HIF-1 alpha in metabolic and functional control of adipose tissue resident macrophages in diabetes induced by obesity

Abstract

Obesity epidemic affects more people around the world each year, been an important risk factor to type 2 diabetes. With the increase in white adipose tissue (AT), there is a greater migration and infiltration of leucocytes, in which classic M1-like macrophages have a prominent position, they produce pro-inflammatory cytokines, that leads to inflammation in AT and insulin resistance on metabolic tissues. The hypoxia-inducible factor 1 alpha (HIF-1±) has been shown to be an essential regulator to a pro-inflammatory switch in macrophages and regulates the energetic metabolism in these cells, so in hypoxia, as in normóxia. Preliminary data indicates that bone marrow derived macrophages (BMDMs), when stimulated with LPS, show greater production of pro-inflammatory cytokines, glucose transporter 1 (GLUT-1) and enzymes from the glycolytic pathway, with the peak of expression with HIF-1±, as increase in glycolytic rate. In vivo experiments AT resident macrophages (ATM) with M1-like phenotype from obese mice, have shown that they feature greater glycolytic capacity, higher levels of HIF-1± and enhanced expression of HIF-1± target genes and pro-inflammatory cytokines when compared with ATM M1 and M2 of lean mice. Because of that, we consider that HIF-1± expression is responsible for the greater metabolic rate in the initial stages of differentiation of M1-like macrophages, been exacerbated in obesity conditions and sustained by other factors, like aryl hydrocarbon receptor (AHR). So, the main objective of this project is to understand the function of HIF-1± in polarization and metabolic regulation of tissue macrophages. To do so, the project is divided in three parts: (1) culture of BMDMs with or without adipocytes, to analyze the metabolic pathways and activation in different stages of differentiation; (2) analyze the inflammatory and metabolic profile of ATM of lean and obese mice; (3) investigate the role of HIF-1± ATM in obese and insulin resistant animals to compare with lean controls. We will use BMDMs culture and mice WT, Lysmcre, HIF-1±LoxP and with macrophage specific deletion of HIF-1± (MÕhif-1±ko), fed with high fat diet to induce obesity, insulin resistance and low-grade inflammation. The data generated in this project will establish the role of HIF-1± in functional and metabolic modulation of ATM, providing subsidies to better understand the function of these cells in physiological and metabolic contexts, cooperating in the development of new therapeutic approaches. (AU)