Abstract 700: Accelerated Glycolysis in Adipose Tissue Macrophages Triggers Hif-1α in Obesity and Promotes Insulin Resistance.

Abstract

During obesity, macrophages (Mø) accumulate in the visceral adipose tissue (VAT), giving rise to a state of chronic, low-grade inflammation that promotes insulin resistance and type 2 diabetes. We hypothesized that activation of HIF-1α in highly-metabolically active Mø sustains inflammation in obese VAT and promotes metabolic dysfunction. We show that hypoxic Mø, like M1-polarized Mø, shift their metabolism from oxidative phosphorylation to glycolysis, leading to the accumulation of HIF-1α-stabilizing intermediates. Extracellular flux analysis showed that treating Mø with the hypoxia mimetic CoCl2 or the saturated fatty acid palmitate reduced cellular oxygen consumption and increased the rate of extracellular acidification indicative of enhanced glycolysis. Metabolites known to accumulate during persistent glycolysis, such as succinate and lactic acid, activated HIF-1α in Mø and promoted inflammatory gene expression. To test the role of Mø HIF-1α in promoting VAT inflammation and metabolic dysfunction in obesity, we fed wild type or Mø-specific HIF-1α knock-out mice a high-fat diet (60% kcal fat) for 20 weeks. Notably, the ablation of HIF-1α in Mø reduced VAT inflammation as indicated by the reduced accumulation of F4/80+ cells and decreased expression of inflammatory cytokines (TNFα, IL-6, MCP-1). In addition, adipose tissue Mø isolated from Mø-HIF-1α knock-out mice showed increased expression of markers characteristic of M2 reparative Mø (Ym1, Fizz1, Aldh2) and reduced expression of M1 inflammatory Mø markers (Ccl2, Il1b), compared to Mø from WT mice. Furthermore, Mø-HIF-1α knock-out mice showed improved glucose homeostasis and insulin sensitivity, and reduced plasma insulin and free fatty acid levels compared to WT mice. Together, these data indicate that activation of HIF-1α in VAT Mø during obesity promotes tissue inflammation and insulin resistance.