Endocannabinoids and Energy Homeostasis

Abstract

The body's endogenous endocannabinoid system includes two endogenous agonists for cannabinoid-(CB)-1 receptors, anadamide and 2-arachidonoyl-glycerol (2-AG). Both of these endocannabinoids (ECs) are fatty acid signals derived from cell membranes. They exert a coordinated action at multiple tissues to promote increased food intake, lipogenesis, and storage of fat. Endocannabinoids interact with multiple hypothalamic circuits and transmitter systems to stimulate food intake in general, and they also act in reward areas of the brain to selectively enhance intake of palatable foods. Activation of CB1 receptors increases enzyme activity that causes de novo fatty acids to be formed in the liver and circulating lipids to be taken up by fat cells. All these actions are reversed in animals lacking CB1 receptors, and there is growing evidence that activity of the endocannabinoid system is tonically increased in animal and human obesity. Acute or chronic administration of selective synthetic CB1 antagonists to overweight or obese individuals causes weight loss, reduced waist circumference, and an improved lipid and glycemic profile. Developing ligands for endocannabinoid receptors is an important novel therapeutic strategy for the treatment of metabolic dysregulation.