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The RANKL system and the TLR4 pathway in hypofagia induced in sepsis model

Grant number: 17/10774-4
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2017
Effective date (End): March 31, 2018
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal researcher:Mariana Kiomy Osako
Grantee:João Sakuray Pais
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/11092-6 - RANKL system in phenotypic switch of macrophages in adipose tissue inflammation, AP.JP

Abstract

Recent studies demonstrated that in situations of sepsis both in human and animal models, one of the symptoms that manifest is the hypophagia. This hypophagia would be a consequence of the acute inflammation caused by the activation of the TLR4 pathway in cells in contact with the bacterial components, such as the LPS, releasing pro-inflammatory cytokines that trigger leptin production. The leptin production is a hormone produced by the white adipose tissue that acts in the hypothalamus, and the activation of the leptin receptor (Ob-R) initiates an internal signaling that involves the activation of JAK2 and STAT3 and culminates in the phosphorylation of AMPK, in the activation pathway for the satiety. Associated with the context of inflammation is the RANK/RANKL/OPG system, the focus of the studies of our laboratory. The RANKL is a molecule mainly associated to the bone metabolism, acting as an activator of osteoclasts and target of the OPG. In this area, studies of our research group already demonstrated an anti-inflammatory effect of the RANKL in murine models of cerebral ischemia and macrophage activation by LPS, once that it reduces the production of pro-inflammatory cytokines due to activation of TLR4. Therefore, the objective of this project is to elucidate the relation between the RANK/RANK/OPG system with the hypophagia that manifests in bacterial infections, ad to elucidate what are the cells involved in this process and the signal transmission underpinning the leptin production and the generation of hypophagia. (AU)