title: Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: M
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China [2] Translational Research Institute, Brisbane, QLD, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.affiliation: The Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Center, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Boden
authors.affiliation: Department of Pediatrics, University of Mississippi Medical Center, Mississippi, MS, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Technology Transfer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Z A
authors.initials: ZA
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors.forename: G
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D055106:Genome-Wide Association Study; D015309:Glucose Clamp Technique; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: D001786:Blood Glucose; D009363:Neoplasm Proteins; D014157:Transcription Factors; D058539:Phosphatidylinositol 3-Kinase