Obesity epidemic affects more people each year and is an important risk factor for type 2 diabetes. During obesity, there is an increase in white adipose tissue, which is accompanied by leukocyte infiltration, especially of pro-inflammatory. This classically activated macrophage phenotype (M1) produce pro-inflammatory cytokines (TNF-± and IL-1²), which leads to adipose tissue inflammation-induced insulin resistance. The hypoxia-inducible factor subunit 1 alpha (HIF-1±) is an important regulator of macrophage pro-inflammatory activation, which regulates the energetic metabolism of macrophages in both hypoxia and normoxia. The objective of this proposal is to determine the role of HIF-1± in the polarization and metabolic regulation of adipose tissue macrophages (ATMs). Our results show that LPS-activated macrophages have high expression of HIF-1±, HIF-1± target genes, pro-inflammatory cytokines and also increased dysfunctional mitochondria. Treatment of macrophages with HIF-1± inhibitor followed by LPS stimulation leads to IL-1² reduction, without altering TNF-± level. Preliminary data show that inhibition of HIF-1± reduces expression of macrophage M2-related markers after IL-4-induced M2 polarization. LPS and IFN-³-polarized macrophages from HIF-1±KO animals display greater glycolysis and increased dysfunctional mitochondria than LPS and IFN-³-polarized AT macrophages. Adipose tissue (AT) CD11c+ M1 macrophages from obese mice have higher glycolysis and increased expression of enzymes of the glycolytic pathway. The metabolomic analysis of obese AT macrophages shows that both M1 and M2 macrophages have differentially regulated metabolic pathways in comparison to M1 and M2 macrophages from lean AT. Our results allow us to conclude that HIF-1± is an important regulator of the cellular metabolism of macrophages, making them more glycolytic, but also altering mitochondrial dynamics. This proposal will allow us to understand the role of HIF-1± in ATMs from mice and human samples using multi-omics analyzes.
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