Macrophage HIF-2a 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 obesityrelated metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2a, 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-2a would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2a decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2a-overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2a augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2a heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fedHif-2a 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-2a upon HFD. Taken together, these data suggest that macrophage HIF-2awould counteract the proinflammatory responses to relieve obesityinduced insulin resistance in adipose tissue. Emerging evidence has suggested that obesity is characterized by chronic and low-grade inflammation accompanied by macrophage accumulation in the adipose tissue, which eventually leads to metabolic diseases, including insulin resistance and type 2 diabetes (1–3). Increased adipose tissue macrophages (ATMs) play crucial roles in the altered production of proinflammatory cytokines in the adipose tissue of obesity (1–3). In healthy lean mice, ATMs are mostly composed of alternatively activated (M2)-type macrophages, which express high levels of anti-inflammatory cytokines such as interleukin (IL)-10 and specific enzymes such as arginase (ARG) 1 in company with low levels of proinflammatory signals (4,5). Thus M2 ATMs contribute to metabolic homoeostasis by keeping down adipose tissue inflammation (4,5). In the progress of obesity, some ATMs are polarized from the M2 type to the classically activated (M1) type. In obese adipose tissue, M1 ATMs enhance nitric oxide (NO) production with stimulation of inducible NO synthase (iNOS) and the secretion of proinflammatory cytokines such as tumor necrosis factor a (TNFa), IL-6, and IL-1b. Proinflammatory cytokines secreted from M1 ATMs repress insulin action and potentiate proinflammatory transcription factors such as nuclear factor kB to further stimulate the expression of proinflammatory genes, which eventually leads to insulin resistance (1,6,7). Recently, it has been reported that M2 ATMs are also elevated in obesity, where they would function to repair and/or remodel dysregulated adipose tissue (4,5,8). Alternative activation of M2