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 bona fide 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.
Highlights
A central question in physiology is how different organs communicate with each other to maintain whole-organism homeostasis
We show that growth differentiation factor 15 (GDF15) is both sufficient and required for inhibition of liver growth hormone (GH) signaling in failure to thrive (FTT) associated with pediatric heart disease
The heart synthesizes and secretes GDF15 to inhibit body growth, thereby relieving potential extra cardiac burden as well as helping the body adapt to decreased cardiac output, a theme seen in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) (Fig 6B)
Summary
A central question in physiology is how different organs communicate with each other to maintain whole-organism homeostasis. Research in the past 20 years has revealed that certain non-glandular organs including adipose tissue, liver, skeletal muscle, intestine, and bone have secondary endocrine functions and secrete various hormones that regulate whole-body metabolism (Zhang et al, 1994; Deng & Scherer, 2010; Potthoff et al, 2012; Stefan & Haring, 2013; Liu et al, 2014; Wang et al, 2015a; Gribble & Reimann, 2016; Karsenty & Olson, 2016). Little is known regarding heart-derived hormones besides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) discovered more than 30 years ago (de Bold, 1985; Frohlich, 1985; Karsenty & Olson, 2016). Identification of new heart-derived hormones and study of their biological functions will significantly advance our understanding of cardiac biology and whole-organism homeostasis
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