Journal of Clinical Investigation -- Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Clin Invest. doi:10.1172/JCI42551.
Copyright © 2010, The American Society for Clinical Investigation.
Research Article
Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
Joseph Tam1, V. Kiran Vemuri2, Jie Liu1, Sándor Bátkai1, Bani Mukhopadhyay1, Grzegorz Godlewski1, Douglas Osei-Hyiaman1, Shinobu Ohnuma3, Suresh V. Ambudkar3, James Pickel4, Alexandros Makriyannis2 and George Kunos1

1Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
2Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA.
3Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
4Laboratory of Genetics, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.

Address correspondence to: George Kunos, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA. Phone: 301.443.2069; Fax: 301.480.0257; E-mail: gkunos@mail.nih.gov. Or to: Alexandros Makriyannis, Center for Drug Discovery, Northeastern University, Boston, Massachusetts 02115, USA. Phone: 617.373.4200; Fax: 617.373.7493; E-mail: a.makriyannis@neu.edu.

Authorship note: Joseph Tam and V. Kiran Vemuri contributed equally to this work.


Published July 26, 2010
Received for publication February 3, 2010, and accepted in revised form May 19, 2010.

Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.

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

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Journal of Clinical Investigation -- Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity