Expression of cannabinoid system in muscle: effects of high fat diet and CB1 receptor blockade
Abstract
The endocannabinoid system (ECS) plays an important role on the onset of obesity and metabolic disorders implicating central and peripheral mechanisms predominantly via CB1 receptor. CB1 receptor antagonist/inverse agonist treatment improves cardio-metabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. Here we have identified the presence of the endocannabinoid-signaling machinery in the skeletal muscle and also investigated the impact of a very high-fat diet (HFD) on lipid metabolism-related genes and endocannabinoid-related proteins. Finally we tested whether CB1 inverse agonist AM251 administration restored the alterations induced by HFD. Rats were fed either with a standard diet (SD) and a HFD for 10 weeks and then treated with AM251 (3 mg/kg/day) for 14 days. The accumulated kilocalorie intake was progressively higher in HFD than SD, resulting in a divergence on body weight gain. AM251 treatment reduced accumulated food/kilocalorie intake and body weight gain, being more marked in HFD. CB1, CB2 and PPARa gene expression was decreased in HFD rats, while DAGLb and MAGL were upregulated. These data suggest an altered endocannabinoid-signaling as results of HFD. AM251 treatment reduced CB1, CB2, PPARa, PPARg and adipoR1 gene expression in SD, but only partially normalized CB1 and CB2 receptors in HFD. Protein levels corroborated gene expression results, but also showed an increase of DAGLb after AM251 in SD. Present data indicates a diet-sensitive ECS in the skeletal muscle, and that blockade of CB1 receptors partially restores the metabolic adaption imposed by diet.
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