Cannabinoid Receptors in Metabolic Regulation and Diabetes.

There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB and CB), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB receptor is overactivated in metabolic alterations, pharmacological blockade of the CB receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB and CB receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB and CB open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB and CB might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.