Understanding Metabolic Homeostasis and Imbalance: What Is the Role of the Endocannabinoid System?

Abstract 

Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB₁) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB₁ receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB₁ blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB₁ blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB₁ receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB₁ blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB₁ receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.

Keywords: Adiponectin, Cannabinoid-1 receptors, Endocannabinoid system, Fatty liver disease, Leptin, Rimonabant