title: Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity.
abstract: Myeloid cells, particularly macrophages, mediate metabolic inflammation, thus promoting insulin resistance and metabolic disease progression in obesity. Numerous cytokines, toxic metabolites, damage-associated molecular patterns, and pathogen-associated molecular patterns are involved in activating macrophages via their cognate receptors in obesity. TRAF3 (TNF receptor-associated factor 3) is a common signaling molecule for these ligands/receptors and negatively regulates the proinflammatory NF-κB and MAPK pathways, but its metabolic activity is unknown. We here show that myeloid cell TRAF3 is required for metabolic inflammation and metabolic disease progression in obesity. Myeloid cell-specific deletion of TRAF3 significantly attenuated insulin resistance, hyperglycemia, hyperinsulinemia, glucose intolerance, and hepatic steatosis in mice with either genetic (ob/ob) or high-fat diet (HFD)-induced obesity. Myeloid cell-specific deletion of TRAF3 had the opposite effects on metabolic inflammation between obese and lean mice. It decreased the expression of proinflammatory cytokines in the liver and adipose tissue of obese mice and largely prevented HFD-induced inflammation in these metabolic tissues; by contrast, in lean mice, it increased the expression of proinflammatory cytokines in the liver and adipose tissue. These data suggest that, in obesity progression, myeloid TRAF3 functionally switches its activity from anti-inflammatory to proinflammatory modes, thereby coupling overnutrition to metabolic inflammation, insulin resistance, and metabolic disease.
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Zheng
authors: Z
authors: Chen
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Hong
authors: H
authors: Shen
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Chengxin
authors: C
authors: Sun
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Lei
authors: L
authors: Yin
authors: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Fei
authors: F
authors: Tang
authors: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Pan
authors: P
authors: Zheng
authors: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan;
authors: Yang
authors: Y
authors: Liu
authors: Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors: Robert
authors: R
authors: Brink
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and ruily@umich.edu.
authors: Liangyou
authors: L
authors: Rui
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005234:Fatty Liver / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000502:physiology*
chemical_list: D048008:TNF Receptor-Associated Factor 3
keywords: TRAF3; insulin resistance; metabolic inflammation; obesity; steatosis
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