title: Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine.
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.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Kook Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Yeon Taek
authors.initials: YT
authors.lastname: Jeong
authors.forename: Hyunhee
authors.initials: H
authors.lastname: Oh
authors.forename: Seong Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Cho
authors.forename: Yo-Na
authors.initials: YN
authors.lastname: Kim
authors.forename: Su Sung
authors.initials: SS
authors.lastname: Kim
authors.forename: Do Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: TaeHee
authors.initials: T
authors.lastname: Ko
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Hong Lim
authors.initials: HL
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Hsiuchen
authors.initials: H
authors.lastname: Chen
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
authors.forename: Morichika
authors.initials: M
authors.lastname: Konishi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Itoh
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D004032:Diet; D004734:Energy Metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D017353:Gene Deletion; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C081452:Atf4 protein, mouse; C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D000071193:Autophagy-Related Protein 7