Abstract
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.
Highlights
The farnesoid X receptor (FXR) is a bile acid activated nuclear receptor
Impaired leptin signaling leads to hyperinsulinemia, hyper-glycemia, hyper-triglyceridemia, hyper-cholesterolemia, insulin resistance, and liver fat accumulation and increased aminotrasnferases plasma levels
Obese fa/fa rats had an increased expression of genes involved in gluconeogenesis (PEPCK) and fatty acid (SREPB-1C and FAS) and cholesterol (HMGCoA synthase) synthesis and impaired cholesterol efflux from hepatocytes (ABCA1 and Apo-C2) leading to accumulation of triglyceride and cholesterol in the liver
Summary
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. 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). Activation of FXR reduced liver expression of genes involved in fatty acid synthesis, lipogenesis, and gluconeogenesis. 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 reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker ( fa/fa) obese rats. FXR-deficient mice develop insulin resistance and administration of FXR ligands to wild-type mice lowers blood glucose levels as a result of enhanced phosphorylation of IRS-1 in tyrosine residues in the liver and peripheral tissues including muscle and adipose tissue [12, 13]. FXR induces glucose transporter 4 (GLUT-4) expression through the direct activation of an FXR response element (FXRE) in the GLUT-4 promoter [14]
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