Linking energy balance to systemic inflammation: role of leptin

• Grant number: 12/03831-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: October 01, 2012
• End date: September 30, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Alexandre Alarcon Steiner
• Grantee: Alexandre Alarcon Steiner
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 14/03719-9 - Role of leptin in regulation of systemic inflammation, BP.PD

Abstract

Systemic inflammation is invariably associated with a thermoregulatory response: fever or hypothermia. The mechanisms of the selection between these responses are virtually unknown. We propose that the adipocyte-derived hormone, leptin, links the energy status of a subject to the selection of an appropriate thermoregulatory response during systemic inflammation. Conscious rats will be injected with bacterial lipopolysaccharide at doses that activate both febrigenic signaling (mediates fever) and cryogenic signaling (mediates hypothermia). Manipulations of the thermal environment will be employed to distinguish febrigenic from cryogenic signaling, a strategy that is based on the fact that the body temperature of rats in a warm environment is influenced only by febrigenic signals, whereas the body temperature of rats in a cooler environment is subject to the effects of cryogenic signals as well. Such a strategy will be used in conjunction with measurements of inflammatory mediators with known febrigenic or cryogenic actions. We expect to show that leptin inhibits cryogenic signaling while having little or no impact on febrigenic signaling. Withdrawal of this inhibition in food-deprived rats, in which leptin production is low, is expected to favor the development of hypothermia over fever. We will also identify the site of the anti-cryogenic action of leptin, with emphasis on the dorsomedial hypothalamus. Last, but not least, we will test two possible mechanisms by means of which leptin could inhibit cryogenic signaling. The first mechanism involves the preferential inhibition of cryogenic signaling over febrigenic signaling by an overactivation of the hypothalamo-pituitary-adrenal axis. The second mechanism involves altered responsiveness of thermoregulatory neurons to cryogenic mediators. (AU)

Scientific publications

(8)

(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. (12/03831-8, 18/03418-0, 14/03719-9, 13/13691-1, 15/04557-5, 16/04921-1, 17/13350-0, 14/17407-9)

STEINER, ALEXANDRE A.. Should we let fever run its course in the early stages of COVID-19?. JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, v. 113, n. 10, p. 3-pg., 2020-09-15. (18/03418-0, 12/03831-8, 16/04921-1)

CORRIGAN, JOSHUA J.; FONSECA, MONIQUE T.; FLATOW, ELIZABETH A.; LEWIS, KEVIN; STEINER, ALEXANDRE A.. Hypometabolism and hypothermia in the rat model of endotoxic shock: independence of circulatory hypoxia. JOURNAL OF PHYSIOLOGY-LONDON, v. 592, n. 17, p. 3901-3916, SEP 1 2014. (12/03831-8)

FONSECA, MONIQUE T.; RODRIGUES, ABNER C.; CEZAR, LUANA C.; FUJITA, ANDRE; SORIANO, FRANCISCO G.; STEINER, ALEXANDRE A.. Spontaneous hypothermia in human sepsis is a transient, self-limiting, and nonterminal response. Journal of Applied Physiology, v. 120, n. 12, p. 1394-1401, JUN 15 2016. (09/15530-0, 13/00506-1, 12/03831-8, 11/50761-2, 14/09576-5)

DANTONIO, VALTER; BATALHAO, MARCELO E.; FERNANDES, MARCIA H. M. R.; KOMEGAE, EVILIN N.; BUQUI, GABRIELA A.; LOPES, NORBERTO P.; GARGAGLIONI, LUCIANE H.; CARNIO, EVELIN C.; STEINER, ALEXANDRE A.; BICEGO, KENIA C.. Nitric oxide and fever: immune-to-brain signaling vs. thermogenesis in chicks. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 310, n. 10, p. R896-R905, MAY 15 2016. (14/13586-6, 12/19966-0, 13/13386-4, 12/03831-8, 14/50265-3)

STEINER, ALEXANDRE A.; ROMANOVSKY, ANDREJ A.. Energy Trade-offs in Host Defense: Immunology Meets Physiology. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 30, n. 12, p. 4-pg., 2019-12-01. (18/03418-0, 12/03831-8, 16/04921-1)

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. (16/04921-1, 13/09799-1, 14/03719-9, 12/03831-8)

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. (16/04921-1, 14/03719-9, 12/03831-8)