Enhanced glycolysis and HIF-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1 alpha in ATM of obese visceral adipose tissue resulted in induction of IL-1 beta and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1 alpha nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1 alpha and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1 alpha expression, which culminated in IL-1 beta induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1 alpha, we demonstrate the critical role of HIF-1 alpha -derived from macrophages in regulating ATM accumulation, and local and systemic IL-1 beta production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1 alpha activation as drivers of low-grade inflammation in obesity.