Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase

Abstract

Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are 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. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, 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. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.

Of mice and men: The physiological role of adipose triglyceride lipase (ATGL)

“…Remarkably, two very recent reports also indicate a crucial role for adipocyte ATGL in protecting the failing heart. Adipocyte-specific gene deletion and acute pharmacological inhibition of ATGL prevented the progression of heart failure induced by pressure-overload [161,162]. This concept suggests that reducing the FA flux from adipose tissue during the progression of heart failure prevents cardiac lipid remodeling presumably by stabilizing cardiomyocyte membrane integrity.NLSDM patients but not muscle ATGL knockout mice exhibit progressive myopathy…”

Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation

“…Its adipocyte-specific deletion decreased adipocyte lipolysis and serum lipids in mice (30). More recently, pharmacologic inhibition of ATGL has been shown to slow progression of heart failure in mice (31). Because cardiovascular failure, shock (32,33), and lipotoxicity from NEFAs (14,34) can contribute to severe acute pancreatitis, we therefore also considered whether ATGL can mediate severe acute pancreatitis.…”

Norepinephrine promotes triglyceride storage in macrophages via beta2‐adrenergic receptor activation

“…57 Intriguingly, systemic atglistatin treatment has already been shown to improve the recovery from heart failure in mice. 58 While these effects were originally attributed to inhibited adipose tissue lipolysis, 35,58 it is tempting to speculate that atglistatin-mediated increase in triglyceride storage in macrophages could also be beneficial for cardiac repair. In future, it would be interesting to investigate such hypothesis by subjecting macrophage-specific Dgat1 or Hilpda knockout mice (macrophages from both models exhibit defects in triglyceride storage) to myocardial injury, and assessing their recovery.…”