RT Journal Article
SR Electronic
T1 Genome-wide Expression Profiling Revealed Peripheral Effects of Cannabinoid Receptor 1 Inverse Agonists in Improving Insulin Sensitivity and Metabolic Parameters
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 350
OP 359
DO 10.1124/mol.110.064980
VO 78
IS 3
A1 Wenqing Zhao
A1 Olivia Fong
A1 Eric S. Muise
A1 John R. Thompson
A1 Drew Weingarth
A1 Su Qian
A1 Tung M. Fong
YR 2010
UL http://molpharm.aspetjournals.org/content/78/3/350.abstract
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.