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Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin-Induced Diabetic Mice

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Abstract

Activation of liver X receptors (LXRs) can improve glucose tolerance in insulin-independent diabetes, however, whether similar effects can be achieved in insulin-dependent diabetes remains unclear. Here, we evaluated the anti-diabetic activity of T0901317, a potent agonist of LXRs, in diabetic mice induced by streptozotocin, and our data demonstrate that T0901317 is most effective when combined with cold treatment of animals. Treatment with T0901317 improved glucose tolerance of diabetic mice, which was associated with repressed expression of key genes involved in hepatic gluconeogenesis such as Pepck and G6p. Combined treatment by T0901317 and cold exposure reduced transcription of gluconeogenic genes to similar levels. Intriguingly, combined treatment greatly increased expression of Ucp1, Cidea, Dio2, and Elvol3 predominantly in the inguinal white adipose tissue, consequently leading to browning of this fat pad, and resulting in further improvement of glucose tolerance which was associated with increased protein levels of UCP1 and GLUT4. Collectively, these results suggest that browning of white adipose tissue via cold exposure in combination with activation of liver X receptors is an alternative and effective strategy to manage insulin-dependent diabetes.

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Acknowledgments

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

Conflict of Interest

The authors claim no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 450 Pharmacy South, 250 West Green Street, Athens, Georgia, 30602, USA

    Mingming Gao, Chunbo Zhang, Yongjie Ma & Dexi Liu

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  1. Mingming Gao
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Correspondence to Dexi Liu.

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Supplementary Figure 1

Cold exposure increased glucose tolerance in metabolically normal mice. a. Glucose profiles of IPGTT. (b) AUC analysis of IPGTT. Values in (a) and (b) represent average ± SD (n = 5). ** p < 0.01 compared with control mice kept at 25°C. (GIF 127 kb)

High Resolution (TIFF 2202 kb)

Supplementary Figure 2

Cold exposure increased mRNA and protein levels of FGF21 in normal mice. (a) Expression of FGF21 in the liver and brown adipose tissue. (b) Protein level of FGF21 in blood. Values in (a) and (b) represent average ± SD (n = 5). ** p < 0.01 compared with control mice kept at 25°C. (GIF 67 kb)

High Resolution (TIFF 324 kb)

Supplementary Table 1

(DOCX 16 kb)

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Gao, M., Zhang, C., Ma, Y. et al. Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin-Induced Diabetic Mice. AAPS J 17, 700–710 (2015). https://doi.org/10.1208/s12248-015-9746-4

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  • DOI: https://doi.org/10.1208/s12248-015-9746-4

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