A2A Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21

Adipocytes play important roles in regulating cardiovascular health and disease. However, the molecular mechanism underlying the endocrine role of brown adipose tissue (BAT) in pathological cardiac remodeling remains unknown. Herein we show that adenosine A(2A) receptor (A(2A)R) knockout (A(2A)RKO) causes interscapular BAT (iBAT) dysfunction, leading to accelerated cardiac remodeling in hypertension compared with wild-type (WT) mice. Surgical iBAT depletion induces dramatic cardiac remodeling in WT but not in A(2A)RKO hypertensive mice. AMPK/PGC1 alpha signaling-induced fibroblast growth factor 21 (FGF21) in brown adipocytes is required for A(2A)R-mediated inhibition of hypertensive cardiac remodeling. Recombinant FGF21 administration improves cardiac remodeling in iBAT-depleted hypertensive mice. More importantly, brown adipocyte-specific A(2A)RKO inhibits FGF21 production and accelerates cardiac damage in hypertension. Consistently, brown adipocyte-specific FGF21 knockout abolishes the effects of A(2A)R agonism in attenuating hypertensive cardiac remodeling. Our findings reveal a distinctive endocrine role of BAT in hypertensive cardiac remodeling via activating A(2A)R/FGF21 pathway.