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Comparative Study
. 2010 Apr;51(4):771-84.
doi: 10.1194/jlr.M001602. Epub 2009 Sep 25.

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

Sabrina Cipriani  1 , Andrea Mencarelli, Giuseppe Palladino, Stefano Fiorucci
Affiliations
Comparative Study

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

Sabrina Cipriani et al. J Lipid Res. 2010 Apr.

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.

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Figures

Fig. 1.
Fig. 1.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on body weight and liver and fat weight. Zucker obese fa/fa rats were administered daily with 6E-CDCA (10 mg/kg) and rosiglitazone (10 mg/kg) alone or in combination (5 mg/kg each) for 7 weeks starting at the age of 15 weeks. Data are mean ± SE of 12 rats. * P < 0.05 naïve fa/fa versus lean. ** P < 0.05 treated versus naïve fa/fa.
Fig. 2.
Fig. 2.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on liver fat. Zucker obese fa/fa rats were administered daily with 6E-CDCA (10 mg/kg) and rosiglitazone (10 mg/kg) alone or in combination (5 mg/kg each) for 7 weeks starting at the age of 15 weeks. Figure shown is representative of one animal per group. A–E: Macroscopic appearance of the liver. F–J: H&E staining, magnification 40×. K–O: Oil Red O, magnification 40×. Lean rats (A, F, K); fa/fa rats (B, G, L); fa/fa rats administered with 6E-CDCA (C, H, M); fa/fa rats administered with rosiglitazone (D, I, N); fa/fa rats administered with 6E-CDCA in combination with rosiglitazone (E, J, O). Livers from fa/fa rats have higher fat content than lean rats. In G and I, arrows indicate ballooning. This pattern was ameliorated by treatment with 6E-CDCA.
Fig. 3.
Fig. 3.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on the liver histopathology. The hustophatology score was calculated according to the scoring system shown in supplementary Table I. Data are mean ± SE. * P < 0.001 naive fa/fa versus lean; ** P < 0.01 treatment versus naive fa/fa.
Fig. 4.
Fig. 4.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on liver expression of genes involved in fatty acid and triglyceride (TG) metabolism, cholesterol homeostasis, and bile acid synthesis. The relative expression (q-RT-PCR) of each gene was obtained by comparing lean and fa/fa rats. RNA samples were from six animals per group and loaded in triplicates. * P < 0.01 naive fa/fa versus lean or treatment versus naïve fa/fa.
Fig. 5.
Fig. 5.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on liver expression of genes involved in fatty acid β-oxidation and TNF-α. The relative expression (q-RT-PCR) of each gene was obtained by comparing lean and fa/fa rats. RNA samples were from six animals per group and loaded in triplicates. * P < 0.01 naive fa/fa versus lean or treatment versus naïve fa/fa.
Fig. 6.
Fig. 6.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on liver expression of nuclear receptors. The relative expression (q-RT-PCR) of each gene was obtained by comparing lean and fa/fa rats. RNA samples were from six animals per group and loaded in triplicates. * P < 0.01 naive fa/fa versus lean or treatment versus naïve fa/fa.
Fig. 7.
Fig. 7.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on liver expression of genes involved in glucose homeostasis. The relative expression (q-RT-PCR) of each gene was obtained by comparing lean and fa/fa rats. RNA samples were from six animals per group and loaded in triplicates. * P < 0.01 naive fa/fa versus lean or treatment versus naïve fa/fa.
Fig. 8.
Fig. 8.
Effect of administration of obese fa/fa rats with nuclear receptor ligands on expression of key regulatory genes in the muscle. The relative expression (q-RT-PCR) of each gene was obtained by comparing lean and fa/fa rats. RNA samples were from six animals per group and loaded in triplicates. * P < 0.01 naive fa/fa versus lean or treatment versus naïve fa/fa.
Fig. 9.
Fig. 9.
FXR and PPARγ ligands revert insulin resistance in obese fa/fa rats: effect on OGTT and ITT. Zucker obese fa/fa rats were administered daily with 6E-CDCA (10 mg/kg) and rosiglitazone (10 mg/kg) alone or in combination (5 mg/kg each) for 7 weeks starting at the age of 15 weeks. The OGTT and ITT were performed after 7 weeks treatment. Data are mean ± SE of 12 rats. * P < 0.05 naïve fa/fa versus lean and treated fa/fa rats.
Fig. 10.
Fig. 10.
FXR and PPARγ ligands revert insulin resistance in obese fa/fa rats: effect on IRS Ser(312) and AKT Ser(473) phosphorylation in liver and muscle tissues. * P < 0.05 treated versus naïve fa/fa rats.
Fig. 11.
Fig. 11.
Schematic diagram of the effects induced by 6E-CDCA and rosiglitazone in lipid and glucose metabolism.
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