RANKL and osteoprotegerin expression profile in high fat diet fed mice

• Grant number: 17/14368-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date until: September 01, 2017
• End date until: July 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Mariana Kiomy Osako
• Grantee: Karen Cristine de Oliveira Santos Ferreira
• Host 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

Adipose tissue is one of the important insulin-dependent tissue responsible for glucose uptake. Hypertrophic adipocytes may undergo lysis and recruit macrophages, resulting in release of pro-inflammatory cytokines such as TNFa, that interferes with the insulin signaling pathway and result in insulin resistance: that is one of the trigger of type 2 diabetes mellitus (DM2). Osteoprotegerin (OPG) is a protein that acts as a decoy receptor of RANKL (ligand for the receptor activator of NFkB) preventing its interaction with its real receptor RANK (receptor activator of NFkB). Preliminary studies of our group indicate that OPG knockout mice (OPG-/-) under a hyper caloric diet are resistant to the establishment of DM2. Our data and other studies suggest that OPG is a biomarker of DM2. However, the contribution of OPG, if it is beneficial or deleterious, is still not elucidated in this context. Therefore, this project aimed to evaluate the expression profile of OPG and RANKL in C57BL6/J wild type or OPG-/- during 3 months of high fat diet and to check the gene expression of these proteins in the visceral adipose tissue. Our data show that plasmatic OPG level increases in WT mice under high fat diet, and it is high correlated with crown like structures present in visceral adipose tissue, which may potentialize adipose tissue inflammation since OPG inhibits RANKL induction of macrophage M2 polarization; therefore the increase in OPG level may contribute to inflammation and worsening of insulin resistance in adipose tissue, and DM2 development. Both WT and OPG-/- show increase in plasmatic RANKL level when fed high fat diet, and likely RANKL works as a compensatory anti-inflammatory mechanism and induces browning of adipose tissue under high fat diet and in the context of high OPG level. This project renewal aims to evaluate the OPG dose effect in OPG+/- heterozygous group, as in this genotype the impact of osteoporosis on the weigh is less severe than observed in OPG-/- compared to wild type mice. Therefore, the role of RANK-RANKL signaling and the contribution of OPG level and expression will be more evident in adipose tissue analysis. (AU)