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

Joseph Tam*, Resat Cinar, Jie Liu, Grzegorz Godlewski, Daniel Wesley, Tony Jourdan, Gerg Szanda, Bani Mukhopadhyay, Lee Chedester, Jeih San Liow, Robert B. Innis, Kejun Cheng, Kenner C. Rice, Jeffrey R. Deschamps, Robert J. Chorvat, John F. McElroy, George Kunos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

283 Scopus citations

Abstract

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 CB1 receptor (CB1R) 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 CB1R 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 CB1R 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 CB1R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.

Original languageAmerican English
Pages (from-to)167-179
Number of pages13
JournalCell Metabolism
Volume16
Issue number2
DOIs
StatePublished - 8 Aug 2012
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism, NIH. Design and synthesis of JD5037 was funded by Jenrin Discovery, Inc. J.F.M. and R.J.C. hold a patent on JD5037. We thank V. Pike and C. Morris for support and advice with the PET studies, and M. Allen, R. Schwartzbeck, A. Noguchi, D. Springer, and R. Kechrid for their assistance with the animal studies.

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