Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, Louisiana, USA.
J Neurosci Res. 2013 Sep;91(9):1226-38. doi: 10.1002/jnr.23230. Epub 2013 Jul 3.
This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, counterregulatory hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -β proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction.
本研究旨在验证雌激素是否控制后脑 AMP 激活蛋白激酶（AMPK）活性以及血糖调节、代偿性激素分泌和下丘脑神经细胞转录状态的假说。将雌二醇苯甲酸酯（E）或油（O）植入的卵巢切除雌性大鼠的第四脑室（CV4）后，用 AMPK 激活剂 5-氨基咪唑-4-甲酰胺-核糖苷（AICAR）进行激光微切割，分离背侧迷走复合体 A2 去甲肾上腺素能神经元，用于 Western blot 分析。E 可提前增强 AICAR 诱导的 A2 磷酸化 AMPK（pAMPK）表达和血糖水平，并且是增强 A2 神经元中 Fos、雌激素受体-α（ERα）、单羧酸转运蛋白-2 和葡萄糖转运蛋白-3 蛋白以及该治疗方案增强皮质酮分泌所必需的。CV4 AICAR 还导致下丘脑代谢结构（包括室旁核、腹内侧核和弓状核）的 Fos 免疫标记的特定部位改变。目前的研究表明，在大脑这一区域的能量短缺的药理学复制过程中，雌激素调节后脑 A2 去甲肾上腺素能神经元中的 AMPK 激活，并且该传感器参与了葡萄糖稳态的神经调节，部分通过控制皮质酮分泌。这些数据提供了独特的证据，证明 A2 神经元表达 ERα 和 -β 蛋白，并且在模拟能量不足的情况下，AMPK 上调细胞对 ERα 介导的信号转导的敏感性。结果还表明，在这些条件下，雌激素促进这些细胞吸收葡萄糖和乳酸。后脑 AMPK 与下丘脑神经细胞基因组激活之间的相关性提供了该后脑传感器与更高阶代谢脑区之间功能连接的新证据，同时证明了雌激素在这种相互作用中的调节作用。
