Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
Nat Commun. 2017 Mar 22;8:14859. doi: 10.1038/ncomms14859.
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.
升高的循环脂肪酸（FAs）会导致肥胖相关代谢并发症的发生，如胰岛素抵抗（IR）和非酒精性脂肪肝（NAFLD）。因此，减少脂肪组织的脂解作用以减少 FAs 的动员并降低其相应的血浆浓度，是一种潜在的治疗策略，可以对抗肥胖相关疾病。在这里，我们表明，用化学抑制剂 Atglistatin 特异性抑制脂肪甘油三酯脂肪酶（Atgl）可有效减少高脂肪饮食喂养的小鼠的脂肪组织脂解、体重增加、IR 和 NAFLD。重要的是，即使长期治疗也不会导致脂肪在骨骼肌或心脏等异位组织中堆积。因此，在 Atgl 基因缺失的遗传模型中观察到的严重心脏脂肪变性和心肌病不会发生在 Atglistatin 治疗的小鼠中。我们的数据验证了 Atgl 的药理学抑制作为一种潜在的强大治疗策略，可用于治疗肥胖症和相关代谢紊乱。
