Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice.
Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice.
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转录因子 Pdx1 参与小鼠年龄相关的 GIP 分泌过多。
DOI：
10.1152/ajpgi.00054.2018
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Inagaki N.
中科院分区：
文献类型：
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作者：
Ikeguchi E;Harada N;Kanemaru Y;Sankoda A;Yamane S;Iwasaki K;Imajo M;Murata Y;Suzuki K;Joo E;Inagaki N.
随着年龄的增长，脂肪堆积是一个严重的问题；葡萄糖依赖的促胰岛素多肽/胃抑制多肽(GIP)是一种在脂肪堆积过程中发挥重要作用的胰岛素。随着年龄的增长，GIP受体基因敲除小鼠的脂肪质量减少，胰岛素敏感性提高。因此，随着年龄的增长，GIP参与了脂肪积累和胰岛素抵抗。然而，GIP分泌的年龄相关性变化仍不清楚。本研究旨在利用GIP报告基因[GIP-绿色荧光蛋白(GFP)敲入杂合子(GIPgfp/+)]小鼠，阐明GIP分泌和肠内分泌K细胞的增龄变化。与年轻(3-4月龄)GIPgfp/+小鼠相比，1岁龄GIPgfp/+小鼠表现出脂肪堆积、胰岛素抵抗和GIP高分泌的表型。老龄小鼠小肠K细胞数量增加，K细胞GIP和转录因子胰腺及十二指肠同源盒-1(Pdx1)的mRNA表达水平升高。通过肠道特异性基因转移抑制Pdx1基因后，小鼠小肠K细胞数量、GIP基因表达和含量以及GIP分泌减少。因此，Pdx1正向调节小肠GIP mRNA和K细胞数量。Pdx1表达增加可能参与了GIP的增龄性高分泌。我们发现老龄小鼠的K细胞数量和GIP以及胰腺和十二指肠同源盒-1(Pdx1)的表达增加，表现出比青年小鼠更多的GIP分泌。此外，我们还利用肠道特异性基因转移的方法成功地抑制了Pdx1在小肠中的表达，结果表明，Pdx1基因敲除后的小肠K细胞数量、GIP表达和GIP分泌均减少。
Fat accumulation with aging is a serious problem; glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, age-related changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter [GIP-green fluorescent protein (GFP) knock-in heterozygous (GIPgfp/+)] mice. Aged 1-yr-old GIPgfp/+mice exhibited a phenotype of fat accumulation, insulin resistance, and GIP hypersecretion compared with young (3–4 mo old) GIPgfp/+mice. In aged mice, K-cell number in the small intestine and the mRNA expression levels of GIP and transcriptional factor pancreatic and duodenal homeobox-1 (Pdx1) in K cells were increased. K-cell number, GIP mRNA expression and content in small intestine, and GIP secretion were decreased after posteriori suppression of Pdx1 using intestine-specific gene transfer. Thus, Pdx1 positively regulates GIP mRNA and K-cell number in small intestine. Increased Pdx1 expression might be involved in GIP hypersecretion with aging.NEW & NOTEWORTHYAge-related changes of glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) secretion and K cells were investigated. We found that K-cell number and GIP and pancreatic and duodenal homeobox-1 (Pdx1) expression in K cells were increased in aged mice, which showed greater GIP secretion compared with young mice. In addition, we have succeeded in posteriori suppression of Pdx1 in small intestine using the method of intestine-specific gene transfer, and showed that K-cell number, GIP expression, and GIP secretion were decreased in the Pdx1-knockdown intestine.