Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
College of Arts and Sciences, Vanderbilt University, Nashville, TN 37232, USA.
Mol Metab. 2023 Dec;78:101811. doi: 10.1016/j.molmet.2023.101811. Epub 2023 Sep 26.
ASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional K channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells.
We generated β-cell-specific Ascl1 knockout mice (Ascl1) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential K channel component.
Ascl1 expression is increased in response to both a HFD and membrane depolarization and requires CREB-dependent Ca signaling. No differences in glucose homeostasis or islet morphology were observed in Ascl1 mice fed a normal diet or in the absence of K channels. However, male Ascl1 mice fed a HFD exhibited decreased blood glucose levels, improved glucose tolerance, and increased β-cell proliferation. Bulk RNA-seq analysis of islets from Ascl1 mice from three studied conditions showed alterations in genes associated with the secretory function. HFD-fed Ascl1 mice showed the most extensive changes with increased expression of genes necessary for glucose sensing, insulin secretion and β-cell proliferation, and a decrease in genes associated with β-cell dysfunction, inflammation and dedifferentiation. HFD-fed Ascl1 mice also displayed increased expression of parasympathetic neural markers and cholinergic receptors that was accompanied by increased insulin secretion in response to acetylcholine and an increase in islet innervation.
Ascl1 expression is induced by stimuli that cause Ca-signaling to the nucleus and contributes in a multifactorial manner to the loss of β-cell function by promoting the expression of genes associated with cellular dedifferentiation, attenuating β-cells proliferation, suppressing acetylcholine sensitivity, and repressing parasympathetic innervation of islets. Thus, the removal of Ascl1 from β-cells improves their function in response to metabolic stress.
ASCL1 是一种先驱转录因子，对神经细胞的分化和功能至关重要。先前的研究表明，在缺乏功能性 K 通道的胰腺β细胞或高脂饮食（HFD）喂养后，Ascl1 的表达增加，这表明它可能有助于β细胞的代谢应激反应。
我们生成了β细胞特异性的 Ascl1 敲除小鼠（Ascl1），并在正常饮食或 HFD 喂养 12 周后，或与 Abcc8 的遗传破坏（一种必需的 K 通道成分）相结合时，评估了它们的葡萄糖稳态、胰岛形态和基因表达。
Ascl1 的表达增加是对 HFD 和膜去极化的反应，需要 CREB 依赖性 Ca 信号。在正常饮食或缺乏 K 通道的情况下，Ascl1 小鼠的葡萄糖稳态或胰岛形态没有差异。然而，喂食 HFD 的雄性 Ascl1 小鼠表现出降低的血糖水平、改善的葡萄糖耐量和增加的β细胞增殖。来自三种研究条件的 Ascl1 小鼠胰岛的 bulk RNA-seq 分析显示，与分泌功能相关的基因发生了改变。HFD 喂养的 Ascl1 小鼠显示出最广泛的变化，表现为与葡萄糖感应、胰岛素分泌和β细胞增殖相关的基因表达增加，以及与β细胞功能障碍、炎症和去分化相关的基因表达减少。HFD 喂养的 Ascl1 小鼠还显示出副交感神经标记物和胆碱能受体的表达增加，这伴随着对乙酰胆碱的胰岛素分泌增加和胰岛神经支配增加。
Ascl1 的表达是由引起核内 Ca 信号的刺激诱导的，并通过促进与细胞去分化相关的基因的表达、减弱β细胞增殖、抑制乙酰胆碱敏感性以及抑制胰岛的副交感神经支配等多种因素共同作用，导致β细胞功能丧失。因此，从β细胞中去除 Ascl1 可改善它们对代谢应激的功能。
