Role of the endocannabinoid system in regulating cardiovascular and metabolic risk factors.

Increased endocannabinoid (EC) system activity promotes excessive food intake and obesity in animals and humans. The EC system regulates food intake and hedonic reward through central mechanisms located within the hypothalamus and limbic forebrain. In rodent models, cannabinoid1 (CB1) receptor blockade reduces appetite and weight and prevents obesity and insulin resistance. The EC system also regulates food intake and metabolic factors through peripheral CB1 receptors located at multiple sites throughout the body, including adipose tissue, skeletal muscle, liver, and the gastrointestinal (GI) tract. In rodent models, CB1 receptor antagonists act in the liver to decrease lipogenesis, act in the GI tract to increase satiety, and function in adipose tissue to normalize adiponectin levels and reduce fat storage. The CB1 receptor antagonist rimonabant has been shown to reduce food intake and improve metabolic parameters, such as insulin resistance and fatty liver, in animal models of obesity. In preliminary human studies, upregulation of the EC system has been linked to obesity through mechanisms that include high-fat diet, insulin resistance, and genetic malfunction of an EC inactivation enzyme. Evidence suggests that CB1 receptor blockade is a novel therapeutic strategy that addresses the underlying mechanisms of both obesity and cardiometabolic risk.