한빛사논문, 상위피인용논문
Abstract
Kook Hwan Kim1,2, Yeon Taek Jeong1,14, Hyunhee Oh3,14, Seong Hun Kim2, Jae Min Cho1, Yo-Na Kim3, Su Sung Kim3, Do Hoon Kim1, Kyu Yeon Hur1, Hyoung Kyu Kim4, TaeHee Ko4, Jin Han4, Hong Lim Kim5, Jin Kim6, Sung Hoon Back7, Masaaki Komatsu8, Hsiuchen Chen9, David C Chan9,10, Morichika Konishi11, Nobuyuki Itoh12, Cheol Soo Choi3,13,* & Myung-Shik Lee1,2,*
1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea. 3Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, Korea. 4National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, FIRST Mitochondrial Research Group, Inje University, Busan, Korea. 5Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea. 6Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea. 7School of Biological Sciences, University of Ulsan, Ulsan, Korea. 8Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. 9Division of Biology, California Institute of Technology, Pasadena, California, USA. 10Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA. 11Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan. 12Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan. 13Department of Internal Medicine, Gil Medical Center, Gachon University Graduate School of Medicine, Incheon, Korea. 14These authors contributed equally to this work.
*Correspondence to: Cheol Soo Choi or Myung-Shik Lee
Abstract
Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle-specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.
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