Characterization of hypothalamic AMPK/mTOR in cancer-induced anorexia

Orientador: Jose Barreto Campello CarvalheiraTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A teoria das doenças geradas por citocinas inflamatórias trouxe ao longo dos anos indícios que o organismo pode produzir citocinas que desempenham respostas biológicas benéficas ou prejudiciais. Com o passar dos anos ficou claro que a inflamação é um mecanismo chave na fisiopatologia do câncer. Interessantemente, diversos estudos sugerem que a AMPK e mTOR hipotalâmica, importantes moléculas no controle do balanço energética também seja responsável por modular a inflamação e anorexia. Nesse sentido, foi observado: 1) A inibição da AMPK hipotalâmica proporciona redução do peso corporal e da inflamação central e periférica potencializando o crescimento tumoral. Por outro lado, a ativação da AMPK com AICAR, salicilato e vetor viral reverte à anorexia induzida pelo câncer. Entretanto, os efeitos benéficos do AICAR foram bloqueados quando associados com os antagonistas colinérgicos, sugerindo que a AMPK no núcleo ventromedial é responsável pelo controle da anorexia e inflamação. 2) A AMPK no núcleo ventromedial do hipotálamo, principalmente a isoforma alfa 1 ativa a termogênese aumentando a produção de calor na qual converte tecido adiposo branco em bege. Além disso, o uso do antagonista ?3 adrenérgico ou a ativação da AMPK foram capazes de atenuar a produção de calor melhorando a caquexia induzida pelo câncer. 3) Roedores com câncer possuem a via do IKK/mTOR ativada no núcleo arqueado do hipotálamo proporcionando anorexia e caquexia. Por outro lado, o bloqueio da S6K com adenovírus foi capaz de melhorar a anorexia. Portanto, esses achados permitem concluir que o hipotálamo funciona como um centro regulador da anorexia e caquexia induzida pelo câncer, abrindo novos horizontes para o tratamento do câncerAbstract: The theory of diseases generated by inflammatory cytokine brought over the years evidence that the organism may produce cytokine with beneficial and deleterious responses. Nowadays, it is clear that the inflammation is a key mechanism in cancer pathophysiology. Interestingly, several studies suggest that hypothalamic AMPK and mTOR, important molecules in the energy balance control also is responsible for modulation of both inflammation and anorexia. The studies presented herein observed that: 1) Inhibition of hypothalamic AMPK leads to weight loss and central and systemic inflammation which potentiates the tumor growth. However, AMPK activation with AICAR, salicylate and vector viral might reverse the cancer-mediated anorexia. Nevertheless, benefic effects of AICAR are blunted with a combination of cholinergic antagonists, suggesting that ventromedial of hypothalamus (VMH)-specific AMPK action is responsible for the anorexia and inflammation control. 2) VMH-specific AMPK, particularly the isoform alpha 1 activates thermogenesis increasing heat production which switches the white adipose tissue in beige. Furthermore, ?3 adrenergic antagonist and AMPK activation were able to attenuate the heal generation, block the "browning of WAT" and improve the cancer cachexia. 3) Cancer rats have activated IKK/mTOR pathway in arcuate nucleus (ARC) of the hypothalamus. In contrast, neutralization of S6K through adenovirus was able to improve anorexia. Therefore, our data show evidences that the hypothalamus a key center that integrates a number of mechanisms triggered by cancer-induced anorexia and -cachexia, opening new horizons for the treatment of cancerDoutoradoFisiopatologia MédicaDoutor em Ciência

Foods and nutrients modulates the release of gastrointestinal hormones anorexigenic

FOODS AND NUTRIENTS MODULATES THE RELEASE OF GASTROINTESTINAL HORMONES ANOREXIGENICThe short-term regulation of food intake controls what, how much and when we eat during one day or a single meal. When ingested, the nutrients produce satiety by means of mechanic stimulation and hormonal release. Many of these hormones also inhibit gastric empting and increase the gastric mecanorreceptor stimulaton. The present review of the literature focuses on the effect of different food and nutrients on the release of anorexigenic regulators of food intake, as polypeptide insulinotropic glucose dependent, oxyntomodulin, peptide YY, cholecystokinin, and glucagon-like peptide 1.Univ Fed Sao Paulo, Disciplina Fisiol Nutr, Sao Paulo, BrazilUniv Fed Sao Paulo, Disciplina Fisiol Nutr, Sao Paulo, BrazilWeb of Scienc

