ニューロメジンUと関連ペプチドによるデクレチン効果と糖尿病病態との関連の解析

1)NMU及其通过神经元信号传导的作用我们曾报道β细胞产生的NMU通过NMUR 1及其下游信号Gαi/o蛋白以自分泌/旁分泌的方式抑制GSIS并导致β细胞衰竭。然而，迷走神经最近被认为是参与胰腺功能调节的另一条途径，我们假设NMU从肠道分泌后可以作为decretin。从我们的研究结果，外周给药的NMU小鼠增加的表达的神经元激活标记FOS在迷走神经结状神经节（NG）和孤束核。禁食24小时后，NMU在回肠和NG中上调。在禁食期间，NG和胰岛中的NMUR 1上调。禁食24 h后下丘脑NMUR 2表达下调。总的来说，感觉到禁食的肠道增加NMU的表达，并通过迷走神经将禁食信息传递到中枢神经系统。推测下丘脑对NMU的敏感性在下丘脑中降低，并且NMU的兴奋作用降低。2）NMU受体相关肽（NMU Accumulator-related peptide，NMU）的表达及其胰岛素抑制作用NMU受体相关肽（NMU Accumulator-related peptide，NMU Accumulator-related peptide，NMU）与NMU的前体相同，但我们证实它在胰腺α细胞中表达，在β细胞中抑制GSIS。此外，BMPs抑制钙内流和诱导线粒体功能障碍。

1) NMU and its action via neuronal signalingWe previously reported that NMU produced in β cells suppressed GSIS and caused β-cell failure via NMUR1 and its downstream signaling Gαi/o proteins in an antocrine/paracrine manner. However, vagus nerve has recently been considered another pathway that engages in the regulation of pancreatic function, and we hypothesized that NMU could act as a decretin after its secretion from the gut. From our results, peripheral administration of NMU to mice increased the expression of the neuronal activation marker FOS in the vagus nodose ganglion (NG) and the nucleus tractus solitarius. NMU was upregulated in the ileum and NG after 24h fasting. NMUR1 was upregulated in the NG and pancreatic islets during fasting. NMUR2 in hypothalamic was downregulated by 24h fasting. Collectively, the intestinal tract that senses fasting increases the expression of NMU and transmits fasting information to the central nervous system via the vagus nerve. It was presumed that the hypothalamic sensitivity to NMU was reduced in the hypothalamus, and the anorexic effect of NMU was reduced. In response to fasting, the changes are considered to promote appetite, prevent hypoglycemia from suppressing insulin secretion, and maintain the homeostasis of the body.2) NURP expression and its insulinostatic effect.NMU precursor-related peptide (NURP) is produced from the same precursor of NMU, but we confirmed that it expressed in pancreatic α cells and suppressed GSIS in β cells. Furthermore, NURP suppressed calcium influx and induced mitochondrial dysfunction.