Journal Article 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

156 ( 10 )  , pp.3570 - 3580 , 2015-10 , Endocrine Society
ISSN:0013-7227
Description
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.
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http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/60275/2/supplemental_data.pdf

http://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/60275/1/manuscript.pdf

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