title: Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis.
abstract: Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and -non-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondrial proteotoxic stress. Using mice with skeletal muscle-specific deficiency of Crif1 (muscle-specific knockout [MKO]), an integral protein of the large mitoribosomal subunit (39S), we identified growth differentiation factor 15 (GDF15) as a UPRmt-associated cell-non-autonomous myomitokine that regulates systemic energy homeostasis. MKO mice were protected against obesity and sensitized to insulin, an effect associated with elevated GDF15 secretion after UPRmtactivation. In ob/ob mice, administration of recombinant GDF15 decreased body weight and improved insulin sensitivity, which was attributed to elevated oxidative metabolism and lipid mobilization in the liver, muscle, and adipose tissue. Thus, GDF15 is a potent mitohormetic signal that safeguards against the onset of obesity and insulin resistance.
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Hyo Kyun
authors.identifier: http://orcid.org/0000-0001-6737-8372
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Dongryeol
authors.identifier: http://orcid.org/0000-0001-5905-6760
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Koon Soon
authors.identifier: http://orcid.org/0000-0002-5545-2093
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Yong Kyung
authors.identifier: http://orcid.org/0000-0001-9841-3695
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Hyon-Seung
authors.identifier: http://orcid.org/0000-0002-3767-1954
authors.initials: HS
authors.lastname: Yi
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Seul Gi
authors.identifier: http://orcid.org/0000-0001-7529-8460
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Seong Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Saet-Byel
authors.identifier: http://orcid.org/0000-0001-5747-087X
authors.initials: SB
authors.lastname: Jung
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Ryu
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Soung Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-338, South Korea.
authors.forename: Hail
authors.identifier: http://orcid.org/0000-0002-6652-1349
authors.initials: H
authors.lastname: Kim
authors.affiliation: Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-764, South Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-764, South Korea.
authors.forename: Chul-Ho
authors.identifier: http://orcid.org/0000-0002-6996-5746
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Se-Jin
authors.identifier: http://orcid.org/0000-0003-1523-0389
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037.
authors.forename: Christopher E
authors.identifier: http://orcid.org/0000-0002-4059-2042
authors.initials: CE
authors.lastname: Wall
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037.
authors.forename: Ronald M
authors.identifier: http://orcid.org/0000-0002-9986-5965
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland admin.auwerx@epfl.ch minhos@cnu.ac.kr.
authors.forename: Johan
authors.identifier: http://orcid.org/0000-0002-5065-5393
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea admin.auwerx@epfl.ch minhos@cnu.ac.kr.|Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
authors.forename: Minho
authors.identifier: http://orcid.org/0000-0002-0247-7115
authors.initials: M
authors.lastname: Shong
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D055436:Growth Differentiation Factor 15 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006706:Homeostasis; D007333:Insulin Resistance; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D008066:Lipolysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008930:Mitochondria, Liver / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010641:Phenotype; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D056811:Unfolded Protein Response; D015430:Weight Gain
chemical_list: D018797:Cell Cycle Proteins; C527307:Crif1 protein, mouse; C497250:Ddit3 protein, mouse; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D020738:Leptin; D011994:Recombinant Proteins; D051742:Transcription Factor CHOP