The cannabinoid CB1 receptor antagonist SR141716A (Rimonabant) enhances the metabolic benefits of long-term treatment with oleoylethanolamide in Zucker rats.
Anandamide and oleoylethanolamide (OEA) are lipid mediators that regulate feeding and lipid metabolism. While anandamide, a cannabinoid CB1 receptor agonist, promotes feeding and lipogenesis, oleoylethanolamide, an endogenous agonist of peroxisome proliferator activated receptor alpha (PPAR-alpha), decreases food intake and activates lipid mobilization and oxidation. The treatment with a cannabinoid CB1 receptor antagonist results in reduction of body weight gain and cholesterol in obese humans and rodents. In the present study, we show the benefits of the treatment of obese Zucker rats with a combination of a cannabinoid CB1 receptor antagonist (Rimonabant) and oleoylethanolamide. This combinational therapy improved the separate effects of Rimonabant and OEA, and resulted in marked decreases on feeding, body weight gain, and plasma cholesterol levels. Additionally, the treatment with both drugs reduced the hepatic steatosis observed in Zucker rats, decreasing liver fat deposits and damage, as revealed by the levels of alanine aminotransferase activity in serum. The combined treatment inhibits the expression of stearoyl coenzyme-A desaturase-1 (SCD-1), a pivotal enzyme in lipid biosynthesis and triglyceride mobilization that is linked to obesity phenotypes. These results support the use of combined therapies with cannabinoid CB1 receptor antagonists and PPAR-alpha agonists for the treatment of obesity associated with dyslipemia.
Serrano
Antonia
A
Fundacion IMABIS, Hospital Carlos Haya de Malaga, Laboratorio de Medicina Regenerativa, Avenida Carlos Haya 82, 7(a) planta, E-29010 Málaga, Spain.
Del Arco
Ignacio
I
Javier Pavón
Francisco
F
Macías
Manuel
M
Perez-Valero
Vidal
V
Rodríguez de Fonseca
Fernando
F
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001834:Body Water / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects; D063388:Endocannabinoids; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D009765:Obesity / Q000188:drug therapy*; D009829:Oleic Acids / Q000008:administration & dosage*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D063388:Endocannabinoids; D009829:Oleic Acids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C488250:oleoylethanolamide; D013230:Stearoyl-CoA Desaturase; D000077285:Rimonabant