Diabetologia

, Volume 60, Issue 12, pp 2443–2452 | Cite as

KLF10 transcription factor regulates hepatic glucose metabolism in mice

  • Xiaoying Yang
  • Qi Chen
  • Lihong Sun
  • Huabing Zhang
  • Lu Yao
  • Xiaona Cui
  • Yong Gao
  • Fude Fang
  • Yongsheng Chang
Article

Abstract

Aim/hypothesis

Abnormal activation of hepatic gluconeogenesis leads to hyperglycaemia. However, the molecular mechanisms underlying dysregulated hepatic gluconeogenesis remain to be fully defined. Here, we explored the physiological role of Krüppel-like factor 10 (KLF10) in regulating hepatic glucose metabolism in mice.

Methods

Hepatic KLF10 expression in wild-type C57BL/6J mice, the db/db mouse model of diabetes, the ob/ob mouse model of obesity and high-fat-diet-induced obese (DIO) mice was measured. Adenoviruses expressing Klf10 or Klf10-specific short-hairpin RNA were injected into wild-type C57BL/6J mice, db/db or DIO mice. Expression of gluconeogenic genes in the liver and blood glucose levels were measured. GTTs and pyruvate tolerance tests were performed. The molecular mechanism by which KLF10 regulates hepatic glucose metabolism was explored.

Results

Hepatic KLF10 expression was regulated by nutritional status in wild-type mice and upregulated in diabetic, obese and DIO mice. Overexpression of KLF10 in primary hepatocytes increased the expression of gluconeogenic genes and cellular glucose output. C57BL/6J mice with KLF10 overexpression in the liver displayed increased blood glucose levels and impaired glucose tolerance. Conversely, hepatic KLF10 knockdown in db/db and DIO mice decreased blood glucose levels and improved glucose tolerance. Furthermore, luciferase reporter gene assay and chromatin immunoprecipitation analysis indicated that KLF10 activates Pgc-1α (also known as Ppargc1a) gene transcription via directly binding to its promoter region.

Conclusions/interpretation

KLF10 is an important regulator of hepatic glucose metabolism and modulation of KLF10 expression in the liver may be an attractive approach for the treatment of type 2 diabetes.

Keywords

Gluconeogenesis KLF10 PGC-1α Type 2 diabetes 

Abbreviations

Ad-gfp

Adenovirus expressing green fluorescent protein

Ad-Klf10

Adenovirus expressing Krüppel-like factor 10

Ad-shCtrl

Control adenovirus expressing short-hairpin RNA against luciferase

Ad-shKlf10

Adenovirus expressing short-hairpin RNA against Krüppel-like factor 10

Ad-shPgc-1α

Adenovirus expressing short-hairpin RNA against peroxisome proliferator-activated receptor, gamma, coactivator 1, alpha

ChIP

Chromatin immunoprecipitation

CREB

Cyclic AMP response element-binding protein

DIO

Diet-induced obese

KLF

Krüppel-like factor

PGC-1α

Peroxisome proliferator-activated receptor, gamma, coactivator 1α

PTT

Pyruvate tolerance test

qPCR

Quantitative PCR

shRNA

Short-hairpin RNA

siRNA

Small interfering RNA

SREBP

Sterol regulatory element-binding transcription factor

Supplementary material

125_2017_4412_MOESM1_ESM.pdf (698 kb)
ESM(PDF 697 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Xiaoying Yang
    • 1
  • Qi Chen
    • 2
  • Lihong Sun
    • 3
  • Huabing Zhang
    • 1
  • Lu Yao
    • 1
  • Xiaona Cui
    • 1
  • Yong Gao
    • 1
  • Fude Fang
    • 1
  • Yongsheng Chang
    • 1
  1. 1.The State Key Laboratory of Medical Molecular Biology, Department of Molecular Biochemistry, Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople’s Republic of China
  2. 2.Hangzhou Center for Disease Control and PreventionZhejiangPeople’s Republic of China
  3. 3.Center for Experimental Animal Research, Institute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople’s Republic of China

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