title: Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity.
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.
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Choe
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
authors.forename: Kyung Cheul
authors.initials: KC
authors.lastname: Shin
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
authors.forename: Sojeong
authors.initials: S
authors.lastname: Ka
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Initiatives Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Korea.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
authors.affiliation: Department 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.
authors.forename: Jae Bum
authors.initials: JB
authors.lastname: Kim
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1