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

Kim, Kook Hwan and Jeong, Yeon Taek and Oh, Hyunhee and Kim, Seong Hun and Cho, Jae Min and Kim, Yo-Na and Kim, Su Sung and Kim, Do Hoon and Hur, Kyu Yeon and Kim, Hyoung Kyu and Ko, TaeHee and Han, Jin and Kim, Hong Lim and Kim, Jin and Back, Sung Hoon and Komatsu, Masaaki and Chen, Hsiuchen and Chan, David C. and Konishi, Morichika and Itoh, Nobuyuki and Choi, Cheol Soo and Lee, Myung-Shik (2013) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nature Medicine, 19 (1). pp. 83-92. ISSN 1078-8956. doi:10.1038/nm.3014. https://resolver.caltech.edu/CaltechAUTHORS:20130219-151454535

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nm.3014DOIArticle
http://www.nature.com/nm/journal/v19/n1/full/nm.3014.htmlPublisherArticle
http://rdcu.be/cnKFPublisherFree ReadCube access
ORCID:
AuthorORCID
Chan, David C.0000-0002-0191-2154
Additional Information:© 2012 Nature Publishing Group. Received 28 June; accepted 22 October; published online 2 December 2012. 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). Author 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. Competing Financial Interests: The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
National Research Foundation of Korea Global Research Laboratory GrantK21004000003-10A0500-00310
Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family AffairsA080967
Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family AffairsA102060
Bio R&D Program2008-04090
Ministry of Education, Science & Technology, Korea, Bio & Medical Technology Development Program grant20110019335
Issue or Number:1
DOI:10.1038/nm.3014
Record Number:CaltechAUTHORS:20130219-151454535
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130219-151454535
Official Citation:Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine - pp83 - 92 Kook Hwan Kim, Yeon Taek Jeong, Hyunhee Oh, Seong Hun Kim, Jae Min Cho, Yo-Na Kim, Su Sung Kim, Do Hoon Kim, Kyu Yeon Hur, Hyoung Kyu Kim, TaeHee Ko, Jin Han, Hong Lim Kim, Jin Kim, Sung Hoon Back, Masaaki Komatsu, Hsiuchen Chen, David C Chan, Morichika Konishi, Nobuyuki Itoh, Cheol Soo Choi & Myung-Shik Lee doi:10.1038/nm.3014
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36992
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:19 Feb 2013 23:51
Last Modified:09 Nov 2021 23:26

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