Melatonin has an ergogenic effect but does not prevent inflammation and damage in exhaustive exercise

It is well documented that exhaustive physical exercise leads to inflammation and skeletal muscle tissue damage. With this in mind, melatonin has been acutely administered before physical exercise; nevertheless, the use of melatonin as an ergogenic agent to prevent tissue inflammation and damage remains uncertain. We evaluated the effects of melatonin on swimming performance, muscle inflammation and damage and several physiological parameters after exhaustive exercise at anaerobic threshold intensity (iLAn) performed during light or dark circadian periods. The iLAn was individually determined and two days later, the animals performed an exhaustive exercise bout at iLAn 30 minutes after melatonin administration. The exercise promoted muscle inflammation and damage, mainly during the dark period and the exogenous melatonin promoted a high ergogenic effect. The expressive ergogenic effect of melatonin leads to longer periods of muscle contraction, which superimposes a possible melatonin protective effect on the tissue damage and inflammation5CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305650/2009- 22009/08535-5; 2011/13226-1; 2012/20501-

Efeitos moleculares do exercício físico sobre as vias de sinalização insulínica

O músculo esquelético representa aproximadamente 40% da massa corporal total e exerce papel primordial no metabolismo da glicose (SMITH; MUSCAT, 2005). Este tecido é responsável por aproximadamente 30% do dispêndio de energia, e é um dos principais tecidos responsável pela captação, liberação e estocagem de glicose(NUUTILA et al., 1992). Trabalhos das últimas décadas demonstram claramente que o exercício físico aumenta a captação de glicose pelo (JAMES et al., 1983; ERIKSSON et al., 1998; KENNEDY et al., 1999; LUCIANO et al., 2002). Além disso, recentemente foi demonstrado que a redução de peso corporal associada com o aumento da atividade física em indivíduos com risco aumentado para desenvolver diabetes reduz em 58% a incidência dessa doença (KNOWLER et al., 2002). Assim, atualmente o exercício físico é considerado uma das pedras angulares tanto do tratamento como da prevenção do Diabetes tipo 2. Os mecanismos moleculares envolvidos no aumento da captação de glicose muscular estão sendo intensamente pesquisados. Nesta revisão serão abordados alguns aspectos dessa fascinante área que está se desenvolvendo rapidamente

Molecular Mechanisms Of Glucose Uptake In Skeletal Muscle At Rest And In Response To Exercise

Glucose uptake is an important phenomenon for cell homeostasis and for organism health. Under resting conditions, skeletal muscle is dependent on insulin to promote glucose uptake.Insulin, after binding to its membrane receptor, triggers a cascade of intracellular reactions culminating in activation of the glucose transporter 4, GLUT4, among other outcomes.This transporter migrates to the plasma membrane and assists in glucose internalization.However, under special conditions such as physical exercise, alterations in the levels of intracellular molecules such as ATP and calcium actto regulate GLUT4 translocation and glucose uptake in skeletal muscle, regardless of insulinlevels.Regular physical exercise, due to stimulating pathways related to glucose uptake, is an important non-pharmacological intervention for improving glycemic control in obese and diabetic patients. In this mini-review the main mechanisms involved in glucose uptake in skeletal muscle in response to muscle contraction will be investigated.23especia

Strength Training Prevents Hyperinsulinemia, Insulin Resistance, And Inflammation Independent Of Weight Loss In Fructose-fed Animals

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The aim of this study was to compare the effects of aerobic, strength, and combined training on metabolic disorders induced by a fructose-rich diet. Wistar rats (120 days old) were randomized into five groups (n = 8-14): C (control diet and sedentary), F (fed the fructose-rich diet and sedentary), FA (fed the fructose-rich diet and subject to aerobic exercise), FS (fed the fructose-rich diet and subject to strength exercise), and FAS (fed the fructose-rich diet and subject to combined aerobic and strength exercises). After the 8-week experiment, glucose homeostasis, blood biochemistry, tissue triglycerides, and inflammation were evaluated and analyzed. The strength protocol exerted greater effects on glucose homeostasis, insulin sensitivity, and liver lipid contents than other protocols (all P < 0.05). All three exercise protocols induced a remarkable reduction in inflammation, tissue triglyceride content, and inflammatory pathways, which was achieved through c-Jun NH2-terminal kinase (JNK) phosphorylation and factor nuclear kappa B (NFkB) activation in both the liver and the muscle. Our data suggest that strength training reduced the severity of most of the metabolic disorders induced by a fructose-rich diet and could be the most effective strategy to prevent or treat fructose-induced metabolic diseases.6Brazilian foundation FAPESP [2013/20293-2, 2013/21491-2, 2016/14380-8]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Mecanismos moleculares de indução de obesidade e resistência à insulina em animais destreinados submetidos a uma dieta rica em lipídes.

