A new FGF15 /19‐mediated gut‐to‐heart axis controls cardiac hypertrophy

• Published in: The Journal of pathology Vol. 261; no. 3; pp. 335 - 348
• Main Authors: Morón‐Ros, Samantha, Blasco‐Roset, Albert, Navarro‐Gascon, Artur, Rupérez, Celia, Zamora, Monica, Crispi, Fatima, Uriarte, Iker, Fernández‐Barrena, Maite G, Avila, Matias, Ferrer‐Curriu, Gemma, Lupón, Josep, Bayés‐Genis, Antoni, Villarroya, Francesc, Gavaldà‐Navarro, Aleix, Planavila, Anna
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01-11-2023
• Subjects: Adipose tissue; Atrial natriuretic peptide; Bile acids; Cardiomyocytes; Congestive heart failure; Enterocytes; Fatty acids; Gene regulation; Heart; High fat diet; Hypertrophy; Metabolism; Myocardium; Signal transduction; Skeletal muscle; Tibia
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.6193

Abstract
FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high‐fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy‐inducing conditions were lower in
Fgf15
‐null mice than in wild‐type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (
Nppa
) were up‐regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down‐regulated in
Fgf15
‐null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy
in vivo
, without changes in
Nppa
and up‐regulation of metabolic genes. Finally,
in vitro
studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter‐organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors.
The Journal of Pathology
published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.