Peripheral CB1 cannabinoid receptors as therapeutic targets in obesity and diabetes

2012

Challenge

Endogenous cannabinoids are lipid messengers that activate CB1 receptors in the brain to stimulate food intake. They are known to play a role in pathogenesis, including dyslipidemia and insulin resistance, and increased activity of the endocannabinoid system is associated with obesity. Molecules that disrupt the CB1 receptor (CB1 antagonists) are effective not only in reducing body weight, but also in alleviating metabolic complications. However, therapeutic development of this class of compounds was halted due to unwanted neuropsychiatric side effects from CB1 blockade in the brain.

Advance

IRP researchers led by George Kunos, M.D., Ph.D., hypothesized that CB1 antagonists with limited brain penetrance may retain their metabolic efficacy without the unwanted neuropsychiatric effect. The team provided the first proof of this concept using a novel peripheral CB1 antagonist in an animal model of diet-induced obesity and type 2 diabetes.

Impact

The team’s research shows that peripheral CB1 antagonists have potential for treating metabolic syndrome and type 2 diabetes without causing unwanted neuropsychiatric side effects. Their prototype compound is currently undergoing toxicology screening in preparation for testing in clinical trials.

Publications

Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow J-S, Innis RB, Rice KC, Deschamps JR, Chorvat RJ, McElroy JF, Kunos G. (2012). Peripheral CB1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 16(2):167-79.

Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhyay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G. (2013). Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med. 19(9):1132-40.