Nisr Raid B, Shah Dinesh S, Hundal Harinder S
Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Cell Signal. 2025 Feb;126:111516. doi: 10.1016/j.cellsig.2024.111516. Epub 2024 Nov 24.
The EP4 (prostaglandin E2) receptor plays a crucial role in myogenesis and skeletal muscle regeneration, yet its involvement in regulating insulin-dependent metabolic pathways is not well characterised. Our research investigates the expression of EP4 in rat skeletal L6 myotubes and its impact on insulin signalling. We found that activation of EP4 by selective agonists disrupts insulin signalling and insulin-stimulated glucose uptake. This impairment is associated with enhanced pro-inflammatory NF-κB signalling, a process that can be attenuated by EP4 antagonists. Importantly, EP4 antagonism also reduces NF-κB activation induced by palmitate and the associated reduction in insulin signalling, an effect not replicated by antagonists of EP1, EP2, or EP3 receptors. These observations indicate that the EP4 receptor is a modulator of insulin action and that it contributes to fatty-acid-induced insulin resistance in skeletal muscle cells. Our findings suggest that EP4 could be a potential therapeutic target for managing insulin resistance.
EP4（前列腺素E2）受体在肌生成和骨骼肌再生中起关键作用，但其在调节胰岛素依赖的代谢途径中的作用尚未得到充分表征。我们的研究调查了EP4在大鼠骨骼肌L6肌管中的表达及其对胰岛素信号传导的影响。我们发现，选择性激动剂激活EP4会破坏胰岛素信号传导和胰岛素刺激的葡萄糖摄取。这种损害与促炎NF-κB信号传导增强有关，EP4拮抗剂可减弱这一过程。重要的是，EP4拮抗作用还可降低棕榈酸诱导的NF-κB激活以及相关的胰岛素信号传导减少，而EP1、EP2或EP3受体拮抗剂则不会产生这种效果。这些观察结果表明，EP4受体是胰岛素作用的调节剂，并且它在骨骼肌细胞中导致脂肪酸诱导的胰岛素抵抗。我们的研究结果表明，EP4可能是治疗胰岛素抵抗的潜在靶点。
