2024-03-29T15:44:28Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/616982022-04-07T09:01:50Zcom_10261_81com_10261_5col_10261_334
2012-12-03T10:32:19Z
urn:hdl:10261/61698
Anti-obesity efficacy of LH-21, a cannabinoid CB 1 receptor antagonist with poor brain penetration, in diet-induced obese rats
Alonso, 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.
BACKGROUND 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.
2012-12-03T10:32:19Z
2012-12-03T10:32:19Z
2012
2012-12-03T10:32:20Z
artículo
British Journal of Pharmacology 165: 2274- 2291 (2012)
http://hdl.handle.net/10261/61698
10.1111/j.1476-5381.2011.01698.x
21951309
eng
closedAccess
Nature Publishing Group