Physical Exercise Reduces Circulating Lipopolysaccharide and TLR4 Activation and Improves Insulin Signaling in Tissues of DIO Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)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 I kappa B kinase (IKK beta) 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 IKK beta 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. Diabetes 60:784-796, 2011603784796Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de PesquisaINCT-Obesidade e DiabetesFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Inducing the cosmological constant from five-dimensional Weyl space

We investigate the possibility of inducing the cosmological constant from extra dimensions by embedding our four-dimensional Riemannian space-time into a five-dimensional Weyl integrable space. Following approach of the induced matter theory we show that when we go down from five to four dimensions, the Weyl field may contribute both to the induced energy-tensor as well as to the cosmological constant, or more generally, it may generate a time-dependent cosmological parameter. As an application, we construct a simple cosmological model which has some interesting properties.Comment: 7 page

Long-term effects of moderate physical exercise during early childhood on insulin sensitivity in rats during adulthood

It is of great importance to investigate the effects of physical exercise for metabolic health when performed in early life, and what the adulthood response would be. The aim of this study is to analyse the effects of moderate intensity physical exercise protocol during childhood on the adipose tissue and insulin sensitivity of rats during adulthood. Twenty weaned Wistar (28 days old) were divided into control and trained groups. The Control Group was kept sedentary, and the Trained group was submitted to swimming exercise at 80% of the anaerobic threshold (determined by the lactate minimum test) for 1 hour/day, 5 days/week from 28 to 90 days of age. At the end of the experiment, the body weight, adiposity (adipose tissue weight), insulin sensitivity, glycemia, insulinemia, pancreatic insulin, lipogenic activity in mesenteric fat, lipogenic activity and glycogen store in gastrocnemius and glucose uptake by soleus were analyzed. Trained group showed lower body weight gain, fat acumulation, lipid synthesis, glycemia, insulinemia and pancreatic insulin level. Kitt, HOMA-IR, glycogen store in gastrocnemius and glucose uptake by soleus were higher in this group. Therefore, we conclude that the moderate physical exercise performed during childhood can contribute to the reduction of body fat and insulin resistance during adulthood in Wistar rats.É de grande importância a investigação dos efeitos do exercício para a saúde metabólica quando realizado no início da vida, e quais seriam as respostas durante a fase adulta. O objetivo desse estudo é analisar os efeitos do exercício físico de intensidade moderada durante a infância na adiposidade e sensibilidade à insulina de ratos durante a fase adulta. Vinte ratos Wistar desmamados de 28 dias de vida foram divididos em grupos Controle e Treinado. O grupo Controle permaneceu sedentário, enquanto o grupo Treinado realizou exercício de natação a 80% do limiar anaeróbio (determinado pelo teste de lactato mínimo) por 1hora/dia, 5dias/semana do 28º até o 90º dia de vida. No fim do experimento, a massa corporal, adiposidade, sensibilidade à insulina, glicemia, insulinemia, insulina pancreática, atividade lipogênica do tecido adiposo mesentérico, atividade lipogênica e estoques de glicogênio no músculo gastrocnêmio e captação de glicose pelo músculo sóleo foram analizadas. O grupo Treinado apresentou menor ganho de massa corporal, acúmulo de gordura, síntese de lipídios, glicemia, insulinemia e insulina pancreática. Kitt, HOMA-IR, estoques de glicogênio no gastrocnêmio e captação de glicose pelo sóleo foram maiores nesse grupo. Portanto, concluímos que o exercício físico moderado realizado durante a infância pode contribuir para a redução da adiposidade corporal e resistência à insulina durante a fase adulta em ratos Wistar

High-Fat Diet Induces Apoptosis of Hypothalamic Neurons

Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells. Here, we show that consumption of dietary fats induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus. This effect is dependent upon diet composition, and not on caloric intake, since pair-feeding is not sufficient to reduce the expression of apoptotic markers. The presence of an intact TLR4 receptor, protects cells from further apoptotic signals. In diet-induced inflammation of the hypothalamus, TLR4 exerts a dual function, on one side activating pro-inflammatory pathways that play a central role in the development of resistance to leptin and insulin, and on the other side restraining further damage by controlling the apoptotic activity

Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice

Physical exercise is considered a fundamental strategy in improving insulin sensitivity and glucose uptake in skeletal muscle. However, the molecular mechanisms underlying this regulation, primarily on skeletal muscle glucose uptake, are not fully understood. Recent evidence has shown that Rho-kinase (ROCK) isoforms play a pivotal role in regulating skeletal muscle glucose uptake and systemic glucose homeostasis. The current study evaluated the effect of physical exercise on ROCK2 signaling in skeletal muscle of insulin-resistant obese animals. Physiological (ITT) and molecular analysis (immunoblotting, and RT-qPCR) were performed. The contents of RhoA and ROCK2 protein were decreased in skeletal muscle of obese mice compared to control mice but were restored to normal levels in response to physical exercise. The exercised animals also showed higher phosphorylation of insulin receptor substrate 1 (IRS1 Serine 632/635) and protein kinase B (Akt) in the skeletal muscle. However, phosphatase and tensin homolog (PTEN) and protein-tyrosine phosphatase-1B (PTP-1B), both inhibitory regulators for insulin action, were increased in obesity but decreased after exercise. The impact of ROCK2 action on muscle insulin signaling is further underscored by the fact that impaired IRS1 and Akt phosphorylation caused by palmitate in C2C12 myotubes was entirely restored by ROCK2 overexpression. These results suggest that the exercise-induced upregulation of RhoA-ROCK2 signaling in skeletal muscle is associated with increased systemic insulin sensitivity in obese mice and further implicate that muscle ROCK2 could be a potential target for treating obesity-linked metabolic disorders

Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice

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

Unsaturated Fatty Acids Revert Diet-Induced Hypothalamic Inflammation in Obesity

Background: In experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown. Methodology/Principal Findings: Here we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both v3 and v9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, v3 and v9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of v3 and v9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor. Conclusions/Significance: Unsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting dietinduced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and geneti