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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Acknowledgements
We thank S.R. Farmer (Boston University) for pGL3B-Fgf21 (−1370/+129), D. Ron (University of Cambridge) for Atf4-null MEFs, R.J. Kaufman (University of Michigan Medical Center) for Eif2aS/S and Eif2aA/A MEFs, S.J. Burden (New York University) for Mlc1f-Cre mice, N. Mizushima (Tokyo Medical and Dental University) for Tet-off Atg5-null MEFs, and H.W. Virgin for insightful comments on the manuscript. This study was supported by the Global Research Laboratory Grant of the National Research Foundation of Korea (K21004000003-10A0500-00310 to M.-S.L. and M. Komatsu) and the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Korea (A080967 to M.-S.L. and A102060 to C.S.C). M.-S.L. received the Bio R&D Program (2008-04090) and the Bio & Medical Technology Development Program grant from the Ministry of Education, Science & Technology, Korea (20110019335).
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K.H.K., C.S.C. and M.-S.L. designed the study, analyzed data and wrote the manuscript. K.H.K. conducted all experiments except the portions indicated below, assisted by S.H.K., J.M.C., D.H.K. and K.Y.H. Y.T.J. analyzed the metabolic profiling of Atg7Δhep mice. H.O., Y.-N.K. and S.S.K. performed measurements of body composition, indirect calorimetry, the hyperinsulinemic-euglycemic clamp study and the fatty acid oxidation experiments. H.K.K., T.K. and J.H. measured the mitochondrial oxygen consumption. H.L.K. and J.K. performed the electron microscopy. S.H.B., M. Komatsu, H.C., D.C.C., M. Konishi and N.I. provided reagents, tissues, cells or mice and commented on the manuscript.
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Kim, K., Jeong, Y., Oh, H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19, 83–92 (2013). https://doi.org/10.1038/nm.3014
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DOI: https://doi.org/10.1038/nm.3014
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