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Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Nature Medicine volume 19, pages 83–92 (2013)Cite this article

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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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Figure 1: Decreased muscle and fat mass in Atg7Δsm mice.
Figure 2: Increased energy expenditure and ameliorated insulin resistance in Atg7Δsm mice fed HFD.
Figure 3: Increased β-oxidation, lipolysis and browning of WAT in HFD-fed Atg7Δsm mice.
Figure 4: Atf4-dependent Fgf21 induction is responsible for improved metabolic profile in Atg7Δsm mice.
Figure 5: Impairment of mtOxPhos in autophagy deficiency is responsible for Atf4-dependent Fgf21 induction.
Figure 6: Atg7Δhep mice are protected from HFD-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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Author notes

  1. Yeon Taek Jeong and Hyunhee Oh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Kook Hwan Kim, Yeon Taek Jeong, Jae Min Cho, Do Hoon Kim, Kyu Yeon Hur & Myung-Shik Lee

  2. Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea

    Kook Hwan Kim, Seong Hun Kim & Myung-Shik Lee

  3. Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, Korea

    Hyunhee Oh, Yo-Na Kim, Su Sung Kim & Cheol Soo Choi

  4. Department of Physiology, National Research Laboratory for Mitochondrial Signaling, College of Medicine, Cardiovascular and Metabolic Disease Center, FIRST Mitochondrial Research Group, Inje University, Busan, Korea

    Hyoung Kyu Kim, TaeHee Ko & Jin Han

  5. Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Hong Lim Kim

  6. Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea

    Jin Kim

  7. School of Biological Sciences, University of Ulsan, Ulsan, Korea

    Sung Hoon Back

  8. Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Masaaki Komatsu

  9. Division of Biology, California Institute of Technology, Pasadena, California, USA

    Hsiuchen Chen & David C Chan

  10. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA

    David C Chan

  11. Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Japan

    Morichika Konishi

  12. Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan

    Nobuyuki Itoh

  13. Department of Internal Medicine, Gil Medical Center, Gachon University Graduate School of Medicine, Incheon, Korea

    Cheol Soo Choi

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  1. Kook Hwan Kim
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Contributions

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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Correspondence to Cheol Soo Choi or Myung-Shik Lee.

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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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