title: Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes.
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.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Lim
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Lim
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Wenying
authors.initials: W
authors.lastname: Quan
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Hae-Youn
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Hwanju
authors.initials: H
authors.lastname: Cheon
authors.affiliation: Department of Molecular Cellular Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Division of Life Science, Korea University, Seoul 136-713, Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Hong Lim
authors.initials: HL
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Niigata University School of Medicine, Niigata 950-2181, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001343:Autophagy; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000473:pathology / Q000503:physiopathology*; D013312:Stress, Physiological