Effects of in vitro antagonism of endocannabinoid-1 receptors on the glucose transport system in normal and insulin-resistant rat skeletal muscle

K. A. Lindborg, M. K. Teachey, S. Jacob, E. J. Henriksen

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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 (~30%) was achieved at 50 nM SR141716 and for obese muscle (~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 β-subunit, Akt, glycogen synthase kinase-3β (GSK-3β), AMP-dependent protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK)) was not altered by either CB1 receptor agonism or antagonism. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)722-730
Number of pages9
JournalDiabetes, Obesity and Metabolism
Volume12
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • CB1 receptor
  • Insulin resistance
  • SR141716
  • Soleus muscle
  • Zucker rat

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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