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Role of leptin in regulation of systemic inflammation

Grant number: 14/03719-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2014
Effective date (End): April 08, 2018
Field of knowledge:Biological Sciences - Immunology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Alexandre Alarcon Steiner
Grantee:Evilin Naname Komegae
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/03831-8 - Linking energy balance to systemic inflammation: role of leptin, AP.JP
Associated scholarship(s):16/15555-6 - Role of leptin in regulation of systemic inflammation, BE.EP.PD

Abstract

There is no doubt that obesity is associated with the risk of systemic inflammation and related syndromes (sepsis). It is possible that leptin, a hormone produced by adipose tissue, is an important link between obesity and inflammation, but the existence of contradictory data and the presence of multiple comorbidities in animals deficient in leptin (or leptin receptor) have hindered the understanding the real role of leptin in systemic inflammation. Our proposal is to clarify the roles ofleptin in systemic inflammation employing strategies of acute silencing and overexpression of the leptin receptor, models in which the roles of leptin may be determined before the onset of comorbidities. Our experimental strategy will evaluate whether leptin at physiological concentrations (not obese) is able to contain the sepsis by exert anti -inflammatory effects by the predominance ofcentral mechanisms, since Wistar rats have the leptin receptor b (RLb) silenced sharply by the use of RNA interference before being induced to endotoxic shock. Evaluate the application of the HPA axis and/or anti -inflammatory vagus nerve , via RLb receptors expressed in the CNS in the containment of systemic inflammation by overexpression of RLb in the CNS of adrenalectomized or subjected to subdiaphragmatic vagotomy rats, respectively . In the contrast, we propose that leptin insupraphysiological concentrations associated with obesity lose predominant action in the CNS by resistance to anti -inflammatory effects of leptin generated, and then pass to contribute to the development of sepsis by the predominance of peripheral mechanisms of action, by action inmacrophages. For this, inbred Lewis rats obese or injected with supraphysiological concentrations of leptin will be depleted of macrophages by use of liposomes. These animals will be repopulate with monocytes that are deficient or overexpressing RLb before induction of endotoxic shock. Therefore, this project by using innovative methodologies designed to test two mechanisms (a central and a peripheral) by which the leptin regulate the systemic inflammation. (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)
KOMEGAE, EVILIN N.; FONSECA, MONIQUE T.; CRUZ-MACHADO, SANSERAY DA SILVEIRA; TURATO, WALTER M.; FILGUEIRAS, LUCIANO R.; MARKUS, REGINA P.; STEINER, ALEXANDRE A. Site-Specific Reprogramming of Macrophage Responsiveness to Bacterial Lipopolysaccharide in Obesity. FRONTIERS IN IMMUNOLOGY, v. 10, JUN 28 2019. Web of Science Citations: 0.
FLATOW, ELIZABETH A.; KOMEGAE, EVILIN N.; FONSECA, MONIQUE T.; BRITO, CAMILA F.; MUSTEATA, FLORIN M.; ANTUNES-RODRIGUES, JOSE; STEINER, ALEXANDRE A. Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 313, n. 5, p. R572-R582, NOV 2017. Web of Science Citations: 5.
STEINER, ALEXANDRE A.; FLATOW, ELIZABETH A.; BRITO, CAMILA F.; FONSECA, MONIQUE T.; KOMEGAE, EVILIN N. Respiratory gas exchange as a new aid to monitor acidosis in endotoxemic rats: relationship to metabolic fuel substrates and thermometabolic responses. PHYSIOLOGICAL REPORTS, v. 5, n. 1 JAN 2017. Web of Science Citations: 1.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.