Sex-dimorphic effects of glucose transporter-2 gene knockdown on hypothalamic primary astrocyte phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of rapamycin (mTOR) cascade protein expression and phosphorylation

IF 3.8 3区 医学 Q2 CELL BIOLOGY Molecular and Cellular Endocrinology Pub Date : 2024-08-10 DOI:10.1016/j.mce.2024.112341
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Abstract

Glucose transporter-2 (GLUT2), a unique high capacity/low affinity, highly efficient membrane transporter and sensor, regulates hypothalamic astrocyte glucose phosphorylation and glycogen metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway participates in glucose homeostasis, but its sensitivity to glucose-sensory cues is unknown. Current research used a hypothalamic astrocyte primary culture model to investigate whether glucoprivation causes PI3K/Akt/mTOR pathway activation in one or both sexes by GLUT2-dependent mechanisms. Glucoprivation did not alter astrocyte PI3K levels, yet up-regulated both phosphorylated derivatives in female and down-regulated male p60 phosphoprotein expression. GLUT2 siRNA pretreatment diminished glucoprivic patterns of PI3K and phospho-PI3K expression in each sex. Astrocyte Akt and phospho-Akt/Thr308 proteins exhibited divergent, sex-contingent responses to GLUT2 gene knockdown or glucoprivation. GLUT2 siRNA pretreatment exacerbated glucoprivic-associated Akt diminution in the female, and either amplified (male) or reversed (female) glucoprivic regulation of phospho-Akt/Thr308 expression. GLUT2 gene silencing down- (male) or up-(female) regulated mTOR protein, and phospho-mTOR protein in male. Male astrocyte mTOR and phospho-mTOR profile were refractory to glucoprivation, but glucose-deprived females showed GLUT2-independent mTOR inhibition and GLUT2-dependent phospho-mTOR up-augmentation. Results identify a larger number of glucoprivic-sensitive PI3K/Akt/mTOR pathway proteins in female versus male astrocytes, and document divergent responses of common glucose-sensitive targets. GLUT2 stimulates phosphoPI3K protein expression in each sex, but imposes differential control of PI3K, Akt, phospho-Akt/Thr308, mTOR, and phospho-mTOR profiles in male versus female. Data implicate GLUT2 as a driver of distinctive pathway protein responses to glucoprivation in female, but not male.

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葡萄糖转运体-2基因敲除对下丘脑原发性星形胶质细胞磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(PKB/Akt)/哺乳动物雷帕霉素靶标(mTOR)级联蛋白表达和磷酸化的性别双态影响
葡萄糖转运体-2(GLUT2)是一种独特的高容量/低亲和力高效膜转运体和传感器,它调节下丘脑星形胶质细胞葡萄糖磷酸化和糖原代谢。磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶 B(Akt)/哺乳动物雷帕霉素靶标(mTOR)信号通路参与葡萄糖稳态,但其对葡萄糖感觉线索的敏感性尚不清楚。目前的研究利用下丘脑星形胶质细胞原代培养模型来研究葡萄糖剥夺是否会通过GLUT2依赖性机制导致雌雄一方的PI3K/Akt/mTOR通路激活。葡萄糖剥夺不会改变星形胶质细胞的PI3K水平,但会上调雌性星形胶质细胞的两种磷酸化衍生物,下调雄性星形胶质细胞的p60磷蛋白表达。GLUT2 siRNA预处理减少了葡萄糖剥夺模式下PI3K和磷酸化PI3K在每种性别中的表达。星形胶质细胞的 Akt 和磷酸化-Akt/Thr308 蛋白对 GLUT2 基因敲除或葡萄糖剥夺表现出不同的、与性别相关的反应。GLUT2 siRNA预处理会加剧雌性星形胶质细胞与葡萄糖剥夺相关的Akt减少,并扩大(雄性)或逆转(雌性)葡萄糖剥夺对磷酸-Akt/Thr308表达的调节。GLUT2 基因沉默下调(雄性)或上调(雌性)雄性的 mTOR 蛋白和磷酸化 mTOR 蛋白。雄性星形胶质细胞的 mTOR 和磷酸化-mTOR 蛋白对葡萄糖剥夺具有耐受性,但葡萄糖剥夺的雌性星形胶质细胞则表现出 GLUT2 依赖性 mTOR 抑制和 GLUT2 依赖性磷酸化-mTOR 上调。研究结果在雌性与雄性星形胶质细胞中发现了更多对葡萄糖剥夺敏感的PI3K/Akt/mTOR通路蛋白,并记录了常见葡萄糖敏感靶点的不同反应。GLUT2 在每种性别中都会刺激磷酸化 PI3K 蛋白的表达,但在男性与女性中,GLUT2 对 PI3K、Akt、磷酸化-Akt/Thr308、mTOR 和磷酸化-mTOR 的控制是不同的。数据表明,GLUT2 是雌性(而非雄性)对葡萄糖剥夺的独特途径蛋白反应的驱动因素。
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来源期刊
Molecular and Cellular Endocrinology
Molecular and Cellular Endocrinology 医学-内分泌学与代谢
CiteScore
9.00
自引率
2.40%
发文量
174
审稿时长
42 days
期刊介绍: Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.
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