Precisión de diámetro abdominal sagital como predictor de la grasa abdominal en brasileños adultos: una comparación con la circunferencia de la cintura

Aim: We aim was to compare the sagittal abdominal diameter (SAD) with waist circumference (WC) as a predictor of central obesity among adults and to identify the sensitivity and specificity of the best cut-off point for SAD.Methods: A cross-sectional study of 266 Brazilians adults (euthrophic and overweight), aged 31-84 years old, of which 89 men and 177 women, was carried out. Anthropometric measurements such as SAD, weight, height, waist and hip circumferences, waist and hip ratio, body mass index, body fat percentage were performed. Receiver Operating Characteristics (ROC) curve was used to identify the sensitivity and specificity of the best cut off point for SAD as a predictor of central obesity. Statistical analysis were considered significant with a value of p < 0.05.Results: the SAD measurement was positively correlated with WC for both genders, although stronger among overweight and obesity women (r = 0.71; p < 0.001 and r = 0.79; p < 0.001, respectively) than men. ROC curves identified the best cut-off points for SAD of 23.1 cm and 20.1 cm for men and women (96% and 85% sensitivity, 86% and 84% specificity, respectively).Conclusion: SAD measurement may be used as an anthropometric tool to identify central obesity among women for presenting adequate sensitivity and specificity.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, BrazilSão Paulo State Univ UNESP, Dept Publ Hlth, Ctr Metab Exercise & Nutr CeMENutri, Botucatu, SP, BrazilPUC, Sch Nutr, Campinas, SP, BrazilSão Paulo State Univ UNESP, Dept Stat, Botucatu, SP, BrazilUniversidade Federal de São Paulo, Dept Physiol, BR-04023062 São Paulo, BrazilWeb of Scienc

Perfil lipídico y factores de riesgo cardiovascular en estudiantes universitarios brasileños de primer año de Sao Paulo

Background/aims: the surveillance of cardiovascular risk factors has been recommended worldwide. the current study is aimed to estimate the prevalence of cardiovascular risk factors among first-year students from a public university in the city of São Paulo, Brazil.Methods: A cross-sectional study of 56 first-year students, of both genders, was performed. Information about demographic characteristics, family history of chronic diseases, smoking, and physical activity was obtained by means of a standardised questionnaire. Anthropometrical parameters (BMI, waist circumference, body fat percentage), metabolic parameters (glycaemia, serum lipid profile), and dietary data (total energy intake, percentage of total energy from macronutrients, cholesterol and dietary fiber) were assessed.Results: the risk of cardiovascular diseases was characterised by family history of cardiovascular diseases (44.6%), smoking (10.7%), physical inactivity (35.7%), borderline high total cholesterol and LDL-c levels (16.1% and 5.4, respectively), decreased HDL-c levels (8.9%), increased triglyceride levels (8.9%), and overweight and obesity (17.8% and 7.1%, respectively). the diet of the students was inadequate: it was high in fat and protein, and low in carbohydrate and dietary fibre.Conclusions: the prevalence of risk factors for cardiovascular diseases in young adults draws attention to the need to adopt preventive plans in the university setting.Foundation of Administrative Development (Fundap, Brazil)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Div Nutr, Dept Prevent Med, São Paulo, BrazilUniversidade Federal de São Paulo, Div Nutr Physiol, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Nutr, Dept Prevent Med, São Paulo, BrazilUniversidade Federal de São Paulo, Div Nutr Physiol, Dept Physiol, São Paulo, BrazilWeb of Scienc

Both adiponectin and interleukin-10 inhibit LPS-induced activation of the NF-kappa B pathway in 3T3-L1 adipocytes

