Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca(2+) Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity.
Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca(2+) Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity.
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DOI：
10.1371/journal.pone.0067198
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yada T
中科院分区：
文献类型：
--
作者：
Iwasaki Y;Shimomura K;Kohno D;Dezaki K;Ayush EA;Nakabayashi H;Kubota N;Kadowaki T;Kakei M;Nakata M;Yada T
胰岛素的一些功能，包括葡萄糖/脂质代谢，饱腹感和神经保护，涉及大脑活动的改变。胰岛素可能通过血脑屏障作用于迷走神经传入纤维而向脑内传递信号，但迷走神经传入纤维的作用尚未得到证实。本研究旨在阐明胰岛素是否直接调节小鼠迷走神经传入的结状神经节神经元（NGNs）。NGs表达胰岛素受体（IR）和胰岛素受体底物-2（IRS 2）mRNA，部分NGs对IR呈免疫反应性。在膜片钳和Fura-2微荧光研究中，胰岛素（10−12 × 10−6 M）在单个NGs中去极化并增加胞浆Ca 2+浓度（[Ca 2 +]i）。胰岛素诱导的[Ca 2 +]i增加被L-和N-型Ca 2+通道阻断剂、磷脂酰肌醇3激酶（PI 3 K）抑制剂和来自IRS 2敲除小鼠的NGN减弱。一半的胰岛素反应性NGN含有可卡因和安非他明调节的转录本。表达IR的神经纤维分布在胰岛内或周围。通过将逆行示踪剂注射到胰腺中来识别支配胰腺的NGN，其对胰岛素的反应率比未标记的NGN高得多。胰静脉中测得的胰岛素浓度是循环中的64倍。胰岛素升高到10−7 M时，[Ca 2 +]i增加的NGN数量显著增加。全身注射格列本脲可迅速释放NG中的胰岛素和磷酸化AKT。此外，在IRS 2基因敲除小鼠中，胰岛素抑制下丘脑弓状核中促食欲生长素反应神经元[Ca 2 +]i的作用是完整的，而胰岛素对NGN的作用明显减弱，这些数据表明胰岛素通过IR-IRS 2-PI 3 K-AKT-级联和去极化门控Ca 2+直接激活NGN。流入。胰腺神经元可以有效地感知胰岛素释放的动态变化，以响应营养状态。这些相互作用可用于将胰腺和全身胰岛素的变化传递到大脑。
Some of insulin’s functions, including glucose/lipid metabolism, satiety and neuroprotection, involve the alteration of brain activities. Insulin could signal to the brain via penetrating through the blood-brain barrier and acting on the vagal afferents, while the latter remains unproved. This study aimed to clarify whether insulin directly regulates the nodose ganglion neurons (NGNs) of vagal afferents in mice. NGs expressed insulin receptor (IR) and insulin receptor substrate-2 (IRS2) mRNA, and some of NGNs were immunoreactive to IR. In patch-clamp and fura-2 microfluorometric studies, insulin (10−12∼10−6 M) depolarized and increased cytosolic Ca2+ concentration ([Ca2+]i) in single NGNs. The insulin-induced [Ca2+]i increases were attenuated by L- and N-type Ca2+ channel blockers, by phosphatidylinositol 3 kinase (PI3K) inhibitor, and in NGNs from IRS2 knockout mice. Half of the insulin-responsive NGNs contained cocaine- and amphetamine-regulated transcript. Neuronal fibers expressing IRs were distributed in/around pancreatic islets. The NGNs innervating the pancreas, identified by injecting retrograde tracer into the pancreas, responded to insulin with much greater incidence than unlabeled NGNs. Insulin concentrations measured in pancreatic vein was 64-fold higher than that in circulation. Elevation of insulin to 10−7 M recruited a remarkably greater population of NGNs to [Ca2+]i increases. Systemic injection of glibenclamide rapidly released insulin and phosphorylated AKT in NGs. Furthermore, in IRS2 knockout mice, insulin action to suppress [Ca2+]i in orexigenic ghrelin-responsive neurons in hypothalamic arcuate nucleus was intact while insulin action on NGN was markedly attenuated, suggesting a possible link between impaired insulin sensing by NGNs and hyperphagic obese phenotype in IRS2 knockout mice These data demonstrate that insulin directly activates NGNs via IR-IRS2-PI3K-AKT-cascade and depolarization-gated Ca2+ influx. Pancreas-innervating NGNs may effectively sense dynamic changes of insulin released in response to nutritional states. These interactions could serve to convey the changes in pancreatic and systemic insulin to the brain.
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影响因子：
29.4
作者：
Date, Y;Murakami, N;Nakazato, M
通讯作者：
Nakazato, M
影响因子：
7.7
作者：
Dezaki, K;Hosoda, H;Yada, T
通讯作者：
Yada, T
影响因子：
29.4
作者：
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通讯作者：
Dockray, Graham J.
影响因子：
64.8
作者：
HAVRANKOVA, J;ROTH, J
通讯作者：
ROTH, J
影响因子：
--
作者：
BENDAYAN, M
通讯作者：
BENDAYAN, M