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

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.