Fgf21 is required for cardiac remodeling in pregnancy.

Abstract

Fibroblast growth factor-21 (Fgf21) is an endocrine factor that contributes to many physiological and pathological processes, mainly via its action as a metabolic regulator. Recent studies have shown that Fgf21 plays an important role in cardiac tissue. Pregnancy offers a physiological model of adaptive and reversible heart enlargement, but the molecular mechanisms underlying this cardiac hypertrophy are poorly understood. Therefore, the aim was to analyze the role of Fgf21 during late pregnancy, and assess the physiological relevance of Fgf21 for cardiac tissue during this process. Female mice and rats at day 18 of gestation and pregnant women in their third trimester were used as models of late pregnancy, and our results revealed that their plasma levels of Fgf21 were significantly increased relative to non-pregnant controls. Pregnant wild-type (wt) mice exhibited a PPARα (peroxisome proliferator-activated receptor-α)-dependent enhancement of Fgf21 expression in the liver and heart. Moreover, pregnancy altered the levels of Fgf21 receptor-1 (FGFR1) and β-klotho, and activated intracellular Fgf21 signaling in the heart. Fgf21-/- mice did not develop the pregnancy-induced cardiac remodeling seen in wt mice. Furthermore, the hearts of Fgf21-/- mice exhibited reductions in their fatty acid oxidation levels, which may compromise cardiac function during pregnancy. During pregnancy, both systemic and cardiac-produced Fgf21 act on the heart, leading to the normal physiological cardiac changes that are associated with pregnancy. Thus, Fgf21 acts as an endocrine/autocrine factor required for cardiac remodeling response to gestation.