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Investigation of pro- and anti-inflamatory cytokines in biophysical properties of POMC and AgRP neurons of the arcuate nucleus of the hypothalamus

Grant number: 17/21854-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2018
Effective date (End): September 30, 2020
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Jose Donato Junior
Grantee:Fernanda Machado Chaves
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:17/02983-2 - The role of growth hormone in the brain: relevance for neural functions and in disease, AP.TEM

Abstract

Obesity incidence has grown exponentially around the world and is associated with several comorbidities. Moreover, Obesity is characterized by a low grade systemic inflammation. Hypothalamus main function is to regulate energy homeostasis. The AgRP/NPY and POMC neurons of the arcuate nucleus of the hypothalamus (ARH) are part of the central nervous system that is responsible for the regulation of energy balance and food intake. Since the hypothalamus integrates signals from peripheral systems, translating into neuronal, neuroendocrine and metabolic changes, hypothalamic neurons are also sensitive to changes of inflammatory state. Studies have shown that consumption of diets rich in saturated fatty acids induces inflammation, leading to the production of proinflammatory cytokines. These cytokines may lead to impairment of leptin and insulin signaling in the hypothalamus. On the other hand, some mono and polyunsaturated fatty acids can improve metabolic status and decrease hypothalamic inflammation. Thus, Obesity is a chronic disease and is known to be associated with increased circulating levels of pro-inflammatory cytokines. Understanding how these cytokines interact and regulate the circuits that control energy homeostasis in the ARH is crucial to understand this metabolic disease. Thus, the objective of this study is to evaluate the effects of pro- and anti-inflammatory cytokines on the biophysical properties of POMC and AgRP neurons of the ARH. In order to examine the acute effects of IL-1², IL-6, TNF-± and IL10 cytokines on POMC or AgRP neurons, whole-cell electrophysiological records will be performed, in which we will evaluate the membrane resting potential, frequency of action potentials and ionic conductance. If these cytokines produce significant effects, then we will use pharmacological inhibitors to determine whether the response observed is dependent on action-mediated synaptic transmission. After analyzing the data obtained, we can also determine the signaling pathways that participate in the observed responses. In addition, we will evaluate the effects of the consumption of a high-fat diet for 1 and 6 weeks. Therefore, the results of the proposed project can expand our knowledge regarding the effects of cytokines, which are altered in Obesity, on the activity of neuronal circuits that regulate energy balance. (AU)