Send to

Choose Destination
Cell Metab. 2012 Aug 8;16(2):167-79. doi: 10.1016/j.cmet.2012.07.002. Epub 2012 Jul 26.

Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.

Author information

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.


Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center