Controlled downregulation of the cannabinoid CB1 receptor   provides a promising approach for the treatment of obesity   and obesity-derived type 2 diabetes.
Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.
Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX, 78363, USA.
Dai
D
Lu
Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, CT, 06269-3092, USA.
Rachel
R
Dopart
Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, CT, 06269-3092, USA. debra.kendall@uconn.edu.
Debra A
DA
Kendall
D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D015536:Down-Regulation; D054314:Drug Inverse Agonism; D004435:Eating; D063388:Endocannabinoids / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D009765:Obesity / Q000628:therapy*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects
D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant