Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2 alpha, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2 alpha would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2 alpha decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2 alpha-overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2 alpha augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2 alpha heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). More-over, glucose intolerance in HFD-fed Hif-2 alpha heterozygousnull mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2 alpha upon HFD. Taken together, these data suggest that macrophage HIF-2 alpha would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.