FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats[S]

• Published in: Journal of lipid research Vol. 51; no. 4; pp. 771 - 784
• Main Authors: Cipriani, Sabrina, Mencarelli, Andrea, Palladino, Giuseppe, Fiorucci, Stefano
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2010; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Chenodeoxycholic Acid - administration & dosage; Chenodeoxycholic Acid - analogs & derivatives; Chenodeoxycholic Acid - therapeutic use; Disease Models, Animal; Drug Therapy, Combination; Fatty Liver - blood; Fatty Liver - pathology; Fatty Liver - prevention & control; Gene Expression Regulation - drug effects; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - therapeutic use; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - therapeutic use; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipids - blood; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Obesity - blood; Obesity - complications; Phosphorylation - drug effects; Random Allocation; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - metabolism; Rosiglitazone; Thiazolidinediones - administration & dosage; Thiazolidinediones - therapeutic use; Time Factors
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M001602

The farnesoid X receptor (FXR) is a bile acid activated nuclear receptor. Zucker (fa/fa) rats, harboring a loss of function mutation of the leptin receptor, develop diabetes, insulin resistance, obesity, and liver steatosis. In this study, we investigated the effect of FXR activation by 6-ethyl-chenodeoxycholic acid, (6E-CDCA, 10 mg/kg) on insulin resistance and liver and muscle lipid metabolism in fa/fa rats and compared its activity with rosiglitazone (10 mg/kg) alone or in combination with 6E-CDCA (5 mg/kg each). In comparison to lean (fa/+), fa/fa rats on a normal diet developed insulin resistance and liver steatosis. FXR activation protected against body weight gain and liver and muscle fat deposition and reversed insulin resistance as assessed by insulin responsive substrate-1 phosphorylation on serine 312 in liver and muscles. Activation of FXR reduced liver expression of genes involved in fatty acid synthesis, lipogenesis, and gluconeogenesis. In the muscles, FXR treatment reduced free fatty acid synthesis. Rosiglitazone reduced blood insulin, glucose, triglyceride, free fatty acid, and cholesterol plasma levels but promoted body weight gain (20%) and liver fat deposition. FXR activation reduced high density lipoprotein plasma levels. In summary, FXR administration reversed insulin resistance and correct lipid metabolism abnormalities in an obesity animal model.