The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

The effect of activation of liver X receptor by N -(2,2,2-trifluoroethyl)- N -[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl] benzenesulfonamide (T0901317) on high fat diet (HFD)-induced obesity and insulin resistance was examined in C57BL/6 mice. When on HFD continuously for 10 weeks,...

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Bibliographic Details
Published in:The AAPS journal 2013-01, Vol.15 (1), p.258-266
Main Authors: Gao, Mingming, Liu, Dexi
Format: Article
Language:English
Subjects:
Adipose Tissue - drug effects
Animals
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Body Composition - drug effects
Diet, High-Fat
Eating - drug effects
Energy Metabolism - drug effects
Fatty Liver - drug therapy
Glucose - metabolism
Hydrocarbons, Fluorinated - therapeutic use
Insulin Resistance
Liver X Receptors
Male
Mice
Mice, Inbred C57BL
Obesity - prevention & control
Orphan Nuclear Receptors - agonists
Pancreas - drug effects
Pharmacology/Toxicology
Pharmacy
Research Article
Sulfonamides - therapeutic use
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Summary:The effect of activation of liver X receptor by N -(2,2,2-trifluoroethyl)- N -[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl] benzenesulfonamide (T0901317) on high fat diet (HFD)-induced obesity and insulin resistance was examined in C57BL/6 mice. When on HFD continuously for 10 weeks, C57BL/6 mice became obese with an average body weight of 42 g, insulin resistant, and glucose intolerant. Twice weekly intraperitoneal injections of T0901317 at 50 mg/kg in animals on the same diet completely blocked obesity development, obesity-associated insulin resistance, and glucose intolerance. Quantitative real-time PCR analysis showed that T0901317-treated animals had significantly higher mRNA levels of genes involved in energy metabolism, including Ucp-1 , Pgc1a , Pgc1b , Cpt1a , Cpt1b , Acadm , Acadl , Aox , and Ehhadh. Transcription activation of Cyp7a1 , Srebp-1c , Fas , Scd-1 , and Acc-1 genes was also seen in T0901317-treated animals. T0901317 treatment induced reversible aggregation of lipids in the liver. These results suggest that liver X receptor could be a potential target for prevention of obesity and obesity-associated insulin resistance.
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-012-9429-3