The termination of exercise training (detraining) results in rapid fat accretion, weight gain and insulin resistance in both humans and rats. There is evident relationship between physical inactivity and insulin resistance. Different mechanisms may be involved in insulin resistance in this animal model. The aim of this study was to investigate the PI3-kinase/Akt and CAP/Cbl signaling pathways both involved with insulin-stimulated glucose uptake in white adipose tissue in detrained and sedentary animals submitted a high-fat diet. Wistar rats were submitted to swimming training during 8 weeks. Next this period the animals stop the training and received a rich-fat diet. The proteins from the insulin signaling pathway were analyzed by immunoprecipitation and immunoblotting. The results demonstrated that detraining result in an increased body mass and rapid body fat accretion. This fact was associated with increases insulin responsiveness in adipose tissue through IRS/PI3-Kinase/Akt pathway in detrained rats fed with a rich-fat diet. In addition, the CAP/Cbl pathway in adipose tissue was more insulin responsives in the detrained animals feeding with a rich-fat diet than S-DHL animals. In conclusion, the cessation of exercise is accompanied by increased body mass and rapid fat accretion and this aspect to have relation at least in part to increased insulin responsiveness in adipose tissue through CAP/Cbl pathway.A cessação do treinamento físico (destreinamento) resulta em rápido acréscimo da massa adiposa, ganho de peso e resistência à insulina tanto em humanos quanto em animais. No entanto, os mecanismos moleculares envolvidos nesse processo permanecem desconhecidos. Diferentes proteínas intracelulares podem estar envolvidas no processo de aquisição de ganho de peso e diminuição na ação da insulina nesse modelo animal. Este estudo teve como objetivos investigar as vias PI 3-quinase/Akt e CAP/Cbl, ambas importantes na captação ou utilização de glicose estimulada por insulina no tecido muscular adiposo branco. Utilizou-se, ratos Wistar que foram submetidos a um protocolo de exercício de natação por 8 semanas. Posteriormente os animais foram destreinados e nesse mesmo período de cessamento do programa de exercício foi oferecida aos ratos uma dieta rica em lipídes. Para análise das proteínas de interesse, foi realizado o método de imunoblot e imunoprecipitação. Verifica-se, através dos resultados obtidos, que animais destreinados tem um ganho de peso e de gordura epididimal mais acentuado comparado a animais sedentários. Esse fato foi associado a uma maior responsividade à insulina no tecido adiposo através da via IRS/PI 3-quinase/Akt dos animais destreinados submetidos à dieta rica em lipídes. Além disso, verifica-se, que a via CAP/Cbl encontra-se mais responsiva à insulina no tecido adiposo de animais destreinados em relação aos outros grupos experimentais. Conclui-se, que o destreinamento físico é acompanhado por um rápido período de ganho de peso e de massa adiposa e essas adaptações deve-se no mínimo em parte pela maior responsividade à insulina da via CAP/Cbl em tecido adiposo branco

Hypothalamic S1p/s1pr1 Axis Controls Energy Homeostasis In Middle-aged Rodents: The Reversal Effects Of Physical Exercise

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.91156169Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP2011/09656-0, 2011/13828-1]Conselho Nacional de desenvolvimento cientifico e tecnologico (CNPq) [304815/2014-4]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Atorvastatin Improves Survival in Septic Rats: Effect on Tissue Inflammatory Pathway and on Insulin Signaling

The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult

Characterization of insulin and leptin signaling in the hypothalamus of rodents during cancer induced anorexia

