Shrestha Rami, Briski Karen P
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA.
UL System Foundation and Willis-Knighton Health Systems Professorship in Toxicology, School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Rm 356 Bienville Building 1800 Bienville Drive, Monroe, LA, 71201, USA.
Sci Rep. 2025 Jul 22;15(1):26640. doi: 10.1038/s41598-025-11364-5.
Ventromedial hypothalamic nucleus (VMN) astrocyte glycogen metabolism shapes glucose counterregulatory neurotransmission. Beta-adrenergic receptor (β1-AR) regulates in vitro cortical astrocyte glycogen turnover. Current studies employed VMN β1-AR gene knockdown tools to investigate whether this receptor controls eu- and/or hypoglycemic patterns of VMN astrocyte glucose handling and glycogen amassment in vivo according to sex. Dorsomedial (VMNdm) and ventrolateral (VMNvl) VMN astrocytes were laser-catapult-microdissected as separate populations for Western blot protein analysis. VMNdm and VMNvl astrocyte glucokinase protein exhibited β1-AR-independent inhibition (female) or opposite adjustments (male) after insulin injection. In males, glucose-6-phosphatase-beta responses to hypoglycemia were exacerbated by β1-AR siRNA, whereas down-regulation in females was averted (VMNdm) or amplified (VMNvl) by this pretreatment. β1-AR siRNA did not affect hypoglycemic suppression of VMNdm glycogen synthase, but amplified VMNvl diminution of this protein in both sexes. Hypoglycemia caused divergent changes in VMNdm versus VMNvl glycogen phosphorylase (GP)-brain type protein; β1-AR gene silencing abolished these division-specific responses in female, not male. Hypoglycemic down-regulation of female astrocyte VMNdm and VMNvl GP-muscle type protein expression was averted or exacerbated, respectively, by β1-AR siRNA. β1-AR gene knockdown exacerbated hypoglycemia-associated reductions in female VMNdm and VMNvl glycogen but amplified (VMNdm) or abolished (VMNvl) glycogen augmentation in males. Gene silencing had opposite effects on hypoglycemia-associated growth hormone, glucagon, and corticosterone secretion in male versus female. Results document sex-contingent β1-AR regulation of glucose sensing, endogenous glucose production, and glycogen metabolism in distinct VMN astrocyte populations. Further work is needed to elucidate if and how such control may affect VMN counterregulatory transmission in each sex.
腹内侧下丘脑核（VMN）星形胶质细胞的糖原代谢塑造了葡萄糖的对抗调节神经传递。β-肾上腺素能受体（β1-AR）调节体外培养的皮质星形胶质细胞的糖原周转。目前的研究采用VMN β1-AR基因敲低工具，以研究该受体是否根据性别在体内控制VMN星形胶质细胞葡萄糖处理和糖原积累的正常血糖和/或低血糖模式。背内侧（VMNdm）和腹外侧（VMNvl）VMN星形胶质细胞通过激光弹射显微切割作为不同群体用于蛋白质印迹分析。胰岛素注射后，VMNdm和VMNvl星形胶质细胞的葡萄糖激酶蛋白表现出与β1-AR无关的抑制（雌性）或相反的调节（雄性）。在雄性中，β1-AR siRNA加剧了低血糖对葡萄糖-6-磷酸酶-β的反应，而在雌性中，这种预处理避免了（VMNdm）或放大了（VMNvl）其下调。β1-AR siRNA不影响VMNdm糖原合酶的低血糖抑制，但在两性中均放大了VMNvl中该蛋白的减少。低血糖导致VMNdm与VMNvl糖原磷酸化酶（GP）-脑型蛋白发生不同变化；β1-AR基因沉默消除了雌性而非雄性的这些分区特异性反应。β1-AR siRNA分别避免或加剧了雌性星形胶质细胞VMNdm和VMNvl GP-肌肉型蛋白表达的低血糖下调。β1-AR基因敲低加剧了雌性VMNdm和VMNvl糖原与低血糖相关的减少，但放大了（VMNdm）或消除了（VMNvl）雄性糖原的增加。基因沉默对雄性和雌性与低血糖相关的生长激素、胰高血糖素和皮质酮分泌有相反的影响。结果证明了β1-AR对不同VMN星形胶质细胞群体中葡萄糖感知、内源性葡萄糖生成和糖原代谢的性别依赖性调节。需要进一步的研究来阐明这种控制是否以及如何影响每种性别的VMN对抗调节传递。
