Fibroblast growth factor 21 is linked to ambient temperature-dependent regulation of pathological cardiac hypertrophy in UCP1 knockout mice

Adipocytes play an important role in the regulation of cardiovascular health and disease. However, the molecular mechanisms underlying the endocrine role of brown adipose tissue (BAT) in pathological cardiac remodeling remain unclear. Herein, we show that uncoupling protein 1 (UCP1)-knockout ( Ucp1 KO) mice exhibit reduced abdominal aorta coarctation-induced myocardial hypertrophy compared with wild-type mice in a 24 °C environment. However, this effect is eliminated in a thermoneutral (30 °C) environment. Mechanistically, Ucp1 KO significantly upregulates the expression of fibroblast growth factor 21 (FGF21) in BAT, resulting in increased circulating FGF21 levels. Interscapular BAT resection in Ucp1 KO mice decreases plasma FGF21 levels and reverses the alleviated pathological hypertrophic phenotype. Additionally, activation of the integrated stress response after Ucp1 KO significantly upregulates FGF21 expression in BAT. In conclusion, Ucp1 knockout alleviates heart failure in mice maintained at 24 °C, an effect that is likely associated with increased secretion of FGF21 from BAT.