Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
Joseph Tam, … , Alexandros Makriyannis, George Kunos
Joseph Tam, … , Alexandros Makriyannis, George Kunos
Published July 26, 2010
Citation Information: J Clin Invest. 2010;120(8):2953-2966. https://doi.org/10.1172/JCI42551.
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Research Article

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Abstract

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.

Authors

Joseph Tam, V. Kiran Vemuri, Jie Liu, Sándor Bátkai, Bani Mukhopadhyay, Grzegorz Godlewski, Douglas Osei-Hyiaman, Shinobu Ohnuma, Suresh V. Ambudkar, James Pickel, Alexandros Makriyannis, George Kunos

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Figure 1

Chemical structure and pharmacological profile of AM6545.

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Chemical structure and pharmacological profile of AM6545. (A) Chemical s...
(A) Chemical structure of AM6545 and rimonabant. (B) In vitro interaction of antagonists with CB1R and CB2R: Left: KI values for CB1R (AM6545: 3.3 ± 0.8 nM, rimonabant: 2.9 ± 1.5 nM) and CB2R (AM6545: 624 ± 128 nM) were derived from displacement of [3H]CP-55,940 binding in mouse brain plasma membranes and membranes of HEK293 cells transfected with mouse CB2R, respectively. Right: Agonist effect of HU-210, neutral antagonism by AM6545 (AM), and inverse agonism by rimonabant (Rimo), indicated by increase, no change, and decrease in GTPγS binding, respectively. Data represent percentage of stimulation over basal binding and are mean ± SEM of 3 assays performed in triplicate. (C) Concentration of AM6545 and rimonabant in plasma, brain, and liver, 1 hour after i.p. or po administration by gavage of a dose of 10 mg/kg. Data represent mean ± SEM from 3 mice per group. *P < 0.0001 relative to rimonabant. (D) Brain and plasma concentration of AM6545 and rimonabant 12 hours after dose administration, following daily i.p. dosage at 10 mg/kg for 28 days. Data represent mean ± SEM from 3 mice per group. *P < 0.04 relative to rimonabant. (E) Brain and plasma concentrations of AM6545 in Mdr1a/b–/– and Mdr1a/b–/–Bcrp–/– mice and their wild-type (FVB) controls 1 hour after acute i.p. administration of 10 mg/kg AM6545. Note the dramatic increase in brain levels of AM6545 in the knockout strains relative to wild-type controls. Data represent mean ± SEM from 3 mice per group. *P < 0.01 relative to wild-type controls.