title: Anti-obesity efficacy of LH-21, a cannabinoid CB(1)  receptor antagonist with poor brain penetration, in diet-induced obese rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.affiliation: Laboratorio de Medicina Regenerativa, Hospital Regional Universitario Carlos Haya, Fundación IMABIS, Málaga, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Alonso
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.forename: Margarita
authors.initials: M
authors.lastname: Vida
authors.forename: Ana
authors.initials: A
authors.lastname: Crespillo
authors.forename: Laura
authors.initials: L
authors.lastname: Hernandez-Folgado
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.forename: Pilar
authors.initials: P
authors.lastname: Goya
authors.forename: Carmen
authors.initials: C
authors.lastname: Reyes-Cabello
authors.forename: Vidal
authors.initials: V
authors.lastname: Perez-Valero
authors.forename: Juan
authors.initials: J
authors.lastname: Decara
authors.forename: Manuel
authors.initials: M
authors.lastname: Macías-González
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Bermúdez-Silva
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D000072237:ERG1 Potassium Channel; D004435:Eating / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D015430:Weight Gain / Q000187:drug effects
chemical_list: C515162:5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole; D019440:Anti-Obesity Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020738:Leptin; D047493:PPAR alpha; D047495:PPAR gamma; D043884:Receptor, Cannabinoid, CB1; D014230:Triazoles