The Effects of Acetate on Brain

摘要：NIDA的Nora Volkow博士观察到，酒精摄入降低了酒精受试者的大脑葡萄糖利用率，其模式类似于GABA能刺激[24]。T.K.Ki博士指出，葡萄糖利用率的下降可以用大脑中醋酸盐的代谢来解释，在乙醇代谢过程中，醋酸盐的血液水平达到2 mM。在乔治·库诺斯博士和生理研究实验室成员的合作下，我们确定，当血液中醋酸盐浓度升高到5或2 mM时，大脑对F-葡萄糖的摄取显著减少，醋酸盐进入大脑的Km约为5 mm。简单地测量葡萄糖利用率的降低，很少有关于从葡萄糖代谢转换为醋酸盐代谢对大脑能量、神经递质、转录或神经肽代谢的影响的信息。因此，我们提出了一个代谢计划，利用毛细管电泳质谱来更快地确定大脑底物水平变化的变化，同时确定当大脑从葡萄糖代谢切换到醋酸盐代谢时发生的途径通量变化的速度。预计这些新方法的开发将在这个直接的项目之外具有广泛的适用性，并将通过确定已定义的代谢途径的变化，以实际的方式解决NIH推动代谢组学的问题。这项研究预计需要两年左右的时间才能完成。 尽管NIAAA等人多年来对乙醇对大脑和肝脏功能的影响进行了广泛的研究，但对肝脏乙醇代谢产生的乙酸酯在肝外组织中的利用对能量和神经递质代谢的影响却相对较少。可以预计，从葡萄糖代谢到醋酸盐代谢的转变将产生重大的和到目前为止意想不到的影响。 对本研究所项目的意义 醋酸盐是肝脏在饮用酒精时产生的代谢产物。大脑对醋酸盐代谢的影响尚未得到系统的研究，预计将对我们理解酒精消费的影响，特别是对酒精戒断综合症和酒精对情绪的影响产生重大影响。代谢控制分析方法和更快速的代谢物分析方法有望为NIH研究代谢组的路线图计划做出重大贡献，该路线图计划将酶动力学和热力学结合在一起，研究巨大的代谢图的特定部分。

Summary: Dr. Nora Volkow, of NIDA observed that alcohol consumption decreased brain glucose utilization in alcoholic subjects in a pattern which resemble GABAergic stimulation (24). Dr. T.K. Ki pointed out that the decrease in glucose utilization could be explained by the brain metabolism of acetate, which reaches blood levels of 2 mM during ethanol metabolism. In collaboration with Dr. George Kunos and members of the Lab of Physiological Studies, we determined that brain uptake of F dexoyglucose was significantly decreased by elevation of blood acetate to 5 or 2 mM acetate, the Km for acetate transport into brain being about 5 mM. Simple measurement of a decreased rate of glucose utilization provides little information on the effects of switching from glucose to acetate metabolism on brain energetics, neurotransmitter, transcription or neuropeptide metabolism. Accordingly we have proposed a metabolomic program, utilizing cappilary electrophoresis and mass spectrometry to more rapidly determine the changes in brain substrate levels changes while at the same time determining the rate of the changes in pathway fluxes which occur as the brain switches from glucose to acetate metabolism. It is anticipated that the development of these new methods will have wide applicability beyond this immediate project and will address in a practical way the NIH thrust toward metabolomics by determining changes in defined metabolic pathways. This study is expected to take about 2 years to complete. While the effects of ethanol on brain and liver function have been extensively studied by the NIAAA and others for many years, there has been relatively little attention paid to the effects on energy and neurotransmitter metabolism resulting from the utilization of the acetate produce by hepatic ethanol metabolism upon extra hepatic tissue. It can be expected that the switch from glucose to acetate metabolism will have significant and hither to unexpected effects. SIGNIFICANCE TO THE PROGRAMS OF THIS INSTITUTE Acetate is the metabolic product produced by the liver during ethanol consumption. The effects of the metabolism of acetate by brain have not been systematically investigated and are expected to yield significant results on our understanding of the effects of alcohol consumption, particularly upon alcohol withdrawal syndrome and alcohol effects upon mood. The methods of metabolic control analysis and the more rapid methods of metabolite analysis are expected to contribute significantly to the NIH road map plan of investigating the metabolome in a way which combines enzyme kinetics and thermodynamics of defined portions of the great metabolic chart.