Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion

• Nomoto, Hiroshi

• Kondo, Takuma

• Miyoshi, Hideaki

• Nakamura, Akinobu

• Hida, Yoko

• Yamashita, Ken-ichiro

• Sharma, Arun J.

• Atsumi, Tatsuya

抄録

The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic beta-cell function and maturation. However, insights about the effects of small Maf factors on beta-cells are limited. Our goal was to elucidate the function of small-Maf factors on beta-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with beta-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of beta-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates beta-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve beta-cell function.

収録刊行物

• Endocrinology

  Endocrinology 156 (10), 3570-3580, 2015-10

  Endocrine Society

詳細情報

• CRID: 1050845763949430784
• NII論文ID: 120005674070
• HANDLE: 2115/60275
• ISSN: 00137227
• 本文言語コード: en
• 資料種別: journal article
• データソース種別:
  • IRDB
  • CiNii Articles