Abstract
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 G-protein-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.
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Abbreviations
- 2-AG:
-
2-Arachidonoylglycerol
- AEA:
-
Arachidonoylethanolamide
- CB1:
-
Cannabinoid receptor type 1
- CB2:
-
Cannabinoid receptor type 2
- CRP:
-
C-reactive protein
- CNS:
-
Central nervous system
- EC:
-
Endocannabinoid
- FAAH:
-
Fatty acid amide hydrolase
- GPCR:
-
G-protein-coupled receptor
- HbA1c:
-
Glycated hemoglobin
- MAGL:
-
Monoacylglycerol lipase
- T2DM:
-
Type 2 diabetes mellitus
- ER:
-
Endoplasmic reticulum
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Acknowledgments
The authors thank Kwang Hyun Ahn for his assistance with the manuscript. This work was supported in part by a National Institutes of Health Grant DA020763 (to D.A.K.) and a Faculty Development Fund from Texas A&M Health Sciences Center (to D.L.).
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Lu, D., Dopart, R. & Kendall, D.A. Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes. Cell Stress and Chaperones 21, 1–7 (2016). https://doi.org/10.1007/s12192-015-0653-5
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DOI: https://doi.org/10.1007/s12192-015-0653-5