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

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Abstract

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.

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Acknowledgments

We thank Ms. Ryan Fugett for proofreading this manuscript. The study was supported in part by grants from NIH (RO1EB007357 and RO1HL098295).

Conflict of Interest

The authors claim no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA

    Mingming Gao & Dexi Liu

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  1. Mingming Gao
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  2. Dexi Liu
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Correspondence to Dexi Liu.

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Gao, M., Liu, D. The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance. AAPS J 15, 258–266 (2013). https://doi.org/10.1208/s12248-012-9429-3

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  • DOI: https://doi.org/10.1208/s12248-012-9429-3

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