Orientador: Jose Barreto Campello CarvalheiraTese (doutorado) - Universidade Estadual de Campinas. Faculdade de Ciencias MedicasResumo: A síndrome anorexia-caquexia é observada em cerca de 80% dos pacientes com câncer em estágio avançado e contribui diretamente para o aumento da morbidade e mortalidade desses pacientes. Postula-se que a patogênese da anorexia do câncer seja mediada por persistentes sinais anorexigênicos no hipotálamo, contribuindo com a redução da ingestão alimentar e do peso corporal. No presente estudo, demonstramos que as vias anorexigênicas mediadas pela insulina e pela leptina no hipotálamo estão hipersensíveis durante a anorexia induzida por tumor em roedores. Identificamos que a expressão proteína tirosina fosfatase 1B (PTP1B), proteína que modula negativamente a via de transmissão do sinal da insulina e da leptina, está significativamente reduzida no tecido hipotalâmico em diferentes modelos de anorexia induzida pelo câncer, contribuindo assim para o aumento dos sinais anorexigênicos mediados principalmente pela STAT-3. Evidenciamos que mediadores pró-inflamatórios clássicos, como a IL-1 b e o TNF-a, participam do controle da expressão e atividade da PTP1B em neurônios. Demonstramos que a infusão central do anticorpo anti-IL-1 b ou do inibidor específico do TNF-a, o Infliximab, restaurou a atividade da PTP1B, reduzindo a sensibilidade à insulina e à leptina, aumentando a ingestão alimentar, peso corporal e a sobrevida em animais com tumor. Inversamente, as injeções do recombinante da IL-1 b ou do TNF-a diretamente no terceiro ventrículo hipotalâmico foram capazes de suprimir a expressão PTP1B neuronal e aumentar a sensibilidade à insulina e à leptina em animais controle. Finalmente, a redução seletiva da expressão da PTP1B em áreas em torno do terceiro ventrículo hipotalâmico através do uso do oligonucleotídeo antisense contra a PTP1B (PTP1B ASO), provocou anorexia, perda de peso corporal severa e morte em ratos controle e ainda inibiu os efeitos do anticorpo anti-IL-1 b e do Infliximab em ratos com anorexia. Coletivamente, estes dados mostram que a PTP1B hipotalâmica é proteína chave para o controle da ingestão alimentar e do peso corporal em roedores e representa um potencial avo terapêutico para o tratamento da anorexia induzida pelo câncerAbstract: The anorexia-cachexia syndrome is observed in 80% of patients with advanced cancer and contributes directly to increased morbidity and mortality of these patients. It is postulated that the pathogenesis of cancer anorexia is mediated by persistent anorexigenic signs in the hypothalamus, contributing to the reduction of food intake and body weight. In this study, we demonstrated that the anorexigenic pathways mediated by insulin and leptin in the hypothalamus are hypersensitive during tumor-induced anorexia in rodents. We found that the expression protein tyrosine phosphatase 1B (PTP1B), a protein that negatively modulates the route of signal transmission of insulin and leptin, is significantly reduced in the hypothalamic tissue in different models of cancer-induced anorexia, contributing to the increase in anorexigenic signals mediated by STAT-3. We showed that classical pro-inflammatory cytokines, such IL-1b and TNF-a modulate PTP1B activity in neurons. We have shown that central infusion of, anti-IL-1b antibody or specific inhibitor of TNF-a, Infliximab, restored the PTP1B activity, reducing insulin and leptin sensitivity, increasing food intake, body weight and survival in tumor-bearing animals. Conversely, intracerebroventricular injections of recombinant IL-1b or TNF-a were able to suppress the PTP1B expression and increase the central insulin and leptin sensitivity in control animals. Finally, the selective reduction of PTP1B expression in areas around the third ventricle of the hypothalamus using the antisense oligonucleotide against PTP1B (PTP1B ASO), evoked anorexia, severe weight loss and death in control rats, in addition, PTP1B ASO blunted the effects of anti-IL-1b antibody or Infliximab in anorectic rats. Collectively, these data show that the hypothalamic PTP1B is key protein in the control of food intake and body weight in rodents and presents an attractive opportunity for the treatment of cancer-induced anorexiaDoutoradoMedicina ExperimentalDoutor em Fisiopatologia Medic