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Evaluation of TGF-b1 function in the hypothalamus of animals with obesity and diabetes induced by high-fat diet

Grant number: 16/17810-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2017
Effective date (End): November 30, 2020
Field of knowledge:Biological Sciences - Physiology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Eliana Pereira de Araujo
Grantee:Natália Ferreira Mendes
Home Institution: Faculdade de Enfermagem. Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):17/22511-8 - Role of microglial cells in the high-fat diet-induced hypothalamic inflammation, BE.EP.DR

Abstract

Diabetes is a serious chronic disease that is associated with increased morbidity and premature mortality. Its prevalence has been increasing exponentially in recent decades, becoming a public health problem in many countries. The global diabetes epidemic is driven by increasing in the obesity. Excess body fat increases the risk of insulin resistance and glucose intolerance, and contributes to the low-grade inflammation, triggered in part by diet rich in saturated fat. When this inflammation reaches the hypothalamus, the control of energy homeostasis is impaired. In obese animals, these changes in glycemic control are associated, at least in part, to the increase in TGF-²1 levels in the hypothalamus. At normal levels, TGF-²1 binds to its receptor and activates a cascade of intracellular signaling proteins which several of SMAD family are activated, resulting in gene transcription of several proteins that are important for cell growth and proliferation. In obesity, the increase in TGF-²1 levels in the hypothalamus, however, leads to the formation of RNA stress granules which degrade mRNA IkB and promotes atypical activation of NF-kB, resulting in dysregulation of the ubiquitin-proteasome system and enhancing the inflammatory response in this brain region. It is believed that this is a hypothalamic independent mechanism which results in the pro-diabetic phenotype in overweight/obesity. The molecular mechanisms involved in the deregulation have not yet been fully elucidated. Therefore, the purpose of this study is to identify the effects of increased TGF-²1 expression in the hypothalamus on regulation of glucose homeostasis in response to inflammation triggered by saturated fatty acids. For this we will use Swiss mice and neurospheres culture exposed to high fat diet and palmitate, respectively. We will evaluate proteins involved in the signaling of TGF-²1 in response to fatty acids, blocked the action of TGF-²1 and verified the impact of this event on energy homeostasis. To evaluate the data we'll use test t student and analysis of variance. The level of significance will be p <0.05. (AU)

Scientific publications
(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)
MENDES, NATALIA F.; KIM, YOUNG-BUM; VELLOSO, LICIO A.; ARAUJO, ELIANA P. Hypothalamic Microglial Activation in Obesity: A Mini-Review. FRONTIERS IN NEUROSCIENCE, v. 12, NOV 15 2018. Web of Science Citations: 3.
GASPAR, JOANA M.; MENDES, NATALIA FERREIRA; CORREA-DA-SILVA, FELIPE; DE LIMA-JUNIOR, JOSE C.; GASPAR, RODRIGO C.; ROPELLE, EDUARDO R.; ARAUJO, ELIANA P.; CARVALHO, HUMBERTO M.; VELLOSO, LIDO A. Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity. BRAIN BEHAVIOR AND IMMUNITY, v. 73, p. 550-561, OCT 2018. Web of Science Citations: 1.
MENDES, NATALIA F.; GASPAR, JOANA M.; LIMA-JUNIOR, JOSE C.; DONATO, JR., JOSE; VELLOSO, LICIO A.; ARAUJO, ELIANA P. TGF-beta 1 down-regulation in the mediobasal hypothalamus attenuates hypothalamic inflammation and protects against diet-induced obesity. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 85, p. 171-182, AUG 2018. Web of Science Citations: 6.

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