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

doi:10.1016/j.cmet.2012.07.002

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 journal › Article › peer-review

294 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 language	English
Pages (from-to)	167-179
Number of pages	13
Journal	Cell Metabolism
Volume	16
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2012.07.002
State	Published - 8 Aug 2012
Externally published	Yes

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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10.1016/j.cmet.2012.07.002

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Tam, J., Cinar, R., Liu, J., Godlewski, G., Wesley, D., Jourdan, T., Szanda, G., Mukhopadhyay, B., Chedester, L., Liow, J. S., Innis, R. B., Cheng, K., Rice, K. C., Deschamps, J. R., Chorvat, R. J., McElroy, J. F., & Kunos, G. (2012). Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism, 16(2), 167-179. https://doi.org/10.1016/j.cmet.2012.07.002

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title = "Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance",

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.",

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

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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Tam, J, Cinar, R, Liu, J, Godlewski, G, Wesley, D, Jourdan, T, Szanda, G, Mukhopadhyay, B, Chedester, L, Liow, JS, Innis, RB, Cheng, K, Rice, KC, Deschamps, JR, Chorvat, RJ, McElroy, JF & Kunos, G 2012, 'Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance', Cell Metabolism, vol. 16, no. 2, pp. 167-179. https://doi.org/10.1016/j.cmet.2012.07.002

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AU - Tam, Joseph

AU - Cinar, Resat

AU - Liu, Jie

AU - Godlewski, Grzegorz

AU - Wesley, Daniel

AU - Jourdan, Tony

AU - Szanda, Gerg

AU - Mukhopadhyay, Bani

AU - Chedester, Lee

AU - Liow, Jeih San

AU - Innis, Robert B.

AU - Cheng, Kejun

AU - Rice, Kenner C.

AU - Deschamps, Jeffrey R.

AU - Chorvat, Robert J.

AU - McElroy, John F.

AU - Kunos, George

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PY - 2012/8/8

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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