Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis

• Published in: The Journal of cell biology Vol. 216; no. 1; pp. 149 - 165
• Main Authors: Chung, Hyo Kyun, Ryu, Dongryeol, Kim, Koon Soon, Chang, Joon Young, Kim, Yong Kyung, Yi, Hyon-Seung, Kang, Seul Gi, Choi, Min Jeong, Lee, Seong Eun, Jung, Saet-Byel, Ryu, Min Jeong, Kim, Soung Jung, Kweon, Gi Ryang, Kim, Hail, Hwang, Jung Hwan, Lee, Chul-Ho, Lee, Se-Jin, Wall, Christopher E, Downes, Michael, Evans, Ronald M, Auwerx, Johan, Shong, Minho
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 02.01.2017; The Rockefeller University Press
• Subjects: 3T3-L1 Cells; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Bioenergetics; Cell Cycle Proteins - deficiency; Cell Cycle Proteins - genetics; Cellular biology; Energy Metabolism - drug effects; Genetic Predisposition to Disease; Growth Differentiation Factor 15 - deficiency; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Growth Differentiation Factor 15 - pharmacology; Homeostasis; Insulin Resistance; Leptin - deficiency; Leptin - genetics; Lipolysis; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondria; Mitochondria, Liver - metabolism; Mitochondria, Muscle - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Obesity - genetics; Obesity - metabolism; Obesity - prevention & control; Oxidation-Reduction; Oxidative Phosphorylation; Phenotype; Proteins; Recombinant Proteins - pharmacology; RNA Interference; Signal Transduction; Stress response; Time Factors; Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Transfection; Unfolded Protein Response; Weight Gain
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201607110

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 (UPR ), 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 UPR -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 UPR activation. 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.