Targeting Adipose Tissue Function Protects Against Heart Failure with Preserved Ejection Fraction

Abstract This study seeks to develop a better understanding of how the targeting of adipose tissue (AT) can mediate outcomes in cardiac function. Obesity is highly prevalent among individuals with heart failure with preserved ejection fraction (HFpEF). While thermogenic AT helps counteract obesity‐related conditions, its impact on heart function in obesity‐related HFpEF is unclear. Using a “two‐hit” HFpEF model, the study evaluates the impact of thermogenic AT on cardiac function through pharmacological, surgical, and genetic interventions. Activation of thermogenic AT via the β3‐adrenergic receptor agonist CL‐316,243 (CL) improves cardiac function, protects against HFpEF‐induced remodeling, and enhances energy expenditure. Similarly, transplantation of AT from CL‐treated mice into wild‐type recipients confers cardioprotection. In contrast, genetic suppression of thermogenesis ( Adipoq ‐Cre; Prdm16 fl/fl ) abolishes CL's benefits, while genetic enhancement of thermogenic AT ( Ucp1 ‐Cre ERT2 ; Cdkn2a fl/fl ) improves cardiac structure and function. Mechanistically, AT thermogenesis is linked with significant alterations in the cardiac lipidome, as revealed by lipidomic analysis via LC/MS‐MS. These findings establish the adipose‐heart axis as a promising therapeutic target for obesity‐related HFpEF and cardiometabolic health.