title: Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle.
abstract: OBJECTIVE
  We determined the direct effects of modulating the endocannabinoid-1 (CB1) receptor on the glucose transport system in isolated skeletal muscle from insulin-sensitive lean Zucker and insulin-resistant obese Zucker rats.
  
  
  METHODS
  Soleus strips were incubated in the absence or presence of insulin, without or with various concentrations of the CB1 receptor antagonist SR141716 or with the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA).
  
  
  RESULTS
  CB1 receptor protein expression in visceral adipose (57%), soleus (40%) and myocardial (36%) tissue was significantly (p < 0.05) decreased in obese compared to lean animals, with a trend for a reduction (17%, p = 0.079) in the liver. In isolated soleus muscle from both lean and obese Zucker rats, CB1 receptor antagonism directly improved glucose transport activity in a dose-dependent manner. Basal glucose transport activity was maximally enhanced between 100 and 200 nM SR141716 in lean (26-28%) and obese (22-31%) soleus. The maximal increase in insulin-stimulated glucose transport for lean muscle ( approximately 30%) was achieved at 50 nM SR141716 and for obese muscle ( approximately 30%) at 100 nM SR141716. In contrast, CB1 receptor antagonism did not alter hypoxia-stimulated glucose transport activity. CB1 receptor agonism (1 mM ACEA) significantly decreased both basal (15%) and insulin-stimulated (22%) glucose transport activity in isolated lean soleus. This effect was reversed by 200 nM SR141716. In both lean and obese muscle, the functionality of key signalling proteins (insulin receptor beta-subunit, Akt, glycogen synthase kinase-3beta (GSK-3beta), AMP-dependent protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK)) was not altered by either CB1 receptor agonism or antagonism.
  
  
  CONCLUSIONS
  These results indicate that the engagement of CB1 receptor can negatively modulate both basal and insulin-dependent glucose transport activity in lean and obese skeletal muscles, and that these effects are not mediated by the engagement of elements of the canonical pathways regulating this process in mammalian skeletal muscle.
authors.affiliation: Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Lindborg
authors.forename: M K
authors.initials: MK
authors.lastname: Teachey
authors.forename: S
authors.initials: S
authors.lastname: Jacob
authors.forename: E J
authors.initials: EJ
authors.lastname: Henriksen
mesh_terms: D000818:Animals; D001692:Biological Transport; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
chemical_list: D007004:Hypoglycemic Agents; D010880:Piperidines; D011720:Pyrazoles; D011810:Quinoxalines; D043884:Receptor, Cannabinoid, CB1; C082999:ACEA 1011; D005947:Glucose; D000077285:Rimonabant