title: Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity.
abstract: The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Earley
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.forename: Gergö
authors.initials: G
authors.lastname: Szanda
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D059305:Diet, High-Fat; D002149:Energy Intake / Q000187:drug effects; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
chemical_list: D052242:Adiponectin; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D020738:Leptin; D008055:Lipids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant
keywords: cannabinoid type 1 antagonism; fatty acid uptake; hepatic steatosis and fibrosis; insulin resistance