Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation

Abstract

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.

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

“… 58 A very recent study suggested the role of galectin-3 in Atglistatin-mediated cardioprotection. 27 This protein belongs to the family of β-galactoside-binding proteins and is known to promote inflammation and fibrosis in the heart and other organs. 59 Notably, ATGL inactivation reduced galectin-3 levels in vivo and ameliorated isoproterenol-induced galectin-3 secretion in adipose tissue organ cultures.…”

“…The authors concluded that reduced galectin-3 secretion in response to ATGL inhibition contributes to the protective effects of Ai. 27 …”

Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure

“…Interestingly, pharmacological or genetic inhibition of ATGL in adipocytes ameliorates Iso-induced cardiac inflammation, hypertrophy and fibrosis likely by reducing adipose tissue inflammation and reducing galectin-3 secretion from adipose tissue [ 134 ]. Of note our results indicate that Pnpla2 induction in cardiac Iso ECH macrophages is associated with upregulation of Lgals3 (coding for Galectin-3).…”

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway

“…ATGL plays a critical role in modulating lipid metabolism and cardiac function (Foryst-Ludwig et al 2015;Salatzki et al 2018). Ablation of ATGL in adipose tissues or inhibition of ATGL by Atglistatin (predominantly targeting ATGL in adipose tissue) was shown to prevent cardiac damage and dysfunction by reducing galectin-3 or fatty acid secretion from adipocyte tissues (Takahara et al 2021;Thiele et al 2021), implying that adipocytic ATGL is involved in cardiac remodeling and dysfunctions. However, several studies have revealed that ATGL in cardiomyocytes directly regulates cardiac metabolism and mitochondrial substrate oxidation through different mechanisms (Gao et al 2015, Haemmerle et al 2011Kienesberger et al 2012).…”