Following cardiac injury, increased adrenergic drive plays an important role in compensating for reduced cardiac function. However, chronic excess adrenergic stimulation can be detrimental to cardiac pathophysiology and can also affect other organs including adipose tissue leading to increased lipolysis. Interestingly, inhibition of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in lipolysis, in adipocytes ameliorates cardiac dysfunction in a heart failure model. Thus, we investigated whether inhibition of adipocyte ATGL can mitigate the adverse cardiac effects of chronic adrenergic stimulation and explored the underlying mechanisms. To do this, isoproterenol (ISO) was continuously administered to C57Bl/6N mice for 2 weeks with or without an ATGL inhibitor (Atglistatin). We found that Atglistatin alleviated ISO-induced cardiac remodelling and reduced ISO-induced upregulation of galectin-3, a marker of activated macrophage as well as a potent inducer of fibrosis, in white adipose tissue (WAT), heart and the circulation. To test if the beneficial effects of Atglistatin occur via inhibition of adipocyte ATGL, adipocyte-specific ATGL knock-out (atATGL-KO) mice were utilized for similar experiments. Subsequently, the same cardiac protective effects of atATGL-KO following ISO administration were observed. Furthermore, Atglistatin and atATGL-KO abolished ISO-induced galectin-3 secretion from excised WAT. We further demonstrated that activation of cardiac fibroblasts by the conditioned media of ISO-stimulated WAT is galectin-3 dependent. In conclusion, the inhibition of adipocyte ATGL ameliorated ISO-induced cardiac remodelling possibly by reducing galectin-3 secretion from adipose tissue. The inhibition of adipocyte ATGL might be a potential target to prevent some of the adverse effects of chronic excess adrenergic drive.
|Journal||American Journal of Physiology / Heart and Circulatory Physiology|
|Publication status||E-pub ahead of print - 13 Nov 2020|
Fields of Expertise
- Human- & Biotechnology