Oncotarget

Research Papers: Pathology:

Impaired macrophage autophagy induces systemic insulin resistance in obesity

Young-Ho Kang, Mi-Hyang Cho, Ji-Young Kim, Min-Seo Kwon, Jong-Jin Peak, Sang-Wook Kang, Seung-Yong Yoon and Youngsup Song _

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Oncotarget. 2016; 7:35577-35591. https://doi.org/10.18632/oncotarget.9590

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Abstract

Young-Ho Kang1,3, Mi-Hyang Cho2,3, Ji-Young Kim1,3, Min-Seo Kwon1,3, Jong-Jin Peak2,3, Sang-Wook Kang1,3, Seung-Yong Yoon2,3,* and Youngsup Song1,3,*

1 Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea

2 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

3 Bio-Medical Institute of Technology (BMIT), University of Ulsan, College of Medicine, Seoul, Korea

* These authors have contributed equally to this work

Correspondence to:

Youngsup Song, email:

Seung-Yong Yoon, email:

Keywords: autophagy, adipose tissue macrophage, insulin resistance, obesity, reactive oxygen species, Pathology Section

Received: February 23, 2016 Accepted: May 20, 2016 Published: May 25, 2016

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.


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