Genome-wide expression profiling revealed peripheral effects of cannabinoid receptor 1 inverse agonists in improving insulin sensitivity and metabolic parameters.
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 beta-oxidation were up-regulated with AM251 treatment, probably through the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In adipose tissue, CB1 receptor inhibition led to the down-regulation of genes in the tumor necrosis factor alpha signal transduction pathway and possibly to the activation of PPARgamma, both of which would result in improved insulin sensitivity.
Department of Molecular Profiling, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065, USA. wenqing_zhao@merck.com
Wenqing
W
Zhao
Olivia
O
Fong
Eric S
ES
Muise
John R
JR
Thompson
Drew
D
Weingarth
Su
S
Qian
Tung M
TM
Fong
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D063386:Cannabinoid Receptor Agonists; D015536:Down-Regulation / Q000187:drug effects; D006720:Homozygote; D007328:Insulin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D063386:Cannabinoid Receptor Agonists; D007328:Insulin; D047493:PPAR alpha; D047495:PPAR gamma; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D051780:Sterol Regulatory Element Binding Protein 1; C103505:AM 251; C031280:pyrazole