Abstract
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.
Footnotes
This study was fully funded by Merck and Co.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.064980.
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ABBREVIATIONS:
- CB1
- cannabinoid receptor 1
- SREBP
- sterol regulatory element binding protein
- ACC1
- acetyl CoA carboxylase-1
- FASN
- fatty acid synthase
- KO
- knockout
- WT
- wild type
- eWAT
- epididymal white adipose tissue
- DIO
- diet-induced obese
- RC
- regular chow
- HFD
- high-fat diet
- ANOVA
- analysis of variance
- FDR
- false discovery rate
- PPAR
- peroxisome proliferator-activated receptor
- CPT
- carnitine palmitoyltransferase
- TNF
- tumor necrosis factor
- TNFR
- TNF receptor
- TRAF
- TNFR-associated factor
- RIPK
- receptor-interacting S/T kinase
- CNS
- central nervous system
- MLYCD
- malonyl CoA decarboxylase
- AM251
- 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3-carboxamide
- SR141716
- 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide.
- Received April 19, 2010.
- Accepted June 7, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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