Growth Differentiation Factor 15 is a Myomitokine Governing Systemic Energy Homeostasis

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2016 Dec 18

PMID 27986797

Citations 158

Authors

Hyo Kyun Chung

Dongryeol Ryu

Koon Soon Kim

Joon Young Chang

Yong Kyung Kim

Hyon-Seung Yi

Seul Gi Kang

Min Jeong Choi

Seong Eun Lee

Saet-Byel Jung

Min Jeong Ryu

Soung Jung Kim

Gi Ryang Kweon

Hail Kim

Jung Hwan Hwang

Chul-Ho Lee

Se-Jin Lee

Christopher E Wall

Michael Downes

Ronald M Evans

Johan Auwerx

Minho Shong

Affiliations

Soon will be listed here.

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 (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.

Citing Articles

Mitochondrial genetics, signalling and stress responses.

Liu Y, Sulc J, Auwerx J Nat Cell Biol. 2025; 27(3):393-407.

PMID: 40065146 DOI: 10.1038/s41556-025-01625-w.

Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle-secreted factors.

Sammut M, Thorne B, Melling C Obesity (Silver Spring). 2025; 33(3):435-451.

PMID: 39948829 PMC: 11897867. DOI: 10.1002/oby.24223.

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca handling across the adult lifespan in men.

Cefis M, Marcangeli V, Hammad R, Granet J, Leduc-Gaudet J, Gaudreau P Cell Rep Med. 2025; 6(2):101968.

PMID: 39933528 PMC: 11866497. DOI: 10.1016/j.xcrm.2025.101968.

Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients.

Muffels I, Rodenburg R, Willemen H, van Haaften-Visser D, Waterham H, Eijkelkamp N iScience. 2025; 28(1):111496.

PMID: 39801833 PMC: 11719857. DOI: 10.1016/j.isci.2024.111496.

A systematic review of the neuroprotective role and biomarker potential of GDF15 in neurodegeneration.

Isik F, Thomson S, Cueto J, Spathos J, Breit S, Tsai V Front Immunol. 2024; 15:1514518.

PMID: 39737171 PMC: 11682991. DOI: 10.3389/fimmu.2024.1514518.

References

Kolesar J, Safdar A, Abadi A, MacNeil L, Crane J, Tarnopolsky M . Defects in mitochondrial DNA replication and oxidative damage in muscle of mtDNA mutator mice. Free Radic Biol Med. 2014; 75:241-51. DOI: 10.1016/j.freeradbiomed.2014.07.038. View

Durieux J, Wolff S, Dillin A . The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011; 144(1):79-91. PMC: 3062502. DOI: 10.1016/j.cell.2010.12.016. View

Dani C . Activins in adipogenesis and obesity. Int J Obes (Lond). 2012; 37(2):163-6. DOI: 10.1038/ijo.2012.28. View

Macia L, Tsai V, Nguyen A, Johnen H, Kuffner T, Shi Y . Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PLoS One. 2012; 7(4):e34868. PMC: 3325923. DOI: 10.1371/journal.pone.0034868. View

Wredenberg A, Freyer C, Sandstrom M, Katz A, Wibom R, Westerblad H . Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem Biophys Res Commun. 2006; 350(1):202-7. DOI: 10.1016/j.bbrc.2006.09.029. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Kempf T, Guba-Quint A, Torgerson J, Magnone M, Haefliger C, Bobadilla M . Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur J Endocrinol. 2012; 167(5):671-8. DOI: 10.1530/EJE-12-0466. View

Horibe T, Hoogenraad N . The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS One. 2007; 2(9):e835. PMC: 1950685. DOI: 10.1371/journal.pone.0000835. View

Demontis F, Patel V, Swindell W, Perrimon N . Intertissue control of the nucleolus via a myokine-dependent longevity pathway. Cell Rep. 2014; 7(5):1481-1494. PMC: 4125979. DOI: 10.1016/j.celrep.2014.05.001. View

10.

Morino K, Petersen K, Shulman G . Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006; 55 Suppl 2:S9-S15. PMC: 2995546. DOI: 10.2337/db06-S002. View

11.

Hesselink M, Schrauwen-Hinderling V, Schrauwen P . Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol. 2016; 12(11):633-645. DOI: 10.1038/nrendo.2016.104. View

12.

Tao H, Zhang Y, Zeng X, Shulman G, Jin S . Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat Med. 2014; 20(11):1263-9. PMC: 4299950. DOI: 10.1038/nm.3699. View

13.

Moisoi N, Klupsch K, Fedele V, East P, Sharma S, Renton A . Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 2008; 16(3):449-64. DOI: 10.1038/cdd.2008.166. View

14.

Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M . GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion. 2014; 20:34-42. DOI: 10.1016/j.mito.2014.10.006. View

15.

Kim K, Jeong Y, Oh H, Kim S, Cho J, Kim Y . Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2012; 19(1):83-92. DOI: 10.1038/nm.3014. View

16.

Quintens R, Singh S, Lemaire K, De Bock K, Granvik M, Schraenen A . Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance. PLoS One. 2013; 8(2):e56719. PMC: 3584060. DOI: 10.1371/journal.pone.0056719. View

17.

Perry R, Zhang D, Zhang X, Boyer J, Shulman G . Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015; 347(6227):1253-6. PMC: 4495920. DOI: 10.1126/science.aaa0672. View

18.

Schonthal A . Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 2012; 85(5):653-666. DOI: 10.1016/j.bcp.2012.09.012. View

19.

Nargund A, Fiorese C, Pellegrino M, Deng P, Haynes C . Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell. 2015; 58(1):123-33. PMC: 4385436. DOI: 10.1016/j.molcel.2015.02.008. View

20.

Preusch M, Baeuerle M, Albrecht C, Blessing E, Bischof M, Katus H . GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis. Eur J Med Res. 2013; 18:19. PMC: 3701574. DOI: 10.1186/2047-783X-18-19. View