Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance.
OBJECTIVE
To examine the effect of farnesoid X receptor (FXR) activation by its synthetic agonist, 3-[2-[2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) on diet-induced obesity and hepatic steatosis.


METHODS
Fifteen week-old C57BL/6 mice fed with high-fat diet (HFD) or high-fat, high-cholesterol diet were treated by twice weekly injection of GW4064 (50 mg/kg) intraperitoneally or DMSO (carrier solution) for 6 weeks. Body weight, body composition and food intake were monitored weekly. Serum glucose and insulin levels and lipid content in the liver were measured at the end of study. Additionally, genes involved in lipogenesis, gluconeogenesis and inflammation were analyzed by real time PCR. CD36 protein level was detected by western blot.


RESULTS
Activation of FXR by GW4064 suppressed weight gain in C57BL/6 mice fed with either HFD or high-fat and high-cholesterol diet. GW4064 treatment of mice significantly repressed diet-induced hepatic steatosis as evidenced by lower triglyceride and free fatty acid level in the liver. Analysis of genes involved in lipid metabolism showed GW4064 markedly reduced lipid transporter Cd36 gene expression without affecting expression of genes that are directly involved in lipogenesis. GW4064 treatment attenuated hepatic inflammation while having no effect on white adipose tissue. In addition, activation of FXR by GW4064 avoided diet-induced hyperinsulinemia and hyperglycemia through decreasing the transcript levels of phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6pase), two key enzymes in gluconeogenesis.


CONCLUSIONS
The results verify the important function of FXR in diet-induced obesity and suggest that FXR agonists are promising therapeutic agents for obesity-associated metabolic disorders.
Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia, Room 450 Pharmacy South, 250 West Green Street, Athens, Georgia 30602, USA.
Yongjie
Y
Ma
Yixian
Y
Huang
Linna
L
Yan
Mingming
M
Gao
Dexi
D
Liu
D000818:Animals; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects; D007555:Isoxazoles / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015430:Weight Gain / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D018955:CD36 Antigens; D007555:Isoxazoles; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064