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J Cell Biol. 2017 Jan 2;216(1):149-165. doi: 10.1083/jcb.201607110. Epub 2016 Dec 16.

Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis.

Author information

1
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
2
Department of Medical Science, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
3
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
4
Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 34134, South Korea.
5
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-338, South Korea.
6
Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-764, South Korea.
7
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
8
Gene Expression Laboratory, Salk Institute, La Jolla, CA 92037.
9
Laboratory for Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland admin.auwerx@epfl.ch minhos@cnu.ac.kr.
10
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.

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.

PMID:
27986797
PMCID:
PMC5223607
DOI:
10.1083/jcb.201607110
[Indexed for MEDLINE]
Free PMC Article

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