Center on Aging, University of Connecticut Health Center Farmington, CT, USA.
Front Physiol. 2014 Mar 21;5:100. doi: 10.3389/fphys.2014.00100. eCollection 2014.
Skeletal muscle is a major storage site for glycogen and a focus for understanding insulin resistance and type-2-diabetes. New evidence indicates that overactivation of the peripheral endocannabinoid system (ECS) in skeletal muscle diminishes insulin sensitivity. Specific n-6 and n-3 polyunsaturated fatty acids (PUFA) are precursors for the biosynthesis of ligands that bind to and activate the cannabinoid receptors. The function of the ECS and action of PUFA in skeletal muscle glucose uptake was investigated in proliferating and differentiated C2C12 myoblasts treated with either 25 μM of arachidonate (AA) or docosahexaenoate (DHA), 25 μM of EC [anandamide (AEA), 2-arachidonoylglycerol (2-AG), docosahexaenoylethanolamide (DHEA)], 1 μM of CB1 antagonist NESS0327, and CB2 inverse agonist AM630. Compared to the BSA vehicle control cell cultures in both proliferating and differentiated myoblasts those treated with DHEA, the EC derived from the n-3 PUFA DHA, had higher 24 h glucose uptake, while AEA and 2-AG, the EC derived from the n-6 PUFA AA, had lower basal glucose uptake. Adenylyl cyclase mRNA was higher in myoblasts treated with DHA in both proliferating and differentiated states while those treated with AEA or 2-AG were lower compared to the control cell cultures. Western blot and qPCR analysis showed higher expression of the cannabinoid receptors in differentiated myoblasts treated with DHA while the opposite was observed with AA. These findings indicate a compensatory effect of DHA and DHEA compared to AA-derived ligands on the ECS and associated ECS gene expression and higher glucose uptake in myoblasts.
骨骼肌是糖原的主要储存场所，也是理解胰岛素抵抗和 2 型糖尿病的重点。新的证据表明，外周内源性大麻素系统（ECS）在骨骼肌中的过度激活会降低胰岛素敏感性。特定的 n-6 和 n-3 多不饱和脂肪酸（PUFA）是结合并激活大麻素受体的配体生物合成的前体。在增殖和分化的 C2C12 成肌细胞中，用 25 μM 的花生四烯酸（AA）或二十二碳六烯酸（DHA）、25 μM 的 EC[大麻素（AEA）、2-花生四烯酰甘油（2-AG）、二十二碳六烯酰乙醇胺（DHEA）]、1 μM 的 CB1 拮抗剂 NESS0327 和 CB2 反向激动剂 AM630 处理后，研究了 ECS 和 PUFA 在骨骼肌葡萄糖摄取中的作用。与增殖和分化的成肌细胞中的 BSA 载体对照细胞培养物相比，用 DHEA 处理的细胞培养物具有更高的 24 小时葡萄糖摄取量，而源自 n-6 PUFA AA 的 ECAEA 和 2-AG 的基础葡萄糖摄取量较低。在增殖和分化状态下，用 DHA 处理的成肌细胞中的腺苷酸环化酶 mRNA 水平较高，而用 AEA 或 2-AG 处理的成肌细胞中的腺苷酸环化酶 mRNA 水平较低。Western blot 和 qPCR 分析显示，用 DHA 处理的分化成肌细胞中大麻素受体的表达更高，而用 AA 处理的成肌细胞则相反。这些发现表明，与 AA 衍生的配体相比，DHA 和 DHEA 对内源性大麻素系统及其相关内源性大麻素系统基因表达具有代偿作用，并能提高成肌细胞的葡萄糖摄取量。
