School of Physical Education, Hangzhou Normal University, Hangzhou, China.
NICM Health Research Institute, Western Sydney University, Westmead, New South Wales, Australia.
Clin Exp Pharmacol Physiol. 2022 Feb;49(2):302-310. doi: 10.1111/1440-1681.13600. Epub 2021 Oct 21.
This study aimed to elucidate the role of transcription factor EB (TFEB) in protecting C2C12 myotubes against palmitate (PA)-induced insulin resistance (IR) and explored its mechanism associated with autophagy. PA treatment significantly decreased insulin sensitivity in myotubes and downregulated TFEB protein expression. TFEB overexpression significantly reversed the PA-suppressed glucose transporter 4 (GLUT4) protein expression and improved intracellular glucose uptake and consumption, and also alleviated the decrease of autophagy markers induced by PA. The effect of TFEB overexpression on GLUT4 was also abolished by the autophagy inhibitor 3-MA. In addition, AMPKɑ2-DN inhibited or abolished the effects of TFEB overexpression on upregulation of GLUT4 and PA-induced decrease of autophagy marker expressions. Taken together, our data demonstrated that upregulation of TFEB improved PA-induced IR in C2C12 myotubes by enhancing autophagy and upregulating AMPK activity. TFEB, as a critical regulator of glucose homeostasis in skeletal muscle cells, may be a potential therapeutic target for IR and Type 2 diabetes.
本研究旨在阐明转录因子 EB（TFEB）在保护 C2C12 肌管抵抗棕榈酸（PA）诱导的胰岛素抵抗（IR）中的作用，并探讨其与自噬相关的机制。PA 处理显著降低了肌管的胰岛素敏感性，并下调了 TFEB 蛋白表达。TFEB 过表达显著逆转了 PA 抑制的葡萄糖转运蛋白 4（GLUT4）蛋白表达，改善了细胞内葡萄糖摄取和消耗，同时减轻了 PA 诱导的自噬标志物的减少。自噬抑制剂 3-MA 也消除了 TFEB 过表达对 GLUT4 的影响。此外，AMPKɑ2-DN 抑制或消除了 TFEB 过表达对 GLUT4 的上调和 PA 诱导的自噬标志物表达减少的作用。综上所述，我们的数据表明，TFEB 的上调通过增强自噬和上调 AMPK 活性，改善了 C2C12 肌管中 PA 诱导的 IR。TFEB 作为骨骼肌细胞葡萄糖稳态的关键调节因子，可能成为 IR 和 2 型糖尿病的潜在治疗靶点。
