Diazepam Binding Inhibitor Control of Eu- and Hypoglycemic Patterns of Ventromedial Hypothalamic Nucleus Glucose-Regulatory Signaling.

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2023-01-01 DOI:10.1177/17590914231214116
Sagor C Roy, Subash Sapkota, Madhu Babu Pasula, Khaggeswar Bheemanapally, Karen P Briski
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Abstract

Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65 kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.

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地西泮结合抑制剂控制下丘脑腹内侧核葡萄糖调节信号的Eu-和低血糖模式。
星形胶质肽信号通路的药理刺激/拮抗改变下丘脑腹内侧核(VMN)对γ-氨基丁酸(GABA)和一氧化氮传递的拮抗作用。目前的研究使用新开发的毛细管区带电泳-质谱方法来研究低血糖对VMN octadecaneuropeptide含量的影响,并使用基因敲低工具来确定octadecaneuropeptide信号是否在eu和/或低血糖期间调节这些递质。低血糖引起十八能欧肽前体的不同调整,即地西泮结合抑制剂和十八能欧肽水平在背内侧和腹外侧VMN中。VMN内给药地西帕-结合抑制剂siRNA降低了激光显微解剖的gaba能神经元67和65 kDa谷氨酸脱羧酶mRNA的基线水平,但仅影响腹侧VMN中低血糖转录物的表达。这种低敲疗法对背内侧和腹外侧gaba能神经元中eu-和低血糖葡萄糖激酶以及5'- amp活化蛋白激酶- α1 (AMPKα1)和- α2 (AMPKα2)基因谱的影响不同。地西泮结合抑制剂基因沉默上调的基线(背内侧)或低血糖(腹外侧)氮能神经元神经元一氧化氮合酶mRNA谱。基线氮能细胞葡萄糖激酶mRNA受地西泮结合抑制剂siRNA的上调(腹外侧)或下调(背内侧)调节,但下调这两个位点的低血糖谱增强。在低血糖和低血糖时,氮神经细胞AMPKα1和-α2转录物对这种基因操作表现出分裂特异性反应。结果证明毛细管区带电泳-质谱工具用于定量小体积脑组织样品中的ODN。数据显示,低血糖对VMN的两个主要神经解剖分区的ODN信号传导有不同的影响,并且这种胶质肽在低血糖和低血糖期间对VMNdm和VMNvl中葡萄糖调节神经传递施加不同的控制。
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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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