Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes

Yu-Mi Lim, Hyejin Lim, Kyu Yeon Hur, Wenying Quan, Hae-Youn Lee, Hwanju Cheon, Dongryeol Ryu, Seung-Hoi Koo, Hong Lim Kim, Jin Kim, Masaaki Komatsu and Myung-Shik Lee ()
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Yu-Mi Lim: Samsung Medical Center, Sungkyunkwan University School of Medicine
Hyejin Lim: Samsung Medical Center, Sungkyunkwan University School of Medicine
Kyu Yeon Hur: Samsung Medical Center, Sungkyunkwan University School of Medicine
Wenying Quan: Samsung Medical Center, Sungkyunkwan University School of Medicine
Hae-Youn Lee: Samsung Medical Center, Sungkyunkwan University School of Medicine
Hwanju Cheon: Samsung Medical Center, Sungkyunkwan University School of Medicine
Dongryeol Ryu: Sungkyunkwan University School of Medicine
Seung-Hoi Koo: Korea University
Hong Lim Kim: Integrative Research Support Center, College of Medicine, The Catholic University of Korea
Jin Kim: College of Medicine, The Catholic University of Korea
Masaaki Komatsu: Niigata University School of Medicine
Myung-Shik Lee: Samsung Medical Center, Sungkyunkwan University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7+/− mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7+/−-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7+/−-ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7+/−-ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.

Date: 2014
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DOI: 10.1038/ncomms5934

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