| ANTIOBESITY EFFICACY OF LH-21, A CANNABINOID CB(1) RECEPTOR ANTAGONIST WITH POOR BRAIN PENETRATION, IN DIET-INDUCED OBESE RATS. | |
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MedLine Citation:
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PMID: 21951309 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background and purpose. The peripheral blockade of cannabinoid CB(1) receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting cannabinoid CB(1) receptor antagonists. In this study we have analyzed the effects of LH-21 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole], a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet-induced obesity. Experimental approach. To induce obesity, male Wistar rats were fed a high-fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg kg(-1) LH-21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat-pad samples were analyzed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms as well as cardiac hERG channels was evaluated. Key results. LH-21 treatment resulted in greater efficacy to reduce feeding and body weight gain in HFD-fed animals compared to the control group fed SD. In adipose tissue, this effect was associated with a decrease in gene expression of: 1) leptin, 2) lipogenic enzymes, including SCD-1, 3) cannabinoid CB(1) receptors, and 4) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD- and SD-fed rats, LH-21 did not seem to induce hepatic, cardiac or renal toxicity, suggesting that the drug is not toxic to these organs. Conclusions and implications. These results support the hypothesis that the treatment with the peripherally neutral acting cannabinoid CB(1) receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue. |
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Authors:
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Mónica Alonso; Antonia Serrano; Margarita Vida; Ana Crespillo; Laura Hernandez-Folgado; Nadine Jagerovic; Pilar Goya; Carmen Reyes-Cabello; Vidal Perez-Valero; Juan Decara; Manuel Macías-González; Francisco Javier Bermúdez-Silva; Juan Suárez; Fernando Rodríguez de Fonseca; Francisco Javier Pavón |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-26 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya. Fundación IMABIS. Avenida Carlos Haya 82, sótano. Málaga 29010, Spain CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Spain Instituto de Química Médica, CSIC, Juan de la Cierva 3. Madrid 28006, Spain Servicio de Endocrinología y Nutrición, Hospital Virgen de la Victoria. Fundación IMABIS. Campus Teatinos s/n. Málaga 29010, Spain. |
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