Cannabinoid Receptors in Metabolic Regulation and Diabetes

Abstract

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.

Studies in Rats of Combined Muscle and Liver Perfusion and of Muscle Extract Indicate That Contractions Release a Muscle Hormone Directly Enhancing Hepatic Glycogenolysis

“…This may involve purinergic signaling via G-protein-coupled receptors (GPCRs) activated by adenosine or nucleotides [ 42 , 43 , 44 , 45 ]. Speculatively, endocannabinoids might also influence hepatic glucose metabolism via GPCRs [ 46 ]. Undoubtedly, hitherto unknown exercise-responsive myokines will also be discovered through global mRNA sequencing and secretome and metabolome analysis [ 40 ].…”

Cannabinoids and Cardiac Rhythms: Unveiling the Relationship between Cannabis Use, ECG Changes, and Arrhythmias

“…Additionally, GPR55, another cannabinoid-sensitive receptor, plays a role in cardiovascular homeostasis and disease by influencing intracellular signaling cascades. Endocannabinoids like AEA and 2-AG act as primary ligands for cannabinoid receptors, modulating physiological and pathological conditions through autocrine and paracrine mechanisms [51][52][53][54][55].…”

Cannabinoid Signaling in Kidney Disease

“…Interestingly, CB1 has been identified within the podocytes, allowing the ECS to be a target for study [53]. It has been well-characterized that the ECS plays a major role in diabetes and metabolic diseases, which in turn brings focus to diabetic nephropathy [56][57][58][59]. In a 2014 study performed by Jourdan et al, high glucose levels were found to affect CB1 activation in podocytes, causing increased Cnr1 expression [54].…”