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

Abstract

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.

• Authors: 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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 165 Issue 7 Pg. 2274-91 (Apr 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 21951309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole
• Anti-Obesity Agents
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Leptin
• PPAR alpha
• PPAR gamma
• Receptor, Cannabinoid, CB1
• Triazoles

Topics

• Animals
• Anti-Obesity Agents (pharmacokinetics, pharmacology, toxicity)
• Brain (metabolism)
• Diet, High-Fat (adverse effects)
• ERG1 Potassium Channel
• Eating (drug effects)
• Ether-A-Go-Go Potassium Channels (drug effects)
• Gene Expression (drug effects)
• HEK293 Cells
• Humans
• Intra-Abdominal Fat (drug effects, metabolism)
• Leptin (genetics)
• Lipogenesis (drug effects, genetics)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Knockout
• Obesity (drug therapy, etiology, genetics, metabolism)
• PPAR alpha (deficiency, genetics)
• PPAR gamma (genetics)
• Rats
• Rats, Wistar
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, genetics)
• Triazoles (pharmacokinetics, pharmacology, toxicity)
• Weight Gain (drug effects)