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Oncotarget. 2016 Jun 14;7(24):35577-35591. doi: 10.18632/oncotarget.9590.

Impaired macrophage autophagy induces systemic insulin resistance in obesity.

Kang YH1,2, Cho MH3,2, Kim JY1,2, Kwon MS1,2, Peak JJ3,2, Kang SW1,2, Yoon SY3,2, Song Y1,2.

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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.
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.


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.


Pathology Section; adipose tissue macrophage; autophagy; insulin resistance; obesity; reactive oxygen species

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