Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development.
Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development.
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DOI：
10.1016/j.molmet.2017.03.010
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发表时间：
2017-06
影响因子：
8.1
通讯作者：
Bernal-Mizrachi E
中科院分区：
文献类型：
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作者：
Elghazi L;Blandino-Rosano M;Alejandro E;Cras-Méneur C;Bernal-Mizrachi E
胎儿营养不良会增加后代患2型糖尿病的风险，至少在一定程度上是因为胚胎β细胞生长减少和功能受损。然而，目前尚不完全清楚胎儿营养和生长因子如何在发育过程中影响β细胞，从而改变生命后期的葡萄糖动态平衡和代谢。目前的实验旨在测试胎儿营养和生长因子对内分泌发育的影响，以及这些信号作用于mTOR信号如何调节β细胞质量和葡萄糖稳态。以培养的胰腺组织为材料，研究葡萄糖、生长因子和氨基酸对β细胞发育的影响。在有或无雷帕霉素的情况下，检测胰腺和内分泌祖细胞的数量和增殖情况。体内mTOR信号对胰腺发育和葡萄糖稳态的影响是在表达胰腺祖细胞的pdx1缺乏mTOR或Raptor的模型中评估的。我们发现，氨基酸浓度，特别是亮氨酸，增加了胰腺和内分泌祖细胞的数量，是生长因子诱导的增殖所必需的。MTORC1复合体抑制剂雷帕霉素减少了胰腺和内分泌祖细胞的数量和增殖。缺乏mTOR的小鼠表现为新生儿高血糖、低胰岛素血症和胰腺发育不全/发育不良，胰腺残基含有缺乏分化的腺泡和内分泌细胞的导管结构。此外，在胰腺祖细胞中，由于Raptor基因的缺失，mTORC1mTORC1区的缺失缩小了胰腺的大小，减少了β细胞的数量。综上所述，这些结果表明，氨基酸浓度，特别是亮氨酸调节胰腺和内分泌祖细胞的生长反应，mTOR信号对这些反应至关重要。胰腺祖细胞中mTOR和Raptor的失活表明，在发育过程中这一途径的某些成分的改变可能是胰腺发育不全/发育不全和高血糖的原因之一。亮氨酸浓度对胰腺祖细胞的增殖有调节作用。MTOR信号在调节胰腺和内分泌生长方面起着关键作用。胰腺祖细胞mTOR失活导致胰腺发育不全。胰腺祖细胞中Raptor的失活导致胰腺发育不良。
Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis. Pancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors. We found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells. Together, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia. Leucine concentrations modulate proliferation of pancreatic progenitors. mTOR signaling plays a critical role in regulating pancreatic and endocrine growth. Inactivation of mTOR in pancreatic progenitors leads to pancreatic agenesis. Inactivation of Raptor in pancreatic progenitors leads to pancreatic hypoplasia.