Dept. of Human Health and Nutritional Sciences, Univ. of Guelph, Ontario, Canada, N1G 2W1.
Am J Physiol Regul Integr Comp Physiol. 2010 Aug;299(2):R470-9. doi: 10.1152/ajpregu.00431.2009. Epub 2010 Jun 10.
Agonists targeting the nuclear receptor peroxisome proliferator-activated receptors (PPAR)-delta may be potential therapeutic agents for insulin-resistant related conditions, as they may be able to stimulate fatty acid (FA) oxidation and attenuate the accumulation of harmful lipid species in skeletal muscle. Several reports have demonstrated that PPAR-delta agonists improve whole body insulin sensitivity. However, whether these agonists exert their direct effects on glucose and FA metabolism in skeletal muscle, and specifically with different fiber types, is unknown. This study was undertaken to determine the effects of oral treatment with the PPAR-delta agonist, GW 501516, in conjunction with the administration of a high-saturated-fat diet on insulin-stimulated glucose transport in isolated oxidative (soleus) and glycolytic (epitrochlearis) rodent skeletal muscle in vitro. High-fat feeding significantly decreased maximal insulin-stimulated glucose transport in soleus, but not epitrochlearis muscle, and was associated with increased skeletal muscle diacylglycerol and ceramide content. Unexpectedly, treatment with the PPAR-delta agonist significantly reduced insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, regardless of dietary fat content. The reduction in insulin-stimulated glucose transport induced by the agonist was associated with large increases in total muscle fatty acid translocase (FAT)/CD36protein content, but not diacylglycerol or ceramide contents. Agonist treatment did not alter the protein content of PPAR-delta, GLUT4, or insulin-signaling proteins (IRS-1, p85 PI3-K, Akt). Agonist treatment led to a small, but significant increase, in the oxidative capacity of glycolytic but not oxidative muscle. We propose that chronic treatment with the PPAR-delta agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for FA transport across the sarcolemma without a sufficient compensatory increase in FA oxidation. However, an accumulation of diacylglycerol and ceramide, while associated with diet-induced insulin resistance, does not appear to be responsible for the agonist-induced reduction in insulin-stimulated glucose transport.
激动剂靶向核受体过氧化物酶体增殖物激活受体 (PPAR)-δ 可能是胰岛素抵抗相关疾病的潜在治疗药物，因为它们可能能够刺激脂肪酸 (FA) 氧化并减少骨骼肌中有害脂质物质的积累。几项报告表明，PPAR-δ 激动剂可改善全身胰岛素敏感性。然而，这些激动剂是否对骨骼肌中的葡萄糖和 FA 代谢发挥直接作用，特别是对不同的纤维类型，尚不清楚。本研究旨在确定口服 PPAR-δ 激动剂 GW 501516 联合高饱和脂肪饮食对体外分离的氧化（比目鱼肌）和糖酵解（肱二头肌）啮齿动物骨骼肌中胰岛素刺激的葡萄糖转运的影响。高脂肪喂养显著降低了比目鱼肌的最大胰岛素刺激的葡萄糖转运，但对肱二头肌肌肉没有影响，并且与骨骼肌二酰基甘油和神经酰胺含量增加有关。出乎意料的是，无论饮食中的脂肪含量如何，PPAR-δ 激动剂的治疗都会显著降低胰岛素刺激的葡萄糖转运。激动剂诱导的胰岛素刺激的葡萄糖转运减少与肌肉总脂肪酸转运蛋白 (FAT)/CD36 蛋白含量的大幅增加有关，但与二酰基甘油或神经酰胺含量无关。激动剂处理不会改变 PPAR-δ、GLUT4 或胰岛素信号蛋白（IRS-1、p85 PI3-K、Akt）的蛋白含量。激动剂处理导致糖酵解但不是氧化肌肉的 FA 转运能力略有但显著增加。我们提出，慢性 PPAR-δ 激动剂 GW 501516 治疗可能通过增加跨肌小节 FA 转运的能力而不是足够的 FA 氧化代偿性增加来诱导或加重啮齿动物骨骼肌的胰岛素抵抗。然而，二酰基甘油和神经酰胺的积累虽然与饮食诱导的胰岛素抵抗有关，但似乎不是激动剂诱导的胰岛素刺激的葡萄糖转运减少的原因。
