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

2011; Wiley; Volume: 165; Issue: 7 Linguagem: Inglês

10.1111/j.1476-5381.2011.01698.x

1476-5381

Mónica Alonso, Antonia Serrano, Margarita Vida, Ana Crespillo, Laura Hernández‐Folgado, Nadine Jagerovic, Pilar Goya, Carmen Reyes‐Cabello, Vidal Perez‐Valero, Juan Decara, Manuel Macías‐González, Francisco J. Bermúdez‐Silva, Juan Suárez, Fernando Rodrı́guez de Fonseca, Francisco Javier Pavón,

Sleep and Wakefulness Research

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.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.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.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.