Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice

Abstract

Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.

Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

“…To avoid the accumulation and toxic effects of FFAs, one could target several pathways of the fatty acid metabolism: lipolysis, b-oxidation, or lipogenesis. Pharmacological inhibition of one of the major lipases, adipose triglyceride lipase (ATGL), was successful in correcting high-fat diet-induced insulin resistance and hepatosteatosis in mice (Schweiger et al, 2017). Several potent inhibitors that are directed toward the other major lipase, HSL, have recently been produced and might provide an attractive alternative to treat sepsis (Ogiyama et al, 2017).…”

The herbicide quinclorac as potent lipase inhibitor: Discovery via virtual screening and in vitro/in vivo validation

“…The fact that plasma FFAs are linked to insulin resistance (Schweiger et al, 2017) and neuroinflammation (Butler et al, 2017) renders lipolysis an attractive target to improve insulin sensitivity. HSL and MGL are crucial lipases involved in lipolysis and degradation of stored triglycerides into FFA and glycerol (Bolsoni-Lopes & Alonso-Vale, 2015).…”

“…Elevated levels of circulating FFA play crucial role in insulin resistance and, hence, in the pathogenesis of type II diabetes mellitus (Arner, 2003;Karpe, Dickmann, & Frayn, 2011;Morigny, Houssier, Mouisel, & Langin, 2016;Schweiger et al, 2017). Moreover, MGL is involved in neuroinflammation by releasing proinflammatory eicosanoids and cytokines (Butler et al, 2017;Fowler, 2012;Grabner, Zimmermann, Schicho, & Taschler, 2017).…”

Ganoderma Lucidum Polysaccharide Peptide Alleviates Hepatoteatosis via Modulating Bile Acid Metabolism Dependent on FXR-SHP/FGF

“…Lipid accumulation is a hallmark of NAFLD. Lowering lipid is accepted as an effective measure to ameliorate NAFLD [27][28][29]. Previous study showed that a proteoglycan named Fudan-Yueyang-Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum had antihyperlipidemic effect, but the author paid most attention to the effect of FYGL on antidiabetic while no further study on liver protection [30].…”