Adiponectin and interleukin 10 (IL-10) are adipokines that are predominantly secreted by differentiated adipocytes and are involved in energy homeostasis, insulin sensitivity, and the anti-inflammatory response. These two adipokines are reduced in obese subjects, which favors increased activation of nuclear factor kappa B (NF-kappa B) and leads to elevation of pro-inflammatory adipokines. However, the effects of adiponectin and IL-10 on NF-kappa B DNA binding activity (NF-kappa Bp50 and NF-kappa Bp65) and proteins involved with the toll-like receptor (TLR-2 and TLR-4) pathway, such as MYD88 and TRAF6 expression, in lipopolysaccharide-treated 3T3-L1 adipocytes are unknown. Stimulation of lipopolysaccharide-treated 3T3-L1 adipocytes for 24 h elevated IL-6 levels; activated the NF-kappa B pathway cascade; increased protein expression of IL-6R, TLR-4, MYD88, and TRAF6; and increased the nuclear activity of NF-kappa B (p50 and p65) DNA binding. Adiponectin and IL-10 inhibited the elevation of IL-6 levels and activated NF-kappa B (p50 and p65) DNA binding. Taken together, the present results provide evidence that adiponectin and IL-10 have an important role in the anti-inflammatory response in adipocytes. in addition, inhibition of NF-kappa B signaling pathways may be an excellent strategy for the treatment of inflammation in obese individuals. (C) 2011 Elsevier B.V. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Fis, BR-04023060 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Canc & Metab Grp, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Fis, BR-04023060 São Paulo, BrazilFAPESP: 08/54733-0Web of Scienc

Dietary whey protein lessens several risk factors for metabolic diseases: a review

Obesity and type 2 diabetes mellitus (DM) have grown in prevalence around the world, and recently, related diseases have been considered epidemic. Given the high cost of treatment of obesity/DM-associated diseases, strategies such as dietary manipulation have been widely studied; among them, the whey protein diet has reached popularity because it has been suggested as a strategy for the prevention and treatment of obesity and DM in both humans and animals. Among its main actions, the following activities stand out: reduction of serum glucose in healthy individuals, impaired glucose tolerance in DM and obese patients; reduction in body weight; maintenance of muscle mass; increases in the release of anorectic hormones such as cholecystokinin, leptin, and glucagon like-peptide 1 (GLP-1); and a decrease in the orexigenic hormone ghrelin. Furthermore, studies have shown that whey protein can also lead to reductions in blood pressure, inflammation, and oxidative stress.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ Estadual Campinas UNICAMP, Dept Clin Med, BR-13083970 Campinas, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, São Paulo, BrazilUniv Extremo Catarinense, Lab Bioquim & Fisiol Exercicio, Criciuma, SC, BrazilUniv Estadual Paulista UNESP, Dept Patol, Botucatu, SP, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Fisiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Fisiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Psicobiol, São Paulo, BrazilWeb of Scienc

Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects

Introduction: A sedentary lifestyle increases the risk of developing cardiovascular disease, obesity, and diabetes. This phenomenon is supported by recent studies suggesting a chronic, low-grade inflammation status. Endotoxin derived from gut flora may be key to the development of inflammation by stimulating the secretion of inflammatory factors. This study aimed to examine plasma inflammatory markers and endotoxin levels in individuals with a sedentary lifestyle and/or in highly trained subjects at rest. Methods: Fourteen male subjects (sedentary lifestyle n = 7; highly trained subjects n = 7) were recruited. Blood samples were collected after an overnight fast (similar to 12 h). the plasmatic endotoxin, plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 (MCP1), ICAM/CD54, VCAM/CD106 and lipid profile levels were determined.Results: Endotoxinemia was lower in the highly trained subject group relative to the sedentary subjects (p < 0.002). in addition, we observed a positive correlation between endotoxin and PAI-1 (r = 0.85, p < 0.0001), endotoxin and total cholesterol (r = 0.65; p < 0.01), endotoxin and LDL-c (r = 0.55; p < 0.049) and endotoxin and TG levels (r = 0.90; p < 0.0001). the plasma levels of MCP-1, ICAM/CD54 and VCAM/CD106 did not differ.Conclusion: These results indicate that a lifestyle associated with high-intensity and high-volume exercise induces favorable changes in chronic low-grade inflammation markers and may reduce the risk for diseases such as obesity, diabetes and cardiovascular diseases.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Physiol, Div Nutr, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilUniv São Paulo, Canc Metab Grp, Inst Biomed Sci, Dept Cell & Dev Biol, BR-05508 São Paulo, BrazilUniv Prebiteriana Mackenzie, Dept Phys Educ, Biol & Hlth Sci Ctr, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, Div Nutr, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biosci, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, São Paulo, BrazilFAPESP: 2008/03533-1Web of Scienc

