Lactate is a critical "sensed" variable in caudal hindbrain monitoring of CNS metabolic stasis
Lactate is a critical "sensed" variable in caudal hindbrain monitoring of CNS metabolic stasis
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DOI：
10.1152/ajpregu.00177.2004
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发表时间：
2005-12-01
影响因子：
2.8
通讯作者：
Briski, KP
中科院分区：
文献类型：
--
作者：
Patil, GD;Briski, KP
尾侧后脑对葡萄糖活化的“感知”激活中枢神经机制，增强全身葡萄糖可用性，但与局部代谢不足检测相关的关键分子变量仍不清楚。中枢神经元和胶质细胞通过糖酵解产物乳酸作为神经元氧化呼吸的底物在细胞间运输而代谢偶联。利用互补的体内模型对尾侧后脑内乳酸可用性进行实验操作，我们研究了乳酸不足可能由局部代谢“敏感”神经元监测作为中枢神经系统能量失衡的指标的假设。数据显示，单羧酸转运体抑制剂α -氰基-4羟基肉桂酸（4CIN）的尾侧第四心室（CV4）给药导致血糖呈剂量依赖性升高，而胰岛素引起的低血糖的程度和持续时间因外源性l -乳酸递送到CV4而加剧。后脑对可诱导的c-fos基因产物Fos的免疫细胞化学处理表明，4CIN增强了迷走背复合体（DVC）中Fos的免疫反应性，例如，孤立束核和迷走背运动核，以及邻近的后脑区域，这些区域的细胞对葡萄糖和/或糖酵解中间/终产物水平降低具有独特敏感性。在前庭内侧核（MV）中，并且在胰岛素诱导的低血糖后，cv4l -乳酸注入增加了DVC和MV内的Fos标记。总之，这些结果支持以下观点：乳酸是一个关键的监测代谢变量，在尾侧后脑检测葡萄糖活化引起的能量失衡中，这种燃料摄取和/或氧化分解代谢的减少激活了神经机制，增加了全身葡萄糖的可用性。
Caudal hindbrain "sensing" of glucoprivation activates central neural mechanisms that enhance systemic glucose availability, but the critical molecular variable(s) linked to detection of local metabolic insufficiency remains unclear. Central neurons and glia are metabolically coupled via intercellular trafficking of the glycolytic product lactate as a substrate for neuronal oxidative respiration. Using complementary in vivo models for experimental manipulation of lactate availability within the caudal hindbrain, we investigated the hypothesis that lactate insufficiency may be monitored by local metabolically "sensitive" neurons as an indicator of central nervous system energy imbalance. The data show that caudal fourth ventricular (CV4) administration of the monocarboxylate transporter inhibitor alpha-cyano-4hydroxycinnamate (4CIN) resulted in dose-dependent increases in blood glucose in euglycemic animals, whereas the degree and duration of hypoglycemia elicited by insulin administration were exacerbated by exogenous L-lactate delivery to the CV4. Immunocytochemical processing of the hindbrain for the inducible c-fos gene product Fos revealed that 4CIN enhanced Fos immunoreactivity in the dorsal vagal complex (DVC), e. g., the nucleus of the solitary tract and dorsal vagal motor nucleus, and adjacent area postrema, sites where cells characterized by unique sensitivity to diminished glucose and/or glycolytic intermediate/end product levels reside, and in the medial vestibular nucleus (MV),and that CV4 L- lactate infusion increased Fos labeling within the DVC and MV after insulin-induced hypoglycemia. Together, these results support the view that lactate is a critical monitored metabolic variable in caudal hindbrain detection of energy imbalance resulting from glucoprivation and that diminished uptake and/or oxidative catabolism of this fuel activates neural mechanisms that increase systemic glucose availability.