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Role of STAT3 and ERK in SF1 neurons of hypothalamus in the effects of leptin and estradiol on energy homeostasis

Grant number: 14/17248-8
Support type:Regular Research Grants
Duration: March 01, 2015 - August 31, 2017
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Lucila Leico Kagohara Elias
Grantee:Lucila Leico Kagohara Elias
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated grant(s):16/50015-2 - Development of mouse models using CRISPR-Cas9 technology, AP.R SPRINT

Abstract

The leptin, an adipocyte-derived hormone, and estradiol , , play an important role in the control of energy homeostasis. Through their actions in the central nervous system (CNS), more specifically in the hypothalamus, leptin promotes a state of negative energy balance (decreased food intake and increased energy expenditure). Many of these actions of leptin are mediated by the activation of the STAT3 and ERK signaling pathway in hypothalamic neurons. Of the many neuronal nuclei that express leptin receptors (LepRs) and estradiol receptor (ER), the ventromedial nucleus of the hypothalamus (VMH) is already known to mediate some effects of leptin and estradiol in the energy balance. Studies have shown that the specific deletion of LepRs in this hypothalamic area in mice causes an increase in the body weight and induces obesity by high fat diet (HFD) challenge. However, although the VMH role in mediate the anorexigenic and body weight reduction effects of leptin is already very well determined, little is known about the intracellular mechanisms which leptin activates to mediates its effects in this hypothalamic area. This project aims to evaluate the role of the STAT3 and ERK signaling in mediate the leptin and estradiol effects in the energy balance via VMH. To accomplish that, using cre-lox technology, we will generate mice that do not express STAT3 or ERK only in neurons that express the steroidogenic fator 1 (SF1) in the VMH and, then, we will evaluate the effects of STAT3 or ERK disruption in energy and glucose homeostasis in mice. We will also evaluate leptin sensitivity and its effects on body weight and food intake after chronic leptin infusion. (AU)