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Modulation of hypothalamic AMPK and energy homeostasis by LPS: the role of toll like Receptor-4 (TLR-4)


In modern society the high prevalence of diseases associated with obesity has motivated studies to know the origin molecular and behavioral of these pathologies. the factors that are associated with the development of obesity, the behavioral and nutritional factors have contributed most significantly to the rates achieved today. However, the genetic and molecular characteristics combined with the behavioral factor result in a combination more dangerous to the individual.From the physiological point of view the control of food intake and energy expenditure is performed by redundant mechanisms. Among these mechanisms we can mention the structures and the hypothalamic neuropeptides responsible for receiving hormonal signals from the periphery, such as insulin, leptin, adiponectin and ghrelin. More recently, the nutrients absorbed from the diet and those produced by adipose tissue and liver also were included.The action in the hypothalamus of the above components are integrated and generated signals are directed to other hypothalamic regions and then to the peripheral tissues. For this, the hypothalamic neurons need protein capable of receiving these signals and to promote changes in cell metabolism. The protein AMPK, ACC and mTOR is found in this region of the central nervous system (CNS) and are modulated by factors mentioned above. Currently, chronic inflammatory processes have received great attention in studies to know the molecular mechanisms related to obesity and diabetes. Inflammatory processes promote biochemical changes that lead to a subnormal physiological response to hormones in different tissues. Pro-inflammatory cytokines such as TNFa, IL-1b and IL-6 are the protagonists of these mechanisms by activating serine kinases (JNK and IKK) that phosphorylate serine in the proteins of the signaling pathway of insulin and leptin causing a reduction in the hormonal signal. The expression of these cytokines may be stimulated by the consumption of high fat diet or by presence of pathogens that activate the inflammatory response through receptors like Toll like receptor (TLR). The reduced food intake and the increase in the body temperature are classic signs of inflammation and / or infectious, with important participation of the hypothalamus. Among the numerous studies performed to understand the intricate mechanism of central control of hunger and modulation of energy homeostasis, many investigators has evaluated the involvement of hypothalamic AMPK / ACC and mTOR. In this sense, modulation of these proteins from the hypothalamic activation of TLR in the hypothalamus may be an important triggering mechanism of the negative effects of chronic inflammatory processes.This question could also be addressed by evaluating the side effects on the peripheral metabolism, such as the production of glucose by the liver and insulin sensitivity. Thus, the interest of this project is to characterize, firstly, the effects of TLR activation on the modulation of AMPK, ACC and mTOR in the hypothalamus and then evaluate the effects on energy homeostasis. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SANTOS, G. A.; MOURA, R. F.; VITORINO, D. C.; ROMAN, E. A. F. R.; TORSONI, A. S.; VELLOSO, L. A.; TORSONI, M. A.. Hypothalamic AMPK activation blocks lipopolysaccharide inhibition of glucose production in mice liver. Molecular and Cellular Endocrinology, v. 381, n. 1-2, p. 88-96, . (10/14034-6, 09/16775-6, 11/17656-0)
MELO, ARINE M.; BENATTI, RAFAELA O.; IGNACIO-SOUZA, LETICIA M.; OKINO, CAROLINE; TORSONI, ADRIANA S.; MILANSKI, MARCIANE; VELLOSO, LICIO A.; TORSONI, MARCIO ALBERTO. Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 63, n. 5, p. 682-692, . (11/17656-0, 09/50809-5)

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