O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice.
O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice.
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DOI：
10.1016/j.jbc.2021.100297
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Alejandro EU
中科院分区：
文献类型：
--
作者：
Essawy A;Jo S;Beetch M;Lockridge A;Gustafson E;Alejandro EU
营养传感器O - 连接的N - 乙酰氨基葡萄糖转移酶（OGT）催化O - GlcNAc在翻译后添加到靶蛋白上，影响细胞对营养水平作出反应的信号通路。OGT在胰腺分泌胰高血糖素的细胞（α细胞）中高表达，α细胞在低血糖时分泌胰高血糖素。本研究的目的是确定OGT对体内α细胞数量和功能的调节是否必要。我们利用基因操作构建了两种α细胞特异性OGT敲除模型：组成型胰高血糖素 - Cre（αOGTKO）和诱导型胰高血糖素 - Cre（i - αOGTKO），它们能有效敲除α细胞中的OGT。通过免疫印迹、免疫荧光成像以及体内代谢表型分析等方法，我们首次深入了解了O - GlcNAc糖基化在α细胞数量和功能方面的作用。αOGTKO小鼠表现出正常的葡萄糖耐量和胰岛素敏感性，但在进食和禁食状态下胰高血糖素水平均显著降低。6月龄的αOGTKO小鼠α细胞胰高血糖素含量和α细胞数量显著减少。在禁食状态下，αOGTKO小鼠体内丙酮酸刺激的糖异生受损，体外胰高血糖素分泌减少。i - αOGTKO小鼠的血糖胰高血糖素水平同样降低，体外胰高血糖素分泌存在缺陷，但α细胞数量正常。有趣的是，尽管αOGTKO和i - αOGTKO小鼠的α细胞数量和功能以及胰高血糖素含量受损，但它们在进食或禁食条件下维持血糖稳态方面并无缺陷。总之，这些研究首次揭示了OGT信号在α细胞中的作用、其对α细胞数量的影响以及在低血糖条件下调节胰高血糖素分泌的重要性。
The nutrient sensor O-GlcNAc transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (α-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of α-cell mass and function in vivo. We utilized genetic manipulation to produce two α-cell specific OGT-knockout models: a constitutive glucagon-Cre (αOGTKO) and an inducible glucagon-Cre (i-αOGTKO), which effectively delete OGT in α-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping in vivo, we provide the first insight on the role of O-GlcNAcylation in α-cell mass and function. αOGTKO mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGTKO mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGTKO mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-αOGTKO mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal α-cell mass. Interestingly, both αOGTKO and i-αOGTKO mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in α-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the α-cell, its effect on α-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions.
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影响因子：
8.8
作者：
Lockridge A;Jo S;Gustafson E;Damberg N;Mohan R;Olson M;Abrahante JE;Alejandro EU
通讯作者：
Alejandro EU
影响因子：
3.3
作者：
Llewellyn-Smith, I. J.;Reimann, F.;Gribble, F. M.;Trapp, S.
通讯作者：
Trapp, S.
影响因子：
--
作者：
Gloster TM;Vocadlo DJ
通讯作者：
Vocadlo DJ
影响因子：
8.8
作者：
Alejandro EU;Bozadjieva N;Kumusoglu D;Abdulhamid S;Levine H;Haataja L;Vadrevu S;Satin LS;Arvan P;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E
影响因子：
3.3
作者：
Larsen, PJ;TangChristensen, M;Orskov, C
通讯作者：
Orskov, C