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Title

Anti-obesity efficacy of LH-21, a cannabinoid CB 1 receptor antagonist with poor brain penetration, in diet-induced obese rats

AuthorsAlonso, M.; Serrano, A.; Vida, M.; Crespillo, A; Hernández-Folgado, Laura ; Jagerovic, Nadine ; Goya, Pilar ; Reyes-Cabello, C. .; Pérez-Valero, V.; Decara, Juan; Macías-González, Manuel; Bermúdez-Silva, Francisco Javier; Suárez, J.; Rodríguez de Fonseca, Fernando; Pavón, F.J.
Issue Date2012
PublisherNature Publishing Group
CitationBritish Journal of Pharmacology 165: 2274- 2291 (2012)
AbstractBACKGROUND AND PURPOSE 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 CB 1 receptor antagonists. In this study we analysed the effects of LH-21, 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 analysed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether-à-go-go Related Gene (hERG) channels was evaluated. KEY RESULTS LH-21 reduced feeding and body weight gain in HFD-fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD-1; (iii) CB 1 receptors; and (iv) 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. CONCLUSIONS AND IMPLICATIONS These results support the hypothesis that treatment with the peripherally neutral acting CB 1 receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue. © 2011 The Authors. British Journal of Pharmacology.
URIhttp://hdl.handle.net/10261/61698
DOI10.1111/j.1476-5381.2011.01698.x
Identifiersdoi: 10.1111/j.1476-5381.2011.01698.x
issn: 0007-1188
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