INSERM, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
Diabetes. 2018 Jan;67(1):78-84. doi: 10.2337/db17-0118. Epub 2017 Oct 27.
The mitochondrial carrier uncoupling protein (UCP) 2 belongs to the family of the UCPs. Despite its name, it is now accepted that UCP2 is rather a metabolite transporter than a UCP. UCP2 can regulate oxidative stress and/or energetic metabolism. In rodents, UCP2 is involved in the control of α- and β-cell mass as well as insulin and glucagon secretion. Our aim was to determine whether the effects of UCP2 observed on β-cell mass have an embryonic origin. Thus, we used knockout mice. We found an increased size of the pancreas in fetuses at embryonic day 16.5, associated with a higher number of α- and β-cells. This phenotype was caused by an increase of PDX1 progenitor cells. Perinatally, an increase in the proliferation of endocrine cells also participates in their expansion. Next, we analyzed the oxidative stress in the pancreata. We quantified an increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) in the mutant, suggesting an increased production of reactive oxygen species (ROS). Phosphorylation of AKT, an ROS target, was also activated in the pancreata. Finally, administration of the antioxidant -acetyl-l-cysteine to pregnant mice alleviated the effect of knocking out UCP2 on pancreas development. Together, these data demonstrate that UCP2 controls pancreas development through the ROS-AKT signaling pathway.
线粒体载体解偶联蛋白 2（UCP2）属于 UCP 家族。尽管它的名字如此，但现在人们普遍认为 UCP2 更像是一种代谢物转运蛋白，而不是 UCP。UCP2 可以调节氧化应激和/或能量代谢。在啮齿动物中，UCP2 参与控制 α 和 β 细胞的质量以及胰岛素和胰高血糖素的分泌。我们的目的是确定在β细胞质量上观察到的 UCP2 作用是否具有胚胎起源。因此，我们使用了 UCP2 敲除小鼠。我们发现，在胚胎第 16.5 天的 胎儿中，胰腺的大小增加，α 和 β 细胞的数量也增加。这种表型是由 PDX1 祖细胞的增加引起的。围产期，内分泌细胞的增殖增加也参与了它们的扩张。接下来，我们分析了胰腺中的氧化应激。我们在突变体中定量检测到核因子红细胞 2 相关因子 2（NRF2）的核转位增加，表明活性氧（ROS）的产生增加。ROS 的靶标 AKT 的磷酸化在 胰腺中也被激活。最后，向 怀孕小鼠给予抗氧化剂 -乙酰-l-半胱氨酸可减轻 UCP2 敲除对胰腺发育的影响。综上所述，这些数据表明 UCP2 通过 ROS-AKT 信号通路控制胰腺发育。
