Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1149, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Diderot, Paris, France.
Sorbonne Université, INSERM, Unité Mixte de Recherche (UMR) S1158 Neurophysiologie Respiratoire Expérimentale et Clinique, Paris, France.
FASEB J. 2019 Apr;33(4):5377-5388. doi: 10.1096/fj.201801718R. Epub 2019 Feb 12.
The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
肠道-脑肽神经钙素 U（NMU）可减少食物摄入和体重，改善葡萄糖耐量。在这里，我们将 NMU 鉴定为肠肽，并确定其如何影响血糖波动。NMU 主要在近端小肠中表达，其分泌是由混合餐摄入引发的。尽管在 C57BL/6NRj 小鼠中单次外周注射 NMU 可防止口服而非腹腔内葡萄糖负荷时血糖升高，但它出人意料地阻止了胰岛素分泌，仅略微改善了外周胰岛素敏感性，几乎没有减少肠道葡萄糖吸收。有趣的是，外周给予 NMU 可阻断胃排空。在幽门肌中检测到 NMU 受体 1 和 2，并且 NMU 能够在体外等长室中以剂量依赖性方式直接诱导幽门收缩。使用改良的葡萄糖耐量试验，我们证明 NMU 改善口服葡萄糖耐量的主要原因（如果不是唯一原因）是其对胃排空的影响。在迷走神经切断（VagoX）小鼠中，部分阻断了这种影响，表明涉及迷走神经张力。因此，外周注射 NMU 与孤束核中 c-FOS 阳性神经元的数量增加有关，在 VagoX 小鼠中部分被阻断。最后，NMU 保持其改善肥胖和糖尿病小鼠模型口服葡萄糖耐量的能力。总之，这些数据表明，NMU 是一种肠肽，通过触发幽门收缩和通过迷走传入神经元间接作用来直接阻止胃排空。这种阻断随后减少了肠道营养吸收，从而导致对口服葡萄糖挑战的明显改善耐受力。-Jarry，A.-C.，Merah，N.，Cisse，F.，Cayetanot，F.，Fiamma，M.-N.，Willemetz，A.，Gueddouri，D.，Barka，B.，Valet，P.，Guilmeau，S.，Bado，A.，Le Beyec，J.，Bodineau，L.，Le Gall，M.神经钙素 U 是一种肠道肽，通过直接收缩幽门和依赖迷走神经的机制来延迟胃排空，从而改变口服葡萄糖耐量。
