Central and peripheral cannabinoid receptors as therapeutic targets in the control of food intake and body weight.

The endocannabinoid system consists of lipid-derived agonists that activate cannabinoid (CB) receptors. CB receptor agonists, namely, the phytocannabinoid Δ(9)-THC and the endocannabinoid anandamide, increase hunger sensation and food intake. These discoveries led to the clinical use of Δ(9)-THC derivatives for the treatment of cancer and HIV-related nausea and cachexia. Animal studies clarified the important role of CB1 receptors in the hypothalamus and in the limbic system in mediating orexigenic effects. In parallel, data on CB1-specific blockade either by drugs or by genetic ablation further demonstrated that CB1 inhibition protects against weight gain induced by high-fat feeding and reduces body weight in obese animals and humans. The mechanisms of weight reduction by CB1 blockade are complex: they comprise interactions with several orexigenic and anorexigenic neuropeptides and hormones, regulation of sympathetic activity, influences on mitochondrial function, and on lipogenesis. Although these mechanisms appear to be mainly mediated by the CNS, weight loss also occurs when drugs that do not reach CNS concentrations sufficient to inhibit CB1 signaling are used. The development of peripherally restricted CB1 inverse agonists and antagonists opened new routes in CB1 pharmacology because centrally acting CB1 inverse agonists, e.g., rimonabant and taranabant, exerted unacceptable side effects that precluded their further development and application as weight loss drugs. Tissue and circulating endocannabinoid concentrations are often increased in animal models of obesity and in obese humans, especially those with visceral fat accumulation. Thus, further research on CB1 inhibition is still promising to treat human obesity.