Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?
Mary-Elizabeth Patti
Mary-Elizabeth Patti
Published July 26, 2010
Citation Information: J Clin Invest. 2010;120(8):2646-2648. https://doi.org/10.1172/JCI44099.
View: Text | PDF
Commentary

Rehashing endocannabinoid antagonists: can we selectively target the periphery to safely treat obesity and type 2 diabetes?

Abstract

A growing body of evidence supports an important role for the endocannabinoid system as a regulator of appetite, body weight, and systemic metabolism, which is overactive in obesity and type 2 diabetes. While initial attempts to target this system using the cannabinoid receptor inverse agonist rimonabant were successful in producing modest weight loss and improving obesity-related metabolic complications in humans, adverse central nervous system side effects precluded introduction of this drug into clinical practice. However, new data, presented by Tam and colleagues in this issue of the JCI, demonstrate that selective blockade of peripheral cannabinoid receptors may be a novel successful therapeutic approach.

Authors

Mary-Elizabeth Patti

×

Figure 1

Targeting the endocannabinoid system.

Options: View larger image (or click on image) Download as PowerPoint
Targeting the endocannabinoid system. Endogenous cannabinoids bind to CB...
Endogenous cannabinoids bind to CB1 in both the CNS and multiple peripheral tissues. Rimonabant, a CB1 inverse agonist, inhibits cannabinoid signaling both centrally and peripherally. In clinical trials, it consistently increased weight loss, as compared with placebo, and improved metabolic control. However, due to concerns about adverse CNS-mediated effects such as depression and anxiety, rimonabant was withdrawn from the worldwide market. In contrast, AM6545 does not penetrate the CNS and inhibits cannabinoid signaling only in the periphery (19). It exerts beneficial metabolic effects in mice.