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Direct effects of endocannabinoid receptor antagonism on the glucose transport system in insulin‐resistant skeletal muscle of the obese Zucker rat

The purpose of this study was to determine the role of the endocannabinoid receptor‐1 (CB1) in the regulation of the glucose transport system in insulin‐resistant skeletal muscle of obese Zucker rats. CB1 receptor protein expression in obese soleus was significantly lower (25%, p<0.05) compared to insulin‐sensitive lean Zucker rats. Soleus muscle from obese Zucker rats was incubated in the presence or absence of insulin (5 mU/ml) and in the presence or absence of various concentrations of the CB1 receptor antagonist SR141716. In the absence of insulin, SR141716 activated glucose transport (2‐deoxyglucose uptake) by 29% at 100 nM, with an EC50 of ~50 nM. Insulin‐stimulated glucose transport was enhanced 33% by 200 nM SR141716, with an EC50 of ~25 nM. Potential CB1 receptor antagonist targets in the classical insulin signaling pathway and insulin‐independent pathway for GLUT4 translocation were assessed. SR141716 treatment did not alter tyrosine phosphorylation of the insulin receptor or phosphorylation of Akt ser473 or glycogen synthase kinase‐3 ser9. Likewise, CB1 receptor antagonism did not affect phosphorylation of AMPKα thr172 or p38 MAPK thr180/tyr182. While the CB1 receptor is involved in modulation of the glucose transport system in insulin‐resistant skeletal muscle of the obese Zucker rat, this regulation appears to be independent of the classical pathways mediating glucose transport activities.