Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure
Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure
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DOI：
10.1016/j.regpep.2006.02.002
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发表时间：
2006-07-15
影响因子：
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通讯作者：
Briski, Karen P.
中科院分区：
文献类型：
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作者：
Paranjape, Sachin A.;Vavaiya, Karnlesh K.;Briski, Karen P.
葡萄糖反调节崩溃的CNS组件的支持证据的非均匀的基因组反应的神经元在特征性的中央自主基因座在反复发生的胰岛素诱导的低血糖症（IIH）。我们已经报道，每日皮下注射中效胰岛素制剂优泌林NPH（NPH）治疗的大鼠中，低血糖症加重和胰高血糖素和肾上腺素分泌模式减弱与AP-1转录因子Fos在中枢代谢调节回路的几个组成部分（包括下丘脑外侧区（LHA））中的免疫可显示性降低相关。合成有效的食欲肽神经递质食欲素-A的神经元仅限于LHA和邻近的下丘脑位点，并在整个中枢神经轴投射到支配自主和行为运动输出的结构。双标记免疫细胞化学和实时RT-PCR技术在这里被用来评估功能状态的LHA表型在一个单一的与重复暴露于长期IIH。急性或重复NPH给药后，在预定的LHA吻尾水平收集组织切片，并进行核Fos和细胞质食欲素-A-免疫反应性（-ir）处理。治疗组之间食欲素-A-ir神经元的平均数量没有差异。与对照组相比，单次注射胰岛素后，这些细胞的Fos共标记增加，但Fos阳性食欲素A神经元的数量在用四个剂量的胰岛素治疗后显著减少。在急性低血糖期间，显微切割的LHA组织中的前食欲素原mRNA水平上调，但通过反复IIH恢复至对照水平。这些数据证实了以前的证据，IIH是一个激活刺激食欲素A合成神经元的LHA，并进一步证明，诱导cfos和prepro-orexin基因表达的急性低血糖是衰减的前期暴露于低血糖。因此，目前的结果提供了独特的证据，神经递质特异性习惯LHA神经元的敏感性IIH。(c)2006 Elsevier B. V.保留所有权利。
A CNS component of glucose counterregulatory collapse is supported by evidence for nonuniform genomic responsiveness of neurons in characterized central autonomic loci during recurring insulin-induced hypoglycemia (IIH). We have reported that exacerbated hypoglycemia and attenuated patterns of glucagon and epinephrine secretion in rats treated by daily sc injection of the intermediate-acting insulin formulation, Humulin NPH (NPH), are correlated with diminished immunodemonstrability of the AP-1 transcription factor, Fos, in several components of the central metabolic regulatory circuitry, including the lateral hypothalamic area (LHA). Neurons that synthesize the potent orexigenic peptide neurotransmitter, orexin-A, are restricted to the LHA and adjacent hypothalamic loci, and project throughout the central neuroaxis to structures that govern autonomic and behavioral motor output. Dual-label immunocytochemical and real-time RT-PCR techniques were utilized here to evaluate the functional status of this LHA phenotype during a single versus repetitive exposure to prolonged IIH. Tissue sections were collected at predetermined rostrocaudal levels of the LHA after acute or repeated NPH administration, and processed for nuclear Fos- and cytoplasmic orexin-A-immunoreactivity (-ir). Mean numbers of orexin-A-ir neurons were not different between treatment groups. Colabeling of these cells for Fos was increased relative to controls following a single injection of insulin, but numbers of Fos-ir-positive orexin-A neurons were significantly reduced after treatment with four versus one dose of insulin. Prepro-orexin mRNA levels in microdissected LHA tissue were upregulated during acute hypoglycemia, but were returned to control levels by repeated IIH. These data corroborate previous evidence that IIH is an activational stimulus for orexin-A-synthesizing neurons in the LHA, and further demonstrate that induction of cfos and prepro-orexin gene expression by acute hypoglycemia is attenuated by precedent exposure to hypoglycemia. The current results thus provide unique evidence for neurotransmitter-specific habituation of LHA neuronal sensitivity to IIH. (c) 2006 Elsevier B.V. All rights reserved.