PT  - JOURNAL ARTICLE
AU  - Wenqing Zhao
AU  - Olivia Fong
AU  - Eric S. Muise
AU  - John R. Thompson
AU  - Drew Weingarth
AU  - Su Qian
AU  - Tung M. Fong
TI  - Genome-wide Expression Profiling Revealed Peripheral Effects of Cannabinoid Receptor 1 Inverse Agonists in Improving Insulin Sensitivity and Metabolic Parameters
AID  - 10.1124/mol.110.064980
DP  - 2010 Sep 01
TA  - Molecular Pharmacology
PG  - 350--359
VI  - 78
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/78/3/350.short
4100  - http://molpharm.aspetjournals.org/content/78/3/350.full
SO  - Mol Pharmacol2010 Sep 01; 78
AB  - 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. The peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 knockout mice. In this article, we systematically investigated gene expression changes in peripheral tissues of diet-induced obese mice treated with the CB1 inverse agonist AM251 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide]. CB1 receptor inhibition led to down-regulation of genes within the de novo fatty acid and cholesterol synthetic pathways, including sterol regulatory element binding proteins 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 peroxisome proliferator-activated receptor α (PPARα). In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the tumor necrosis factor α signal transduction pathway and possibly to the activation of PPARγ, both of which would result in improved insulin sensitivity.