Therapeutic efficacy of a peripherally restricted CB1R antagonist/AMPK activator in obesity/metabolic syndrome

Authors

• ZY Liu
• R Cinar
• M Iyer
• T Jourdan
• G Godlewski
• G Szanda
• J Liu
• G Kunos

Abstract

Visceral obesity is associated with increased activity of the endocannabinoid/CB1R system. Globally acting CB1R antagonists reduce body weight and improve the metabolic complications of obesity, including insulin resistance and fatty liver, but cause neuropsychiatric side effects due to blockade of CB1R in the CNS. The enzyme adenosine monophosphate kinase (AMPK) promotes fat oxidation and increases insulin sensitivity. In order to improve the safety and efficacy of CB1R blockade in the treatment of high-fat diet-induced obesity (DIO), we developed a novel bivalent compound, (-)MRI-1891, that selectively and potently inhibits peripheral CB1R and also acts as a direct activator of AMPK. In male, C57Bl/6J mice with DIO, chronic treatment with 0.1–3.0 mg/kg (-)MRI-1891 caused dose-dependent reductions in body weight, food intake and liver triglyceride content, improved glucose tolerance and insulin sensitivity, and reversed the hyperglycemia, hyperinsulinemia and hyperleptinemia of DIO mice, with maximal effects observed at 1 to 3 mg/kg. Unlike rimonabant, (-)MRI-1891 (3 mg/kg) did not elicit hyperambulatory activity and was not anxiogenic (3-30 mg/kg) in the elevated plus maze test. Both rimonabant and (-)MRI-1891 increased total energy expenditure as a result of increased fat oxidation in DIO mice, as assessed by indirect calorimetry. The effect of (-)MRI1891 but not rimonabant was maintained in lean mice, which have low endocannabinoid/CB1R tone. We conclude that selective inhibition of peripheral CB1R coupled with direct activation of AMPK has therapeutic potential for the treatment of the metabolic syndrome.

Scientific Focus Area: Molecular Biology and Biochemistry

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