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 (CB₁ and CB₂), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB₁ receptor is overactivated in metabolic alterations, pharmacological blockade of the CB₁ receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB₁ receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB₂ receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB₁ and CB₂ 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 CB₁ with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB₂ agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB₁ and CB₂ open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB₁ and CB₂ 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.