In Vivo Glucose Transporter-2 Regulation of Dorsomedial Versus Ventrolateral VMN Astrocyte Metabolic Sensor and Glycogen Metabolic Enzyme Gene Expression in Female Rat

IF 3.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemical Research Pub Date : 2024-09-21 DOI:10.1007/s11064-024-04246-1
Sagor C. Roy, Subash Sapkota, Madhu Babu Pasula, Karen P. Briski
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Abstract

Astrocyte glycogenolysis shapes ventromedial hypothalamic nucleus (VMN) regulation of glucostasis in vivo. Glucose transporter-2 (GLUT2), a plasma membrane glucose sensor, controls hypothalamic primary astrocyte culture glycogen metabolism in vitro. In vivo gene silencing tools and single-cell laser-catapult-microdissection/multiplex qPCR techniques were used here to examine whether GLUT2 governs dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN astrocyte metabolic sensor and glycogen metabolic enzyme gene profiles. GLUT2 gene knockdown diminished astrocyte GLUT2 mRNA in both VMN divisions. Hypoglycemia caused GLUT2 siRNA-reversible up-regulation of this gene profile in the VMNdm, but down-regulated VMNvl astrocyte GLUT2 transcription. GLUT2 augmented baseline VMNdm and VMNvl astrocyte glucokinase (GCK) gene expression, but increased (VMNdm) or reduced (VMNvl) GCK transcription during hypoglycemia. GLUT2 imposed opposite control, namely stimulation versus inhibition of VMNdm or VMNvl astrocyte 5’-AMP-activated protein kinase-alpha 1 and -alpha 2 gene expression, respectively. GLUT2 stimulated astrocyte glycogen synthase (GS) gene expression in each VMN division. GLUT2 inhibited transcription of the AMP-sensitive glycogen phosphorylase (GP) isoform GP-brain type (GPbb) in each site, yet diminished (VMNdm) or augmented (VMNvl) astrocyte GP-muscle type (GPmm) mRNA. GLUT2 enhanced VMNdm and VMNvl glycogen accumulation during euglycemia, and curbed hypoglycemia-associated VMNdm glycogen depletion. Results show that VMN astrocytes exhibit opposite, division-specific GLUT2 transcriptional responsiveness to hypoglycemia. Data document divergent GLUT2 control of GCK, AMPK catalytic subunit, and GPmm gene profiles in VMNdm versus VMNvl astrocytes. Ongoing studies seek to determine how differential GLUT2 regulation of glucose and energy sensor function and glycogenolysis in each VMN location may affect local neuron responses to hypoglycemia.

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体内葡萄糖转运体-2 对雌性大鼠背内侧血管网星形胶质细胞代谢传感器和糖原代谢酶基因表达的调控
星形胶质细胞糖原分解影响下丘脑腹内侧核(VMN)对体内葡萄糖稳态的调节。葡萄糖转运体-2(GLUT2)是一种质膜葡萄糖传感器,它在体外控制着下丘脑原代星形胶质细胞培养物的糖代谢。本研究利用体内基因沉默工具和单细胞激光-弹弓-微切片/多重 qPCR 技术来研究 GLUT2 是否控制背内侧(VMNdm)和/或腹外侧(VMNvl)VMN 星形胶质细胞代谢传感器和糖原代谢酶基因图谱。GLUT2基因敲除会减少两个VMN分部的星形胶质细胞GLUT2 mRNA。低血糖会导致 GLUT2 siRNA 在 VMNdm 中可逆地上调该基因谱,但会下调 VMNvl 星形胶质细胞 GLUT2 的转录。GLUT2 增加了基线 VMNdm 和 VMNvl 星形胶质细胞葡萄糖激酶(GCK)基因的表达,但在低血糖期间增加了(VMNdm)或减少了(VMNvl)GCK 的转录。GLUT2 对 VMNdm 或 VMNvl 星形胶质细胞 5'-AMP 激活的蛋白激酶-α 1 和-α 2 基因表达分别施加了相反的控制,即刺激与抑制。GLUT2 可刺激每个 VMN 分裂中星形胶质细胞糖原合成酶(GS)基因的表达。GLUT2 在每个部位都抑制了对 AMP 敏感的糖原磷酸化酶(GP)异构体 GP 脑型(GPbb)的转录,但却减少(VMNdm)或增加(VMNvl)了星形胶质细胞 GP 肌肉型(GPmm)的 mRNA。在优格血糖期间,GLUT2 增强了 VMNdm 和 VMNvl 的糖原累积,并抑制了低血糖相关的 VMNdm 糖原耗竭。研究结果表明,VMN 星形胶质细胞对低血糖表现出相反的、分部特异性的 GLUT2 转录反应。数据表明,在 VMNdm 和 VMNvl 星形胶质细胞中,GLUT2 对 GCK、AMPK 催化亚基和 GPmm 基因的控制存在差异。正在进行的研究试图确定 GLUT2 对葡萄糖和能量传感器功能以及糖原分解的不同调控在每个 VMN 位置可能会如何影响局部神经元对低血糖的反应。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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