First Author | Choe SS | Year | 2014 |
Journal | Diabetes | Volume | 63 |
Issue | 10 | Pages | 3359-71 |
PubMed ID | 24947359 | Mgi Jnum | J:230173 |
Mgi Id | MGI:5755591 | Doi | 10.2337/db13-1965 |
Citation | Choe SS, et al. (2014) Macrophage HIF-2alpha ameliorates adipose tissue inflammation and insulin resistance in obesity. Diabetes 63(10):3359-71 |
abstractText | 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)-2alpha, 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-2alpha would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2alpha decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2alpha-overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2alpha augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2alpha 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-fed Hif-2alpha heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2alpha upon HFD. Taken together, these data suggest that macrophage HIF-2alpha would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue. |