The adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL)–mediated lipolysis play important roles in lipid catabolism. ATGL is considered the central rate-limiting enzyme in the mobilization of fatty acids in mammals. Currently, severe fat accumulation has been commonly detected in farmed fish globally. However, the ATGL-mediated lipolysis and the potential synergy among ATGL, HSL, and autophagy, which is another way for lipid breakdown, have not been intensively understood in fish. In the present study, we added Atglistatin as an ATGL-specific inhibitor into the zebrafish diet and fed to the fish for 5 weeks. The results showed that the Atglistatin-treated fish exhibited severe fat deposition, reduced oxygen consumption, and fatty acid β-oxidation, accompanied with increased oxidative stress and inflammation. Furthermore, the Atglistatin-treated fish elevated total and phosphorylation protein expressions of HSL. However, the free fatty acids and lipase activities in organs were still systemically reduced in the Atglistatin-treated fish, and the autophagy marker LC3 was also decreased in the liver. On the other hand, glycogenolysis was stimulated but blood glucose was higher in the Atglistatin-treated fish. The transcriptomic analysis also provided the hint that the protein turnover efficiency in Atglistatin-treated fish was likely to be accelerated, but the protein content in whole fish was not affected. Taken together, ATGL plays crucial roles in energy homeostasis such that its inhibition causes loss of lipid-sourced energy production, which cannot be compensated by activation of HSL, autophagy, and utilization of other nutrients.

甘油三酸酯脂肪酶（ATGL）和激素敏感性脂肪酶（HSL）介导的脂解在脂质分解代谢中起重要作用。ATGL被认为是哺乳动物脂肪酸动员中的中心限速酶。当前，在全球养殖鱼类中普遍检测到严重的脂肪积累。然而，ATGL介导的脂解作用以及ATGL，HSL和自噬之间的潜在协同作用（这是脂类分解的另一种方式）尚未在鱼类中得到深入了解。在本研究中，我们将Atglistatin作为ATGL特异性抑制剂添加到斑马鱼的饮食中，并喂食了5周的鱼。结果表明，经Atglistatin处理的鱼表现出严重的脂肪沉积，氧气消耗减少和脂肪酸β-氧化，并伴有氧化应激和炎症增加。此外，Atglistatin处理的鱼可升高HSL的总蛋白和磷酸化蛋白表达。但是，在经过Atglistatin处理的鱼中，器官中的游离脂肪酸和脂肪酶活性仍会全身性降低，肝脏中的自噬标记物LC3也会降低。另一方面，经Atglistatin处理的鱼中，糖原分解被刺激，但血糖较高。转录组分析还提供了暗示，即经过阿格列汀处理的鱼的蛋白质更新效率可能会提高，但整条鱼的蛋白质含量没有受到影响。两者合计，ATGL在能量稳态中起着至关重要的作用，因此它的抑制导致脂质来源的能量产生的损失，这不能通过激活HSL，自噬和利用其他营养物质来补偿。