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

  1. Jae Bum Kim1
  1. 1Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea
  2. 2Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
  1. Corresponding author: Jae Bum Kim, jaebkim{at}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.

  • Received December 31, 2013.
  • Accepted May 5, 2014.

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