TY - JOUR T1 - Genome-wide expression profiling revealed peripheral effects of CB1 inverse agonists in improving insulin sensitivity and metabolic parameters JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.064980 SP - mol.110.064980 AU - Wenqing Zhao AU - Olivia Fong AU - Eric S Muise AU - John Thompson AU - Drew Weingarth AU - Su Qian AU - Tung M Fong Y1 - 2010/01/01 UR - http://molpharm.aspetjournals.org/content/early/2010/06/07/mol.110.064980.abstract N2 - Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. Recently, the peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 KO mice. In this report, we systematically investigated gene expression changes in peripheral tissues of DIO mice treated with the CB1 inverse agonist AM251. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including SREBP-1 and -2, and their downstream targets in both liver and adipose tissue. In addition, genes involved in fatty acid β-oxidation were up-regulated with AM251 treatment, probably through the activation of PPARα. In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the TNFα signal transduction pathway and possibly to the activation of PPARγ, both of which would result in improved insulin sensitivity.The American Society for Pharmacology and Experimental Therapeutics ER -