Atglistatin Ameliorates Functional Decline in Heart Failure via Adipocyte-specific Inhibition of Adipose Triglyceride Lipase

Rationale: Despite the advancement in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF is increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Objectives: To assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess if ATGL inhibition works in an adipocyte autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Methods and Results: Using a known ATGL inhibitor, Atglistatin as well mice with germline deletion of adipocyte-specific (atATGL-KO), we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. We show that Atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from Atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis nor are the benefits derived from increased adiposity. Conclusions: Overall, this study suggests that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF.