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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
Authors:Alonso Mónica  Serrano Antonia  Vida Margarita  Crespillo Ana  Hernandez-Folgado Laura  Jagerovic Nadine  Goya Pilar  Reyes-Cabello Carmen  Perez-Valero Vidal  Decara Juan  Macías-González Manuel  Bermúdez-Silva Francisco Javier  Suárez Juan  Rodríguez de Fonseca Fernando  Pavón Francisco Javier
Affiliation:Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya, Fundación IMABIS, Málaga, Spain.
Abstract:

BACKGROUND AND PURPOSE

Peripheral blockade of cannabinoid CB1 receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB1 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) CB1 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 CB1 receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue.
Keywords:cannabinoids   diet-induced obesity   rat   adipose tissue   appetite   PPARs   adiponectin   leptin   SCD-1
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