Exercise training improves sleep pattern and metabolic profile in elderly people in a time-dependent manner

Aging and physical inactivity are two factors that favors the development of cardiovascular disease, metabolic syndrome, obesity, diabetes, and sleep dysfunction. in contrast, the adoption a habitual of moderate exercise may present a non-pharmacological treatment alternative for sleep and metabolic disorders. We aimed to assess the effects of moderate exercise training on sleep quality and on the metabolic profile of elderly people with a sedentary lifestyle. Fourteen male sedentary, healthy, elderly volunteers performed moderate training for 60 minutes/day, 3 days/week for 24 wk at a work rate equivalent to the ventilatory aerobic threshold. the environment was kept at a temperature of 23 +/- 2 degrees C, with an air humidity 60 +/- 5%. Blood and polysomnographs analysis were collected 3 times: at baseline (1 week before training began), 3 and 6 months (after 3 and 6 months of training). Training promoted increasing aerobic capacity (relative VO2, time and velocity to VO(2)max; p < 0.05), and reduced serum NEFA, and insulin concentrations as well as improved HOMA index (p < 0.05), and increased adiponectin levels (p < 0.05), after 3 months of training when compared with baseline data. the sleep parameters, awake time and REM sleep latency were decreased after 6 months exercise training (p < 0.05) in relation baseline values. Our results demonstrate that the moderate exercise training protocol improves the sleep profile in older people, but the metabolism adaptation does not persist. Suggesting that this population requires training strategy modifications as to ensure consistent alterations regarding metabolism.Universidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilCtr Estudo Psicobiol Exercicio, São Paulo, BrazilUniv Estadual Campinas, Dept Internal Med, Campinas, SP, BrazilUniversidade Federal de São Paulo, Dept Biociencia, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Fisiol, Disciplina Fisiol Nutr, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biociencia, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Fisiol, Disciplina Fisiol Nutr, São Paulo, BrazilWeb of Scienc

Importância dos efeitos fisiológicos do exercício na promoção da saúde

O exercício físico crônico realizado com intensidade e volume adequado, associado com suficiente tempo de recuperação, promove adaptações em diversos sistemas fisiológicos. Enquanto o exercício intenso e exaustivo é considerado um agente imunossupressor importante, este aumenta a incidência de infecções do trato respiratório superior. Em contrapartida, o exercício físico crônico moderado esta associado com a prevenção de doenças, e é preconizado no tratamento complementar de muitas doenças crônicas. Os efeitos do exercício físico crônico ocorrem em consequência do treinamento físico induzir várias adaptações bioquímicas, fisiológicas e psicológicas benéficas. Mais recentemente, o efeito do exercício físico agudo e o treinamento sobre o sistema imunológico têm sido discutidos, e muitos estudos sugerem a importância do sistema imunológico na prevenção e recuperação parcial em situações fisiopatológicas. Atualmente, existem duas hipóteses importantes que podem explicar os efeitos do exercício e do treinamento sobre o sistema imunológico, e seus possíveis efeitos sobre a promoção da saúde. Estas hipóteses são: (1) o efeito do exercício sobre os hormônios e citocinas, (2) efeitos do exercício em modular a concentração de glutamina. Nesta revisão, discutiremos a hipótese que o exercício pode modular a função imunológica e a importância do exercício em relação a várias doenças, bem como ele pode perturbar a homeostase