematic Review," by P. H. Whincup,S. J. Kaye and C. G. Owen in a previous issue.

Inflammatory states and body composition changes are associated with a poor prognosis in many diseases, but their role in coronavirus disease 2019 (COVID-19) is not fully understood. To assess the impact of low skeletal muscle radiodensity (SMD), high neutrophil-to-lymphocyte ratio (NLR) and a composite score based on both variables, on complications, use of ventilatory support, and survival in patients with COVID-19. Medical records of patients hospitalized between May 1, 2020, and July 31, 2020, with a laboratory diagnosis of COVID-19 who underwent computed tomography (CT) were retrospectively reviewed. CT-derived body composition measurements assessed at the first lumbar vertebra level, and laboratory tests performed at diagnosis, were used to calculate SMD and NLR. Prognostic values were estimated via univariate and multivariate logistic regression analyses and the Kaplan–Meier curve. The study was approved by the local Institutional Review Board (CAAE 36276620.2.0000.5404). A total of 200 patients were included. Among the patients assessed, median age was 59 years, 58% were men and 45% required ICU care. A total of 45 (22.5%) patients died. Multivariate logistic analysis demonstrated that a low SMD (OR 2.94; 95% CI 1.13–7.66, P = 0.027), high NLR (OR 3.96; 95% CI 1.24–12.69, P = 0.021) and both low SMD and high NLR (OR 25.58; 95% CI 2.37–276.71, P = 0.008) combined, were associated with an increased risk of death. Patients who had both low SMD and high NLR required more mechanical ventilation (P < 0.001) and were hospitalized for a longer period (P < 0.001). Low SMD, high NLR and the composite score can predict poor prognosis in patients with COVID-19, and can be used as a tool for early identification of patients at risk. Systemic inflammation and low muscle radiodensity are useful predictors of poor prognosis, and the assessment of these factors in clinical practice should be considered. [ABSTRACT FROM AUTHOR]

Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IκB kinase complex and c-Jun NH2-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/ HeJ mice, protection from saturated fatty acid-induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions. Diabetes 56:1986-1998, 2007 [ABSTRACT FROM AUTHOR]

We have previously demonstrated that the insulin resistance associated with inducible nitric oxide synthase (iNOS) induction in two different models of obesity, diet-induced obesity and the oblob mice, is mediated by S-nitrosation of proteins involved in insulin signal transduction: insulin receptor β-subunit (IRβ), insulin receptor substrate 1(1RS-1), and Akt. S-nitrosation of IRβ and Akt impairs their kinase activities, and S-nitrosation of 1RS-1 reduces its tissue expression. In this study, we observed that LPS-induced insulin resistance in the muscle of wild-type mice, as demonstrated by reduced insulin-induced tyrosine phosphorylation of IRβ and IRS-1, reduced IRS-1 expression and reduced insulin-induced serine phosphorylation of Akt. This resistance occurred in parallel with enhanced iNOS expression, which was accompanied by S-nitrosation of IRβ/IRS-1 and Akt. In the muscle of iNOS-/--mice, we did not observe enhanced iNOS expression or any S-nitrosation of IRβ/IRS-1 and Akt after LPS treatment. Moreover, insulin resistance was not present. The preservation of insulin-induced tyrosine phosphorylation of IRβ and IRS-1, of IRS-1 protein expression, and of insulin-induced serine phosphorylation of Akt observed in LPS-treated iNOS-/- mice strongly suggests that the insulin resistance induced by LPS is iNOS mediated, probably through S-nitrosation of proteins of early steps of insulin signaling. [ABSTRACT FROM AUTHOR]

Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. Here, we investigated whether this insulin resistance could be mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway. Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. Insulin receptor substrate (IRS)-1 was also rapidly S-nitrosated, and its expression was reduced after chronic GSNO treatment. In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance. [ABSTRACT FROM AUTHOR]

A correction to the article "Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance" by Daniela M. L. Tsukumo, Marco A. Carvalho-Filho, Jose B. C. Carvalheira, and colleagues is presented.

Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem. Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial and complex physiopathology has hindered the understanding of its mechanism. During the last few decades we have witnessed a dramatic increase in the understanding of cancer cachexia pathophysiology. Anorexia and muscle and adipose tissue wasting are the main features of cancer cachexia. These apparently independent symptoms have humoral factors secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an organ that senses the peripheral signals emanating from the tumoral environment, and not only elicits anorexia but also contributes to the development of muscle and adipose tissue loss. Herein, we review the roles of factors secreted by the tumor and its effects on the hypothalamus, muscle and adipose tissue, as well as highlighting the key targets that are being exploited for cancer cachexia treatment. [ABSTRACT FROM AUTHOR]

Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IR and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response. [ABSTRACT FROM AUTHOR]

Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation--induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. Objective: The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. Research Design and Methods: We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. Results and Conclusions: Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. Trial Registration: ClinicalTrials.gov NCT01295177 [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling.Research Design and Methods: The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH(2)-terminal kinase (JNK) and IκB kinase (IKKβ) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats.Results: The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKβ phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels.Conclusions: Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling. RESEARCH DESIGN AND METHODS--The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH2-terminal kinase (JNK) and IKB kinase (IKKβ) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats. RESULTS--The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKβ phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels. CONCLUSIONS--Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

The article discusses the study on the effect of exercise intensity, inflammation signaling, and the insulin resistance of diet-induced obese (DIO) rats in Santa Catarina, Brazil. It states that the aim of the study is to assess the intensity of exercise and expression of the inflammatory proteins of the skeletal muscle of a DIO rats. It notes that the two exercise protocols has increased the insulin sensitivity and insulin stimulated tyrosine phosphorylation of the insulin receptor and receptor substrate 1 and serine phosphorylation of protein kinase B of the muscle of DIO rates. It also mentions that exercise protocols with a low intensity and high volume or an exercise with moderate intensity and low volume has different strategies in restoring insulin sensitivity.

Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKβ/NF-κB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKb and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) and mammalian Target of Rapamycin (mTOR) are key regulators of cellular energy balance and of the effects of leptin on food intake. Acute exercise is associated with increased sensitivity to the effects of leptin on food intake in an IL-6-dependent manner. To determine whether exercise ameliorates the AMPK and mTOR response to leptin in the hypothalamus in an IL-6-dependent manner, rats performed two 3-h exercise bouts, separated by one 45-min rest period. Intracerebroventricular IL-6 infusion reduced food intake and pretreatment with AMPK activators and mTOR inhibitor prevented IL-6-induced anorexia. Activators of AMPK and fasting increased food intake in control rats to a greater extent than that observed in exercised ones, whereas inhibitor of AMPK had the opposite effect. Furthermore, the reduction of AMPK and ACC phosphorylation and increase in phosphorylation of proteins involved in mTOR signal transduction, observed in the hypothalamus after leptin infusion, were more pronounced in both lean and diet-induced obesity rats after acute exercise. Treatment with leptin reduced food intake in exercised rats that were pretreated with vehicle, although no increase in responsiveness to leptin-induced anorexia after pretreatment with anti-IL6 antibody, AICAR or Rapamycin was detected. Thus, the effects of leptin on the AMPK/mTOR pathway, potentiated by acute exercise, may contribute to appetite suppressive actions in the hypothalamus. [ABSTRACT FROM AUTHOR]

Proper activation of phosphoinositide 3-kinase- Akt pathway is critical for the prevention of tumorigenesis. Recent data have characterized a negative feedback loop, wherein mammalian target of rapamycin (mTOR) blocks additional activation of the Akt/mTOR pathway through inhibition insulin receptor substrate 1 (IRS-1) function. However, the potential of IRS-1 inhibition during rapamycin treatment has not been examined. Herein, we show that IRS-1 antisense oligonucleotide and rapamycin synergistically antagonize the activation of mTOR in vivo and induced tumor suppression, through inhibition of proliferation and induction of apoptosis, in prostate cancer cell xenografts. These data demonstrate that the addition of agents that blocks IRS-1 potentiate the effect of mTOR inhibition in the growth of prostate cancer cell xenografts. [ABSTRACT FROM AUTHOR]

OBJECTIVE--A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD. RESEARCH DESIGN AND METHODS--Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD. RESULTS--An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes. CONCLUSIONS--These findings provide support for the hypothesis that AMPK and roTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner. Diabetes 57:594-605, 2008 [ABSTRACT FROM AUTHOR]

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- N6-(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. [ABSTRACT FROM AUTHOR]

The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/ eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyper-activated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS. Diabetes 56: 1014-1024, 2007 [ABSTRACT FROM AUTHOR]

Lifestyle interventions including exercise programmes are cornerstones in the prevention of obesity-related diabetes. In this study, we demonstrate that a single bout of exercise inhibits high-fat diet-induced insulin resistance. Diet-induced obesity (DIO) increased the expression and activity of the protein tyrosine phosphatase 1B (PTP1B) and attenuated insulin signalling in gastrocnemius muscle of rats, a phenomenon which was reversed by a single session of exercise. In addition, DIO was observed to lead to serine phosphorylation of insulin receptor substrate 1 (IRS-1), which was also reversed by exercise in muscle in parallel with a reduction in c-Jun N-terminal kinase (JNK) activity. Thus, acute exercise increased the insulin sensitivity during high-fat feeding in obese rats. Overall, these results provide new insights into the mechanism by which exercise restores insulin sensitivity. [ABSTRACT FROM AUTHOR]

Prolonged exercise of medium to high intensity is known to promote a substantial effect on the energy balance of rats. In male rats, moderately to severely intense programs lead to a reduction in food intake. However, the exact causes for the appetite-suppressive effects of exercise are not known. Here, we show that intracerebroventricular insulin or leptin infusion reduced food intake in exercised rats to a greater extent than that observed in control animals. Exercise was associated with a markedly increased phosphorylation/activity of several proteins involved in leptin and insulin signal transduction in the hypothalamus. The regulatory role of interleukin (IL)-6 in mediating the increase in leptin and insulin sensitivity in hypothalamus was also investigated. Treatment with insulin or leptin markedly reduced food intake in exercised rats that were pretreated with vehicle, although no increase in sensitivity to leptin- and insulin-induced anorexia after pretreatment with anti-IL-6 antibody was detected. The current study provides direct measurements of leptin and insulin signaling in the hypothalamus and documents increased sensitivity to these hormones in the hypothalamus of exercised rats in an IL-6-dependent manner. These findings provide support for the hypothesis that the appetite-suppressive actions of exercise may be mediated by the hypothalamus. Diabetes 55:2554-2561, 2006 [ABSTRACT FROM AUTHOR]

A correction to the article "Exercise Improves Insulin and Leptin Sensitivity in Hypothalamus of Wistar Rats" by Marcelo B. S. Flores, Maria Fernanda A. Fernandes, Eduardo R. Ropelle, and colleagues is presented.

An expression of concern from the journal for the article "A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet-Induced Weight Loss" by Eduardo R. Ropelle, Jose Pauli, Maria Fernanda A. Fernandes, and colleagues is presented.

A correction to the article "Physical Exercise Reduces Circulating Lipopolysaccharide and TLR4 Activation and Improves Insulin Signaling in Tissues of DIO Rats" by Alexandre G. Oliveira, Bruno M. Carvalho, Natalia Tobar, and colleagues is presented.