RANKL system in phenotypic switch of macrophages in adipose tissue inflammation

• Grant number: 14/11092-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2015
• End date: October 31, 2020
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Mariana Kiomy Osako
• Grantee: Mariana Kiomy Osako
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 19/20444-7 - Analysis of glucose metabolism in OPG-/- mice, BP.TT; 17/10774-4 - The RANKL system and the TLR4 pathway in hypofagia induced in sepsis model, BP.IC; 17/14368-0 - RANKL and osteoprotegerin expression profile in high fat diet fed mice, BP.IC; + associated scholarships 16/22009-8 - RANKL system and the metabolically activation of macrophages in adipose tissue inflammation, BP.IC; 15/26088-7 - Study of RANKL/RANK/OPG signaling pathway in beige adipose tissue differentiation, BP.DR; 16/06532-2 - RANKL and osteoprotegerin expression profile in hypercaloric diet, BP.IC; 16/00508-2 - RANKL system in TLR4 signaling pathway, BP.DD; 16/00651-0 - RANKL System on macrophages M1/M2 polarization, BP.MS - associated scholarships

Abstract

High serum osteoprotegerin (OPG) level has been associated with type 2 diabetes mellitus (T2DM), vascular calcification and predicts cardiovascular outcomes, but the biological explanation for the rise of OPG level remains unclear. OPG is a decoy receptor of RANKL, and the binding results in inhibition of RANKL activation of the membrane bound RANK. We have reported the contribution of this RANKL system in vascular calcification, and recent evidences suggest an important role in regulating macrophages inflammatory responses. This study aims to clarify the molecular mechanism underpinning RANKL activation in macrophages, to elucidate its role in macrophage phenotypic switch between pro- (M1) and anti-inflammatory (M2) states. The role in M1/M2 macrophages will be explored in adipose tissue inflammation and insulin resistance by focusing on toll like receptor 4 (TLR-4) pathways in murine model under high fat diet. The results obtained in this study will provide a biological explanation for the increase in serum OPG level of diabetic patients, and whether it can be considered as a contributor for the adipose tissue inflammation and eventually insulin resistance. RANKL/OPG system has the potential to become a therapeutic target to regulate macrophage activation. (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)

PRZYGODDA, FRANCIELE; LAUTHERBACH, NATALIA; BUZELLE, SAMYRA LOPES; GONCALVES, DAWIT ALBIEIRO; ASSIS, ANA PAULA; PAULA-GOMES, SILVIA; RISSATO GAROFALO, MARIA ANTONIETA; HECK, LILIAN CARMO; MATSUO, FLAVIA SAYURI; MOTA, RYERSON FONSECA; et al. Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions. Journal of Applied Physiology, v. 128, n. 4, p. 855-871, APR 2020. (12/24524-6, 18/10089-2, 16/00508-2, 15/26088-7, 14/11092-6, 13/17111-0, 12/18861-0)

MOTA, RYERSON FONSECA; DE ARAUJO, PAULO HENRIQUE CAVALCANTI; CEZINE, MARIA EDUARDA RAMOS; MATSUO, FLAVIA SAYURI; METZNER, RODRIGO JAIR MORANDI; DE BIAGI JUNIOR, CARLOS ALBERTO OLIVEIRA; PERONNI, KAMILA CHAGAS; HAYASHI, HIROKI; SHIMAMURA, MUNEHISA; NAKAGAMI, HIRONORI; et al. RANKL Impairs the TLR4 Pathway by Increasing TRAF6 and RANK Interaction in Macrophages. BIOMED RESEARCH INTERNATIONAL, v. 2022, p. 13-pg., 2022-04-12. (16/22009-8, 16/00508-2, 14/11092-6, 16/00651-0, 15/26088-7)