GDF15 is a Heart-derived Hormone That Regulates Body Growth

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2017 Jun 3

PMID 28572090

Citations 50

Authors

Ting Wang

Jian Liu

Caitlin McDonald

Katherine Lupino

Xiandun Zhai

Benjamin J Wilkins

Hakon Hakonarson

Liming Pei

Affiliations

Soon will be listed here.

Abstract

The endocrine system is crucial for maintaining whole-body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart-derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a heart-derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well-established clinical observation that children with heart diseases often develop FTT.

Citing Articles

Growth Differentiation Factor 15 as a Marker for Chronic Ventricular Pacing.

Edlinger C, Bannehr M, Lichtenauer M, Paar V, Jankowska P, Hauptmann L J Clin Med. 2025; 13(24.

PMID: 39768671 PMC: 11679774. DOI: 10.3390/jcm13247748.

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

Hu P, Rychik J, Zhao J, Bai H, Bauer A, Yu W Sci Transl Med. 2024; 16(744):eadk6213.

PMID: 38657025 PMC: 11103255. DOI: 10.1126/scitranslmed.adk6213.

A method of quantitative chemiluminescence immunoassay for the concentration of Growth differentiation factor-15.

Zhang J, Zhang J, Wu T, Jin P, Huang C MethodsX. 2024; 12:102572.

PMID: 38352663 PMC: 10863303. DOI: 10.1016/j.mex.2024.102572.

Synergistic effects of hormones on structural and functional maturation of cardiomyocytes and implications for heart regeneration.

Galow A, Brenmoehl J, Hoeflich A Cell Mol Life Sci. 2023; 80(8):240.

PMID: 37541969 PMC: 10403476. DOI: 10.1007/s00018-023-04894-6.

plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets.

Mohammad M, Saeed R, Mohammed A, Khalique A, Hamad M, El-Huneidi W Exp Biol Med (Maywood). 2023; 248(4):339-349.

PMID: 36740767 PMC: 10159522. DOI: 10.1177/15353702221146552.

References

Poskitt E . Failure to thrive in congenital heart disease. Arch Dis Child. 1993; 68(2):158-60. PMC: 1029224. DOI: 10.1136/adc.68.2.158. View

McGrath M, Kuroski de Bold M, de Bold A . The endocrine function of the heart. Trends Endocrinol Metab. 2005; 16(10):469-77. DOI: 10.1016/j.tem.2005.10.007. View

Saeki M, Sekine S, Kato S . Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J Biochem. 1997; 122(3):622-6. DOI: 10.1093/oxfordjournals.jbchem.a021798. View

Tsai V, Macia L, Johnen H, Kuffner T, Manadhar R, Jorgensen S . TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS One. 2013; 8(2):e55174. PMC: 3585300. DOI: 10.1371/journal.pone.0055174. View

Gribble F, Reimann F . Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium. Annu Rev Physiol. 2015; 78:277-99. DOI: 10.1146/annurev-physiol-021115-105439. View

Laakmann S, Fortmuller L, Piccini I, Grote-Wessels S, Schmitz W, Breves G . Minimally invasive closed-chest ultrasound-guided substance delivery into the pericardial space in mice. Naunyn Schmiedebergs Arch Pharmacol. 2012; 386(3):227-38. PMC: 3570759. DOI: 10.1007/s00210-012-0815-2. View

Chen Y, Wen R, Yang S, Schuman J, Zhang E, Yi T . Identification of Shp-2 as a Stat5A phosphatase. J Biol Chem. 2003; 278(19):16520-7. DOI: 10.1074/jbc.M210572200. View

Baek S, Kim K, Nixon J, Wilson L, Eling T . Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol. 2001; 59(4):901-8. View

Paralkar V, Vail A, Grasser W, Brown T, Xu H, Vukicevic S . Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem. 1998; 273(22):13760-7. DOI: 10.1074/jbc.273.22.13760. View

10.

Savage M, Hwa V, David A, Rosenfeld R, Metherell L . Genetic Defects in the Growth Hormone-IGF-I Axis Causing Growth Hormone Insensitivity and Impaired Linear Growth. Front Endocrinol (Lausanne). 2012; 2:95. PMC: 3356141. DOI: 10.3389/fendo.2011.00095. View

11.

Frohlich E . The heart. An endocrine organ (revisited). Arch Intern Med. 1985; 145(5):809-11. DOI: 10.1001/archinte.145.5.809. View

12.

Bish L, Morine K, Sleeper M, Sanmiguel J, Wu D, Gao G . Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther. 2008; 19(12):1359-68. PMC: 2940566. DOI: 10.1089/hum.2008.123. View

13.

Grueter C, Van Rooij E, Johnson B, DeLeon S, Sutherland L, Qi X . A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell. 2012; 149(3):671-83. PMC: 3340581. DOI: 10.1016/j.cell.2012.03.029. View

14.

Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M . Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int. 2016; 16 Suppl 1:17-29. DOI: 10.1111/ggi.12724. View

15.

Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodriguez M . GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016; 11(2):e0148709. PMC: 4750949. DOI: 10.1371/journal.pone.0148709. View

16.

Bauskin A, Zhang H, Fairlie W, He X, RUSSELL P, Moore A . The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J. 2000; 19(10):2212-20. PMC: 384362. DOI: 10.1093/emboj/19.10.2212. View

17.

Potthoff M, Kliewer S, Mangelsdorf D . Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012; 26(4):312-24. PMC: 3289879. DOI: 10.1101/gad.184788.111. View

18.

Karsenty G, Olson E . Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. Cell. 2016; 164(6):1248-1256. PMC: 4797632. DOI: 10.1016/j.cell.2016.02.043. View

19.

Baik M, Yu J, Hennighausen L . Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism. Ann N Y Acad Sci. 2011; 1229:29-37. PMC: 3427656. DOI: 10.1111/j.1749-6632.2011.06100.x. View

20.

Wollert K, Kempf T, Wallentin L . Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease. Clin Chem. 2017; 63(1):140-151. DOI: 10.1373/clinchem.2016.255174. View