Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats.
OBJECTIVE
Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome.


METHODS
Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed.


RESULTS
Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers.


CONCLUSIONS
Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.
Department of Physiology, School of Pharmacy, University of Granada, Campus University of Granada s/n, Granada 18071, Spain.
Ikram
I
Merroun
Cristina
C
Sánchez-González
Rosario
R
Martínez
Carlos
C
López-Chaves
Jesús M
JM
Porres
Pilar
P
Aranda
Juan
J
Llopis
Milagros
M
Galisteo
Antonio
A
Zarzuelo
Mohammed
M
Errami
María
M
López-Jurado
D000818:Animals; D015415:Biomarkers / Q000097:blood; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D015415:Biomarkers; D063387:Cannabinoid Receptor Antagonists; D007328:Insulin; D020738:Leptin; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251
ALT; AM 251; AST; Biochemical parameters; CB(1) receptor inverse agonist; DMSO; Liver status; Oxygen consumption; Zucker rats; alanine transminase; aspartate transaminase; dimethyl sulfoxide