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

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

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

Sleep duration in elderly obese patients correlated negatively with intake fatty

Study objectives: The purpose of the present study was to evaluate the relationship between sleep duration and dietary habits in elderly obese patients treated at an institute of cardiology. Methods: The fifty-eight volunteers were elderly patients with obesity (classified as obese according to BMI) of both genders, between 60 and 80 years of age. All participants were subjected to assessments of food intake, anthropometry, level of physical activity, and duration of sleep. Results: The men had significantly greater weight, height, and waist circumference than women. Sleep durations were correlated with dietary nutrient compositions only in men. We found a negative association between short sleep and protein intake (r = -0.43; p = 0.02), short sleep and monounsaturated fatty acids intake (r = -0.40; p = 0.03), and short sleep and cholesterol dietary intake (r = -0.50; p = 0.01). Conclusions: We conclude that mainly in men, volunteers that had short sleep duration showed a preference for high energy-density as fatty food, at least in part, may explain the relationship between short sleep duration and the development of metabolic abnormalities

Long-term interdisciplinary therapy reduces endotoxin level and insulin resistance in obese adolescents

Aim: the purpose of the present study was to assess the dietary fat intake, glucose, insulin, Homeostasis model assessment for insulin resistance HOMA-IR, and endotoxin levels and correlate them with adipokine serum concentrations in obese adolescents who had been admitted to long-term interdisciplinary weight-loss therapy.Design: the present study was a longitudinal clinical intervention of interdisciplinary therapy. Adolescents (n = 18, aged 15-19 y) with a body mass index >95th percentile were admitted and evaluated at baseline and again after 1 year of interdisciplinary therapy. We collected blood samples, and IL-6, adiponectin, and endotoxin concentrations were measured by ELISA. Food intake was measured using 3-day diet records. in addition, we assessed glucose and insulin levels as well as the homeostasis model assessment for insulin resistance (HOMA-IR).Results: the most important finding from the present investigation was that the long-term interdisciplinary lifestyle therapy decreased dietary fat intake and endotoxin levels and improved HOMA-IR. We observed positive correlations between dietary fat intake and endotoxin levels, insulin levels, and the HOMA-IR. in addition, endotoxin levels showed positive correlations with IL-6 levels, insulin levels and the HOMA-IR. Interestingly, we observed a negative correlation between serum adiponectin and both dietary fat intake and endotoxin levels.Conclusions: the present results indicate an association between dietary fat intake and endotoxin level, which was highly correlated with a decreased pro-inflammatory state and an improvement in HOMA-IR. in addition, this benefits effect may be associated with an increased adiponectin level, which suggests that the interdisciplinary therapy was effective in improving inflammatory pathways.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Dept Fisiol, São Paulo, BrazilDept Biociencias, São Paulo, BrazilDept Psicobiol, São Paulo, BrazilUniversidade Federal de São Paulo UNIFESP, São Paulo, BrazilICB Univ São Paulo USP, Grp Metab & Canc, São Paulo, BrazilUniv So Santa Catarina, Hlth Sci Unit, Lab Exercise Biochem & Physiol, Criciuma, SC, BrazilUniversidade Federal de São Paulo UNIFESP, São Paulo, BrazilFAPESP: 2011/50356-0FAPESP: 2011/50414-0Web of Scienc