Caudal Brain Stem Lactate Availability Regulates Feeding

描述（由申请人提供）：葡萄糖抑制理论支持 中央和外围基底"传感器"监测细胞的功能 葡萄糖代谢和激活代偿自主，内分泌， 对能量不平衡的反应。出现暴食和高血糖 响应于第四心室施用葡萄糖摄取抑制剂 或抗代谢物。这些发现表明，降低葡萄糖氧化 (and代谢中间产物的生成减少和/或 糖酵解终产物）是一种刺激， 恢复血糖停滞的运动输出。我们的初步观察表明， 尾侧第四脑室输注单羧酸盐、乳酸盐， 葡萄糖缺乏性喂养支持这一观点。在后脑中， 孤束（NTS）和邻近的最后区（AP）的特点是， 通过电生理学、神经解剖学和 药理学数据。我们的研究表明尾侧第四脑室 施用单羧酸摄取抑制剂， α-氰基-4-羟基肉桂酸（4-CIN），eleventh喂养和表达 基因组调节因子Fos，通过NTS内的儿茶酚胺能神经元 的AP。这些数据表明，控制食物摄入的神经回路是 心室周围乳酸氧化减少时激活 CNS，并且NTS和AP复合物对于CNS的起始和/或中继至关重要。 这部分大脑中代谢失衡的调节信号。 目标1下描述的研究将采用多种药理学策略 评价室周血乳酸利用的意义 调节食物摄入的后脑。目标2下概述的实验将 评价NTS和AP中儿茶酚胺能神经元在乳酸中的作用 通过研究是否选择性消融这些 免疫毒素给药阻断了对减少的 乳酸摄取，以及如果局部去甲肾上腺素能/肾上腺素能细胞表达 神经元单羧酸转运蛋白变异体转录 在中枢葡萄糖缺乏期间的转录激活。根据证据 气体神经递质一氧化氮（NO）对 糖缺乏性摄食过多，而NTS内的氮能神经元 基因组响应2DG，目标3将确定是否神经元一氧化氮 NTS中的nNOS合成酶（nNOS）活性通过降低 葡萄糖衍生的能量底物，如果药理学抑制局部 酶活性减弱了对这种代谢不平衡的摄食反应。

DESCRIPTION (provided by applicant): The glucostatic theory supports the function of central and peripheral substrate 'sensors' to monitor cellular glucose metabolism and activate compensatory autonomic, endocrine, and behavioral responses to energy imbalance. Hyperphagia and hyperglycemia occur in response to fourth ventricular administration of glucose uptake inhibitors or antimetabolites. These findings suggest that decreased glucose oxidation (and consequent diminished generation of metabolic intermediates and/or glycolytic endproducts) within the periventricular hindbrain is a stimulus for motor output that restores glucostasis. Our preliminary observations that caudal fourth ventricular infusion of the monocarboxylate, lactate, attenuates glucoprivic feeding support this view. In the hindbrain, the nucleus of the solitary tract (NTS) and adjacent area postrema (AP) have been characterized as 'glucoprivic-sensitive' by electrophysiological, neuroanatomical, and pharmacological data. Our studies show that caudal fourth ventricular administration of the monocarboxylate uptake inhibitor, alpha-cyano-4hydroxycinnamic acid (4-CIN), elicits feeding and expression of the genomic regulatory factor, Fos, by catecholaminergic neurons within the NTS and AP. These data suggest that the neural circuitry controlling food intake is activated in response to decreased lactate oxidation within the periventricular CNS, and that the NTS and AP complex is critical for initiation and/or relay of regulatory signals of metabolic imbalance within this part of the brain. Studies described under aim 1 will utilize multiple pharmacologicai strategies to evaluate the significance of lactate utilization within the periventricular hindbrain for regulation of food intake. Experiments outlined under aim 2 will evaluate the role of catecholaminergic neurons in the NTS and AP in lactate deficit-induced feeding by investigating whether selective ablation of these cells by immunotoxin administration blocks ingestive responses to diminished lactate uptake, and if local noradrenergic/adrenergic cells that express the neuronal monocarboxylate transporter variant transcription undergo transcriptional activation during central glucoprivation. In light of evidence that the gaseous neurotransmitter, nitric oxide (NO), is critical for glucoprivic hyperphagia, and that nitrergic neurons within the NTS are genomically responsive to 2DG, aim 3 will determine if neuronal nitric oxide synthase (nNOS) activity in the NTS is enhanced by decreased availability of glucose-derived energy substrates, and if pharmacological suppression of local enzyme activity attenuates feeding responses to this metabolic imbalance.