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Diabetes. 2014 Oct;63(10):3359-71. doi: 10.2337/db13-1965. Epub 2014 Jun 19.

Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity.

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  • 1Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
  • 2Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
  • 3Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea jaebkim@snu.ac.kr.

Abstract

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)-2α, 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-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α-overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α 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-2α 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-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

[PubMed - indexed for MEDLINE]
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