Otopetrin 1 Protects Mice From Obesity-Associated Metabolic Dysfunction Through Attenuating Adipose Tissue Inflammation
- Guo-Xiao Wang1,2,
- Kae Won Cho3,4,
- Maeran Uhm1,3,5,
- Chun-Rui Hu6,
- Siming Li1,2,
- Zoharit Cozacov1,2,
- Acer E. Xu1,2,
- Ji-Xin Cheng6,
- Alan R. Saltiel1,3,5,
- Carey N. Lumeng3,4 and
- Jiandie D. Lin1,2⇑
- 1Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI
- 2Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI
- 3Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI
- 4Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI
- 5Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
- 6Weldon School of Biomedical Engineering, Department of Chemistry, Purdue University, West Lafayette, IN
- Corresponding author: Jiandie D. Lin, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1139/-/DC1.
- Received July 23, 2013.
- Accepted December 19, 2013.
- © 2014 by the American Diabetes Association.
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