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  • Original Article
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Animal Models

Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice

International Journal of Obesity volume 39, pages 949–958 (2015)Cite this article

Subjects

Abstract

Background/objectives:

Juxtaposed with another zinc-finger gene 1 (TIP27 or JAZF1) is a 27-kDa transcription factor, and genome-wide association studies have recently revealed TIP27 to be associated with type 2 diabetes. However, little is known about its role in the regulation of metabolism. In this study, we investigated the effects of TIP27 overexpression on glucose homeostasis and insulin signaling in high-fat diet (HFD)-fed TIP27 transgenic (TIP27-Tg) mice and db/db mice.

Methods:

We assessed the effects of TIP27 overexpression in both TIP27-Tg mice and db/db mice on glucose metabolism and changes in insulin sensitivity during glucose (GTT) and insulin (ITT) tolerance tests. A hyperinsulinemic–euglycemic clamp was performed on TIP27-Tg mice. Real-time quantitative PCR and western blotting were used to assess mRNA and protein expressions.

Results:

TIP27 overexpression in TIP27-Tg mice and in db/db mice led to reduced total cholesterol and fasting plasma insulin levels, and enhanced glucose tolerance and insulin sensitivity during GTT and ITT. Hyperinsulinemic–euglycemic clamp experiments demonstrated that HFD-fed TIP27-Tg mice had lower hepatic glucose production and higher insulin sensitivity compared with nontransgenic littermates. In addition, the hepatic expressions of phosphoenolpyruate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) mRNAs and proteins were significantly decreased, whereas the phosphorylation of insulin receptor, insulin receptor substrate-1, adenosine monophosphate-activated protein kinase and Akt kinase (Akt) in the liver was significantly increased in HFD-fed TIP27-Tg mice compared with nontransgenic littermates. Adenovirus-mediated TIP27 overexpression in db/db mice also decreased the expression of gluconeogenic genes and increased the phosphorylation of insulin signaling molecules in the liver compared with controls. Finally, LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, abolished the suppressive effect of TIP27 overexpression on PEPCK and G6Pase expression.

Conclusions:

TIP27 has an important role in glucose homeostasis through the regulation of hepatic glucose metabolism and insulin sensitivity. Furthermore, this regulation requires activation of PI3-kinase.

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Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (81270913, 81070640, 81100567, 81300702 and 81300670 to YG), Doctoral Fund of Ministry of Education of China (20105503110002, 20125503110003 to YG and LL) and Natural Science Foundation Key Project of CQ cstc (cstc2012 jjB10022 to YG).

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Author notes

  1. L Yuan, X Luo and M Zeng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China

    L Yuan, M Zeng, Y Zhang, M Yang, L Zhang, R Liu, L Li & G Yang

  2. Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China

    X Luo

  3. Translational Research Institute, Brisbane, QLD, Australia

    M Yang

  4. The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA

    G Boden

  5. Department of Pediatrics, University of Mississippi Medical Center, Mississippi, MS, USA

    H Liu

  6. Technology Transfer Center, University of Michigan, Ann Arbor, MI, USA,

    Z A Ma

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Correspondence to L Li or G Yang.

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Yuan, L., Luo, X., Zeng, M. et al. Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice. Int J Obes 39, 949–958 (2015). https://doi.org/10.1038/ijo.2015.5

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