한빛사 논문
충남대학교
Hyo Kyun Chung,1,2* Dongryeol Ryu,4* Koon Soon Kim,1,2* Joon Young Chang,1,2 Yong Kyung Kim,1 Hyon-Seung Yi,1 Seul Gi Kang,1,2 Min Jeong Choi,1,2 Seong Eun Lee,1,2 Saet-Byel Jung,1 Min Jeong Ryu,1 Soung Jung Kim,1 Gi Ryang Kweon,3 Hail Kim,5 Jung Hwan Hwang,6 Chul-Ho Lee,6 Se-Jin Lee,7 Christopher E. Wall,8 Michael Downes,8 Ronald M. Evans,8 Johan Auwerx,4,# and Minho Shong1,2,#
1Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea
2Department of Medical Science and 3Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 34134, South Korea
4Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
5Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-338, South Korea
6Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-764, South Korea
7Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
8Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037
*H.K. Chung, D. Ryu, and K.S. Kim contributed equally to this paper.
#Corresponding author
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 UPRmt 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.
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