Abstract Body: Introduction: Heart disease in the presence of obesity results in cardiometabolic disease, a condition where there is dysregulation of adipose and cardiac function. Under conditions of cardiometabolic stress, cardiomyocytes secrete signaling factors that communicate with other organ systems, including adipose tissue. Additionally, the expression and activity of cardiac GPCR kinase 2 (GRK2), which regulates β-adrenergic receptors in the heart, is upregulated in these conditions. However, the mechanisms associated with cardiomyocyte signaling and GRK2 in heart-to-fat communication are unknown. We hypothesize that cardiac secreted signaling factors mediate adiposity, contribute to cardiometabolic disease and these can be regulated by GRK2.

Methods/Results: To investigate this, conditioned media from control and GRK2 overexpressing adult rat cardiomyocytes was collected and applied to 3T3-L1 adipocytes. Conditioned media treated adipocytes exhibited reduced lipid accumulation and adipogenic marker expression, which was further reduced by GRK2 overexpression. In mice with pressure overload-induced heart failure, sex-specific alterations in white adipose tissue (WAT) depots were observed. Male mice in heart failure demonstrated reduced WAT depots when compared to shams, while female mice showed no alterations in WAT depots. Cardiac GRK2 overexpression further exacerbated the reduction in WAT in male mice with heart failure. WAT from male mice in heart failure was also characterized by adipocyte hyperplasia and reduced lipolytic potential when stimulated with isoproterenol ex vivo when compared to sham mice. Notably, male mice in heart failure showed a significant decrease in cardiac fatty acid transporter CD36 expression, while female mice show no changes in expression.

Conclusions: These findings suggest that cardiomyocyte secreted metabolic signaling factors influence adiposity and are further modulated by GRK2 overexpression. These findings also suggest sex-specific differences in heart-to-fat communication. Future studies will identify the key cardiac signaling factors involved in these cardiometabolic alterations.