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Molecular mechanismsof insulin resistance in hypothalamus And peripheral tissues: effects of leptin, grelin and resistin

Grant number: 01/03176-5
Support type:Research Projects - Thematic Grants
Duration: March 01, 2002 - October 31, 2006
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Mario Jose Abdalla Saad
Grantee:Mario Jose Abdalla Saad
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Co-Principal Investigators:Everardo Magalhães Carneiro

Abstract

Insulin resistance, defined as subnormal response to a given concentration of insulin, is an important component in the pathophysiology of diseases with high prevalence in the population as obesity, diabetes mellitus type 2 and hypertension. The investigation of proteins involved in insulin signal transduction has add important information in the molecular mechanisms of insulin resistance. Insulin initiates its growth and metabolic promoting effects by binding to its receptor at the plasma membrane, which has tyrosine-kinase activity, and is able to autophosphorylates and phosphorylates cytoplasmic proteins called insulin receptor substrates (IRSs). The main substrates of insulin receptor are IRS-1 and IRS-2, which when phosphorylated in tyrosine bind and activate proteins with SH2 domains as PI 3-kinase and the phosphatase SHP2. These initial steps lead to the activation of two serine/threonine kinases Akt and MAPK. Previous studies from our and other laboratories demonstrated the regulation of these early steps in insulin action in liver and muscle of animal models of insulin resistance. Recently, it was demonstrated that insulin signal transduction in brain, specially in hypothalamus is important for the control of body weight and peripheral insulin sensitivity. However, it was not investigated the regulation of insulin signaling in the hypothalamus of animal models of insulin resistance. Thus, the first aim of this study is to investigate the early steps in insulin action, i. e. , insulin receptor autophosphorylation, phosphorylation in tyrosine of IRS-1 and IRS-2, and the interaction of these substrates with PI 3-kinase and SHP2, as well as the activation of Akt and MAPK in the hypothalamus of the following animal models of insulin resistance: Zucker rats, rats cronically treated with insulin, and rats fed a high fat diet. We also intend to investigate the effect of drugs that improve insulin action in the regulation of these proteins in hypothalamus. Recently, it was demonstrated that besides insulin signaling through IRSs, the receptor is able to phosphorylate the protein c-Cbl, and this pathway is important for the metabolic effects of insulin in adipocytes. However, it was not investigated yet the expression and insulin-induced phosphorylation levels of this protein in animal tissues in vivo. The second aim of this project is to investigate the regulation of c-Cbl in tissues of animal models of insulin resistance. The cross-talk between insulin and leptin signaling in hypothalamus is of great interest since in some physiopathological situations there is resistance to both hormones. Furthermore, these two hormones use similar pathways to transduce the signal, and our laboratory demonstrated that there is an interaction between insulin and leptin signaling which amplify the signal of each one. The third aim of this project is to investigate the effect of situations that change body weight (caloric restriction, metformin) on... (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
The mystery behind diabetes 

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)
CARVALHO-FILHO, M. A.; UENO, M.; HIRABARA, S. M.; SEABRA, AMEDEA BAROZZI; CARVALHEIRA, J. B.; OLIVEIRA, M. G. DE; VELLOSO, L. A.; CURI, R.; SAAD, M. J. S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt - A novel mechanism of insulin resistance. Diabetes, v. 54, n. 4, p. 959-967, Apr. 2005.

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