Abstract
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.
Highlights
Skeletal muscle serves as a major target organ for glucose removal from circulation and the relevancy of this tissue is bolstered by the disease states of insulin resistance and diabetes
We reported that the mRNA for AEA synthesis enzyme, N-acyl phosphatidylethanolamine phospholipase (NAPE-PLD), and 2-AG synthesis enzyme, diacylglycerol lipase (DAGL)α and diacylglycerol lipase-β (DAGLβ), were higher in muscle of mice fed the n-3 polyunsaturated fatty acids (PUFA) diet compared to the controls
Following 24 h, cells designated for differentiation were exposed to differentiation media (DM) for 48 h, when myotubes formation was present and levels of myogenin and MyoD1 mRNA were elevated verified by RT-PCR
Summary
Skeletal muscle serves as a major target organ for glucose removal from circulation and the relevancy of this tissue is bolstered by the disease states of insulin resistance and diabetes. Under euglycemic conditions in healthy subjects, approximately 75% of glucose removal is mediated by non-insulin stimulated glucose uptake primarily by the brain and to a lesser extent in other tissues such as skeletal muscle (Baron et al, 1988). Researchers have identified a physiologic mechanism that regulates the balance of macronutrient metabolism. While the ECS has been shown to influence several physiological activities, such as hunger, pain modulation, mood, and inflammation, the primary function appears to impact energy homeostasis, as activation of the ECS appears to shift energy balance toward energy storage (De Petrocellis et al, 1999; Soderstrom et al, 2004; Valenti et al, 2005; Piazza et al, 2007)
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