| A selective cannabinoid-1 receptor antagonist, PF-95453, reduces body weight and body fat to a greater extent than pair-fed controls in obese monkeys. | |
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MedLine Citation:
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PMID: 20605903 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cannabinoid-1 (CB(1)) receptor antagonists exhibit pharmacological properties favorable to treatment of obesity, caused by both centrally mediated effects on appetite and peripherally mediated effects on energy metabolism. However, the relative contribution of these effects to the weight loss produced by CB(1) receptor antagonists remains unclear. Here, we compare food intake-related and independent effects of the CB(1)-selective antagonist 1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-(methylamino) azetidine-3-carboxamide (PF-95453) in obese cynomolgus monkeys. Monkeys were divided into three study groups (n = 10 each) and treated once daily for 8 weeks with either vehicle or PF-95453 as follows: 1, fed ad libitum and dosed orally with vehicle; 2, fed ad libitum and dosed orally with PF-95453 (0.5 mg/kg weeks 1-3, 1.0 mg/kg weeks 4-8); and 3, fed an amount equal to the amount consumed by the drug-treated group and dosed orally with vehicle (pair-fed). PF-95453 treatment significantly reduced food consumption by 23%, body weight by 10%, body fat by 39%, and leptin by 34% while increasing adiponectin by 78% relative to vehicle-treated controls. Pair-fed animals did not exhibit reductions in body weight or leptin but did show significantly reduced body fat (11%) and increased adiponectin (15%) relative to vehicle-treated controls but markedly less than after PF-95453 treatment. Indeed, significant differences were noted between the drug-treated and pair-fed groups with respect to body weight reduction, body fat reduction, increased adiponectin, and leptin reduction. Similar to humans, monkeys treated with the CB(1) receptor antagonist exhibited decreased body weight and body fat, a substantial portion of which seemed to be independent of the effects on food intake. |
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Authors:
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Janice D Wagner; Li Zhang; Kylie Kavanagh; Gina M Ward; Janice E Chin; John R Hadcock; Bruce J Auerbach; H James Harwood |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-06 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 335 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-21 Completed Date: 2010-10-21 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 103-13 Citation Subset: IM |
Affiliation:
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Department of Pathology, Wake Forest University, Winston-Salem, NC 27157, USA. jwagner@wfubmc.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adiponectin
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metabolism Adiposity / drug effects* Animals Anti-Obesity Agents* Azetidines / pharmacokinetics, pharmacology* Blood Glucose / metabolism Body Composition / drug effects* Body Weight / drug effects* Diet Dogs Dose-Response Relationship, Drug Eating / drug effects, physiology Endpoint Determination Feeding Behavior / drug effects Glucose Tolerance Test Leptin / metabolism Lipids / blood Macaca fascicularis Male Obesity / drug therapy* Rats Rats, Sprague-Dawley Receptor, Cannabinoid, CB1 / antagonists & inhibitors* Triazines / pharmacokinetics, pharmacology* Weight Loss / drug effects |
| Chemical | |
Reg. No./Substance:
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0/1-(7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo(1,5-a)(1,3,5)triazin-4-yl)-3-(methylamino)azetidine-3-carboxamide; 0/Adiponectin; 0/Anti-Obesity Agents; 0/Azetidines; 0/Blood Glucose; 0/Leptin; 0/Lipids; 0/Receptor, Cannabinoid, CB1; 0/Triazines |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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