Modulation of glycemic homeostasis by CB1 receptor

Obesity has been described as a chronic multifactorial and complex genetic disorder which is associated with several complications and related comorbidities. The increasing prevalence of obesity remains a major public concern. A new therapeutical approach includes drugs that block the cannabinoid receptor type 1 (CB1). The endocannabinoid system (ECS) consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and enzymes that synthesise and degrade the endocannabinoids. Hyperstimulation of the ECS has been described in obesity with elevated levels of endocannabinoids in blood and adipose tissue and with associated insulin resistance. A selective CB1 receptor antagonist called rimonabant has been shown to have beneficial effects on several components of the metabolic syndrome, such as waist circumference, LDL cholesterol, triglyceridemia, blood pressure, fasting glycemia, and insulinemia. Additionally, it has been reported that CB1 receptor blockers enhance insulin sensitivity in obese rats. However, the effects of the ECS on modulation of insulin sensitivity as well as the mechanisms involved remain unknown.

Furuya et al. hypothesise that to modulate glycemic homeostasis the ECS could regulate Slc2a4 gene expression. To address this, they investigated the effects of the selective CB1 receptor agonist ACEA (arachidonyl-2′-chloroethylamide) and the CB1 receptor antagonist/inverse agonist AM251 (1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide) on Slc2a4 gene expression in 3T3-L1 adipocytes and the transcriptional mechanisms potentially involved. Their results showed that both acute and chronic CB1 receptor antagonism greatly increased Slc2a4 mRNA and protein content. Their findings reveal that the blockade of CB1 receptor markedly increases Slc2a4/GLUT4 expression in adipocytes, a feature that involves NF-κB and SREBP-1 transcriptional regulation. Furuya et al. Journal of Molecular Endocrinology 49 97-106.

Read the full article at: DOI: 10.1530/JME-12-0037