Caudal Brain Stem Lactate Availability Regulates Feeding

说明(申请人提供)：降糖理论支持 中枢和外周底物‘传感器’监测细胞的功能 葡萄糖代谢和激活代偿性自主神经、内分泌和 对能量失衡的行为反应。出现高吞噬和高血糖 对第四脑室注射葡萄糖摄取抑制剂的反应 或者抗代谢药。这些发现表明，葡萄糖氧化减少 (以及随之而来的代谢中间体和/或 糖酵解终产物)在脑室周围后脑内是一种刺激 恢复血糖平衡的马达输出。我们的初步观察表明 在第四脑室尾侧注入单羧酸盐，乳酸盐，稀释物 格罗普利维奇喂养支持这一观点。在后脑中， 孤束(NTS)和邻近后区(AP)的特征是 通过电生理、神经解剖学和 药理数据。我们的研究表明，尾侧第四脑室 给予单羧酸盐摄取抑制剂， α-氰基-4-羟基肉桂酸(4-CIN)诱导摄食和表达 NTS内儿茶酚胺能神经元的基因组调节因子Fos 和美联社。这些数据表明，控制食物摄入的神经回路是 脑室周围乳酸氧化减少而激活 CNS，以及NTS和AP复合体对于启动和/或传递 大脑这一部分代谢失衡的调节信号。 在目标1下描述的研究将利用多种药理学策略 评价脑室周围乳酸利用的意义 后脑对食物摄入量的调节。目标2中概述的实验将 儿茶酚胺能神经元在NTS和AP中的作用 通过研究选择性消融这些神经元是否可以诱导摄食 通过免疫毒素给药的细胞阻止对减弱的摄食反应 乳酸摄取，如果局部去甲肾上腺素能/肾上腺素能细胞表达 神经元单羧酸转运体变异体转录 中枢糖基化过程中的转录激活。根据证据 气体神经递质一氧化氮(NO)对 葡萄糖吞噬功能亢进，NTS内的氮能神经元 对2DG的基因组反应，Aim 3将决定神经元一氧化氮是否 NTS中合成酶(NNOS)活性因可获得性降低而增强 葡萄糖衍生的能量底物，如果局部药物抑制 酶的活性减弱了对这种代谢失衡的摄食反应。

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.