Specific targeting of adipose tissue metabolism is superior to caloric restriction in treating obesity-related HFpEF

Obesity is a modifiable major driver of heart failure with preserved ejection fraction (HFpEF), the most common and rapidly increasing form of heart failure. Current metabolic therapies, such as caloric restriction and incretin-based drugs, have shown promise in treating obesity-related HFpEF. However, these interventions neither specifically nor selectively improve adipose tissue metabolism, which is a key etiological factor in HFpEF that may offer a pathway to safer and more effective treatment strategies. Towards this end, we found that genetic inhibition of adipose triglyceride lipase (ATGL) specifically in adipocytes is sufficient to prevent the development of obesity-related HFpEF, and that pharmacological inhibition of ATGL using atglistatin effectively treats established disease. Atglistatin selectively inhibits ATGL in adipose tissue, but not in the heart, leading to superior reduction in adiposity and greater improvement in diastolic dysfunction compared to caloric restriction. These observations underscore the therapeutic potential of selectively targeting adipose tissue, independent of the effects of body weight loss. Mechanistically, atglistatin attenuates HFpEF-associated elevation of inflammatory cytokines, especially IL-1β levels in adipose tissue, more effectively than caloric restriction. In sum, these findings identify dysregulated adipose tissue metabolism as a causal factor and therapeutic target in maladaptive fat-heart crosstalk driving obesity-related HFpEF.