title: Impaired macrophage autophagy induces systemic insulin resistance in obesity.
abstract: Obesity-induced insulin resistance and diabetes are significantly associated with infiltrates of inflammatory cells in adipose tissue. Previous studies recognized the involvement of autophagy in the regulation of metabolism in multiple tissues, including β-cells, hepatocytes, myocytes, and adipocytes. However, despite the importance of macrophages in obesity-induced insulin resistance, the role of macrophage autophagy in regulating insulin sensitivity is seldom addressed. In the present study, we show that macrophage autophagy is important for the regulation of systemic insulin sensitivity. We found that macrophage autophagy is downregulated by both acute and chronic inflammatory stimuli, and blockade of autophagy significantly increased accumulation of reactive oxygen species (ROS) in macrophages. Macrophage-specific Atg7 knockout mice displayed a shift in the proportion to pro-inflammatory M1 macrophages and impairment of insulin sensitivity and glucose homeostasis under high-fat diet conditions. Furthermore, inhibition of ROS in macrophages with antioxidant recovered adipocyte insulin sensitivity. Our results provide evidence of the underlying mechanism of how macrophage autophagy regulates inflammation and insulin sensitivity. We anticipate our findings will serve as a basis for development of therapeutics for inflammatory diseases, including diabetes.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kang
authors.affiliation: Alzheimer's Disease Experts Laboratory (ADEL), Department of Brain Science University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Min-Seo
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Alzheimer's Disease Experts Laboratory (ADEL), Department of Brain Science University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Jong-Jin
authors.initials: JJ
authors.lastname: Peak
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Alzheimer's Disease Experts Laboratory (ADEL), Department of Brain Science University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Youngsup
authors.initials: Y
authors.lastname: Song
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7 / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications*; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D004791:Enzyme Inhibitors; D007328:Insulin; D018942:Macrolides; D017382:Reactive Oxygen Species; C040929:bafilomycin A1; D000071193:Autophagy-Related Protein 7; D005947:Glucose
keywords: Pathology Section; adipose tissue macrophage; autophagy; insulin resistance; obesity; reactive oxygen species