Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
Eur J Pharmacol. 2021 Nov 5;910:174451. doi: 10.1016/j.ejphar.2021.174451. Epub 2021 Aug 27.
Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with development of insulin resistance. In particular, diacylglycerol and ceramide are currently considered as causal bioactive lipids for impaired insulin action. Recently, inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation, has been shown to reduce total IMCL content and improve whole-body insulin resistance. This study aimed to investigate whether ACC2 inhibition-induced compositional changes in bioactive lipids, especially diacylglycerol and ceramide, within skeletal muscle contribute to the improved insulin resistance. In skeletal muscle of normal rats, treatment of the ACC2 inhibitor compound 2e significantly decreased both diacylglycerol and ceramide levels while having no significant impact on other lipid metabolite levels. In skeletal muscle of Zucker diabetic fatty (ZDF) rats, which exhibited greater lipid accumulation than that of normal rats, compound 2e significantly decreased diacylglycerol and ceramide levels corresponding to reduced long chain acyl-CoA pools. Additionally, in the lipid metabolomics study, ZDF rats treated with compound 2e also showed improved diabetes-related metabolic disturbance, as reflected by delayed hyperinsulinemia as well as upregulated gene expression associated with diabetic conditions in skeletal muscle. These metabolic improvements were strongly correlated with the bioactive lipid reductions. Furthermore, long-term treatment of compound 2e markedly improved whole-body insulin resistance, attenuated hyperglycemia and delayed insulin secretion defect even at severe diabetic conditions. These findings suggest that ACC2 inhibition decreases diacylglycerol and ceramide accumulation within skeletal muscle by enhancing acyl-CoA breakdown, leading to attenuation of lipid-induced insulin resistance and subsequent diabetes progression.
肌内甘油三酯 (IMCL) 在骨骼肌中的积累与胰岛素抵抗的发展密切相关。特别是，二酰基甘油和神经酰胺目前被认为是导致胰岛素作用受损的生物活性脂质。最近，抑制乙酰辅酶 A 羧化酶 2 (ACC2)，负调节线粒体脂肪酸氧化，已被证明可以减少总 IMCL 含量并改善全身胰岛素抵抗。本研究旨在探讨 ACC2 抑制诱导的骨骼肌内生物活性脂质（特别是二酰基甘油和神经酰胺）组成变化是否有助于改善胰岛素抵抗。在正常大鼠的骨骼肌中，ACC2 抑制剂化合物 2e 的处理显著降低了二酰基甘油和神经酰胺的水平，而对其他脂质代谢物水平没有显著影响。在 Zucker 糖尿病肥胖 (ZDF) 大鼠的骨骼肌中，脂质积累大于正常大鼠，化合物 2e 显著降低了二酰基甘油和神经酰胺的水平，同时减少了长链酰基辅酶 A 池。此外，在脂质代谢组学研究中，用化合物 2e 处理的 ZDF 大鼠也表现出改善的与糖尿病相关的代谢紊乱，表现为胰岛素血症延迟以及与骨骼肌中糖尿病状况相关的基因表达上调。这些代谢改善与生物活性脂质的减少密切相关。此外，长期用化合物 2e 治疗可显著改善全身胰岛素抵抗，减轻高血糖并延迟胰岛素分泌缺陷，即使在严重的糖尿病情况下也是如此。这些发现表明，ACC2 抑制通过增强酰基辅酶 A 的分解来减少骨骼肌中二酰基甘油和神经酰胺的积累，从而减轻脂质诱导的胰岛素抵抗和随后的糖尿病进展。
