Yadav Rajesh K, Sapkota Subash, Briski Karen P
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
UL System Foundation and Willis-Knighton Health Systems Professorship in Toxicology, College of Pharmacy, University of Louisiana at Monroe, Rm 356 Bienville Building, 1800 Bienville Drive, Monroe, LA, 71201, USA.
Neurochem Res. 2025 Sep 4;50(5):283. doi: 10.1007/s11064-025-04533-5.
Alpha-2 (α2-) tanycytes line the ventral wall of the third ventricle where they ostensibly engage in metabolic screening. The oxidizable glycolytic end-product L-lactate is a gauge of hindbrain energy stability that is imparted to forebrain glucose-regulatory loci by norepinephrine signaling. Current research used a validated whole-animal model for insulin-induced hypoglycemia (IIH) to address the premise that hindbrain lactate status imposes sex-specific control of eu- and/or hypoglycemic patterns of α2-tanycyte chemosensor gene transcription in vivo. Vimentin-immunopositive α2-tanycytes were laser-catapult-microdissected from male and female brain sections after subcutaneous insulin injection and caudal fourth ventricular (CV4) L-lactate- or vehicle infusion for single-cell multiplex qPCR analysis of glucose and energy sensor gene expression. Hindbrain lactate infusion reversed IIH repression of α2-tanycyte glucose transporter-2 mRNA in females and amplified (males) or reversed (females) up-regulated glucokinase gene transcription. Lactate increased α2-tanycyte ATP-sensitive potassium channel Kir6.2 mRNA levels in hypoglycemic rats of each sex, reversing transcriptional inhibition in males or amplifying up-regulated expression in females. In both sexes, IIH-associated down-regulation of energy sensor 5'-AMP-activated protein kinase catalytic subunit isoforms alpha-1 and - 2 gene profiles was correspondingly unaffected or reversed by lactate. Hypoglycemia increased or decreased α2-tanycyte alpha and beta receptor mRNA content, respectively; lactate caused opposite, sex-specific adjustments in transcriptional reactivity of the former gene yet did not affect the latter profile in either sex. Results show that hypothalamic α2-tanycytes are direct target for norepinephrine stimulation and document sex-dimorphic hindbrain lactoprivic regulation of chemosensor gene transcriptional responses to in vivo hypoglycemia.
α2- 型伸展细胞排列在第三脑室的腹侧壁，表面上它们参与代谢筛选。可氧化的糖酵解终产物L-乳酸是后脑能量稳定性的一个指标，通过去甲肾上腺素信号传递赋予前脑葡萄糖调节位点。当前的研究使用了一个经过验证的胰岛素诱导低血糖（IIH）的全动物模型，以探讨后脑乳酸状态在体内对α2- 型伸展细胞化学传感器基因转录的正常血糖和/或低血糖模式施加性别特异性控制这一前提。在皮下注射胰岛素以及向尾侧第四脑室（CV4）注入L-乳酸或赋形剂后，从雄性和雌性脑切片中激光弹射显微切割波形蛋白免疫阳性的α2- 型伸展细胞，用于对葡萄糖和能量传感器基因表达进行单细胞多重定量PCR分析。后脑乳酸注入逆转了雌性中IIH对α2- 型伸展细胞葡萄糖转运蛋白2 mRNA的抑制作用，并放大了（雄性）或逆转了（雌性）上调的葡萄糖激酶基因转录。乳酸增加了各性别低血糖大鼠中α2- 型伸展细胞ATP敏感性钾通道Kir6.2的mRNA水平，逆转了雄性中的转录抑制或放大了雌性中上调的表达。在两性中，与IIH相关的能量传感器5'-AMP激活蛋白激酶催化亚基α-1和 - 2基因谱的下调相应地未受影响或被乳酸逆转。低血糖分别增加或降低了α2- 型伸展细胞α和β受体的mRNA含量；乳酸对前一个基因的转录反应性产生了相反的、性别特异性的调节，但对两性中的后一个基因谱均无影响。结果表明，下丘脑α2- 型伸展细胞是去甲肾上腺素刺激的直接靶点，并证明了后脑对化学传感器基因对体内低血糖的转录反应存在性别二态性的乳酸缺乏调节。
