title: Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation.
abstract: Chronic low-grade inflammation is emerging as a pathogenic link between obesity and metabolic disease. Persistent immune activation in white adipose tissue (WAT) impairs insulin sensitivity and systemic metabolism, in part, through the actions of proinflammatory cytokines. Whether obesity engages an adaptive mechanism to counteract chronic inflammation in adipose tissues has not been elucidated. Here we identified otopetrin 1 (Otop1) as a component of a counterinflammatory pathway that is induced in WAT during obesity. Otop1 expression is markedly increased in obese mouse WAT and is stimulated by tumor necrosis factor-α in cultured adipocytes. Otop1 mutant mice respond to high-fat diet with pronounced insulin resistance and hepatic steatosis, accompanied by augmented adipose tissue inflammation. Otop1 attenuates interferon-γ (IFN-γ) signaling in adipocytes through selective downregulation of the transcription factor STAT1. Using a tagged vector, we found that Otop1 physically interacts with endogenous STAT1. Thus, Otop1 defines a unique target of cytokine signaling that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity.
authors.affiliation: Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Guo-Xiao
authors.initials: GX
authors.lastname: Wang
authors.forename: Kae Won
authors.initials: KW
authors.lastname: Cho
authors.forename: Maeran
authors.initials: M
authors.lastname: Uhm
authors.forename: Chun-Rui
authors.initials: CR
authors.lastname: Hu
authors.forename: Siming
authors.initials: S
authors.lastname: Li
authors.forename: Zoharit
authors.initials: Z
authors.lastname: Cozacov
authors.forename: Acer E
authors.initials: AE
authors.lastname: Xu
authors.forename: Ji-Xin
authors.initials: JX
authors.lastname: Cheng
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D007333:Insulin Resistance / Q000502:physiology; D007371:Interferon-gamma / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C479478:otopetrin 1 protein, mouse; D007371:Interferon-gamma