Hindbrain energy state shapes hypothalamic control of glucostasis. Dorsal vagal complex (DVC) L-lactate deficiency is a potent glucose-stimulatory signal that triggers neuronal transcriptional activation in key hypothalamic metabolic loci. The energy gauge AMPK is activated in DVC metabolic-sensory A2 noradrenergic neurons by hypoglycemia-associated lactoprivation, but sensor reactivity is diminished by antecedent hypoglycemia (AH). Current research addressed the premise that AH alters hindbrain lactoprivic regulation of hypothalamic metabolic transmitter function. AH did not modify reductions in A2 dopamine-beta-hydroxylase and monocarboxylate-2 (MCT2) protein expression elicited by caudal fourth ventricular delivery of the MCT inhibitor alpha-cyano-4-hydroxycinnamic acid (4CIN), but attenuated 4CIN activation of A2 AMPK. 4CIN constraint of hypothalamic norepinephrine (NE) activity was averted by AH in a site-specific manner. 4CIN induction of Fos immunolabeling in hypothalamic arcuate (ARH), ventromedial (VMN), dorsomedial (DMN) and paraventricular (PVN) nuclei and lateral hypothalamic area (LHA) was avoided by AH. AH affected reactivity of select hypothalamic metabolic neurotransmitter/enzyme marker proteins, e.g. ARH neuropeptide Y, VMN glutamate decarboxylase, DMN RFamide-related peptide-1 and -3, and LHA orexin-A profiles to 4CIN, but did not alleviate drug inhibition of ARH proopiomelanocortin. AH prevented 4CIN augmentation of circulating glucagon, but did not alter hyperglycemic or hypocorticosteronemic responses to that treatment. Results identify hindbrain lactate deficiency as a stimulus for glucagon secretion, and imply that habituation of this critical counter-regulatory hormone to recurring hypoglycemia may involve one or more hypothalamic neurotransmitters characterized here by acclimation to this critical sensory stimulus.

中文翻译：

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下丘脑神经元反式激活和葡萄糖调节神经递质表达的后脑乳酸调节：先前胰岛素诱导的低血糖的影响

后脑能量状态影响下丘脑对葡萄糖代谢的控制。背侧迷走神经复合体 (DVC) L-乳酸缺乏是一种有效的葡萄糖刺激信号，可触发关键下丘脑代谢位点的神经元转录激活。能量计 AMPK 在 DVC 代谢-感觉 A2 去甲肾上腺素能神经元中被低血糖相关的乳酸剥夺激活，但传感器反应性因先前的低血糖 (AH) 而减弱。目前的研究解决了 AH 改变下丘脑代谢递质功能的后脑乳酸调节的前提。AH 没有改变 A2 多巴胺-β-羟化酶和单羧酸-2 (MCT2) 蛋白表达的减少，这是由尾侧四心室递送 MCT 抑制剂 α-氰基-4-羟基肉桂酸 (4CIN) 引起的，但减弱了 A2 AMPK 的 4CIN 激活. AH 以特定于位点的方式避免了下丘脑去甲肾上腺素 (NE) 活性的 4CIN 约束。AH 避免了下丘脑弓状 (ARH)、腹内侧 (VMN)、背内侧 (DMN) 和室旁 (PVN) 核和外侧下丘脑区 (LHA) 中 Fos 免疫标记的 4CIN 诱导。AH 影响选择的下丘脑代谢神经递质/酶标记蛋白的反应性，例如 ARH 神经肽 Y、VMN 谷氨酸脱羧酶、DMN RFamide 相关肽-1 和 -3，以及 LHA 食欲素-A 谱对 4CIN 的反应，但没有减轻 ARH 的药物抑制阿黑皮素原。AH 阻止了循环胰高血糖素的 4CIN 增加，但不会改变对该治疗的高血糖或低皮质酮反应。结果确定后脑乳酸缺乏是胰高血糖素分泌的刺激因素，