Exercise-induced adipose tissue ADRB2-PGC1α-FGF21 signaling protects against pathological cardiac hypertrophy

Exercise induces adipose tissue activation and physiological cardiac hypertrophy, but the link between adipose tissue activation and cardiac remodeling has not been fully established. Here, we found that three weeks of swim training activated brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) in a PGC1α-dependent manner. Genetic knockout (Adrb2 ^KO ) or chemical inhibition of the β₂-adrenoceptor (ICI118551) suppressed PGC1α expression and BAT and iWAT activation. To test the role of adipose tissue activation in pressure overload-induced cardiac hypertrophy, abdominal aortic constriction (AAC) surgery was performed in swim-trained Ppargc1a ^fl/fl and adipose-specific knockout of Ppargc1a (Ppargc1a ^aKO ) mice. Compared with Ppargc1a ^fl/fl mice, the protective effect of exercise against pathological remodeling was significantly diminished in Ppargc1a ^aKO mice, whereas exogenous FGF21 administration recovered it. In summary, this study reveals that swim training activates the ADRB2-PGC1α axis and FGF21 generation in the adipose tissue, which protects against pathological cardiac remodeling.