The Effects of Acetate on Brain

总结：NIDA的诺拉罗博士观察到，饮酒会降低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.博士Ki指出，葡萄糖利用率的下降可以用乙酸盐的脑代谢来解释，乙酸盐在乙醇代谢过程中达到2 mM的血液水平。在与乔治库诺斯博士和生理研究实验室成员的合作中，我们确定，血液乙酸盐升高至5或2 mM乙酸盐时，大脑对F-脱氧葡萄糖的摄取显著降低，乙酸盐转运到脑中的Km约为5 mM。简单测量葡萄糖利用率的降低几乎不能提供关于从葡萄糖代谢转换为乙酸盐代谢对脑的影响的信息能量学、神经递质、转录或神经肽代谢。因此，我们提出了一种代谢组学程序，利用毛细管电泳和质谱法更快地确定脑底物水平变化的变化，同时确定当大脑从葡萄糖代谢转换为乙酸盐代谢时发生的通路通量的变化率。预计这些新方法的发展将具有广泛的适用性，超出了这个直接的项目，并将在一个实际的方式解决NIH推力代谢组学确定的代谢途径的变化。这项研究预计需时约两年完成。 虽然多年来NIAAA和其他机构已经广泛研究了乙醇对大脑和肝脏功能的影响，但人们对利用肝脏乙醇代谢产生的醋酸盐对能量和神经递质代谢的影响的关注相对较少。肝外组织。可以预期的是，从葡萄糖代谢到乙酸盐代谢的转换将具有显著的和迄今为止意想不到的效果。 对本研究所方案的意义 乙酸盐是肝脏在消耗乙醇时产生的代谢产物。大脑对醋酸盐代谢的影响尚未得到系统的研究，预计这将对我们理解酒精消费的影响产生重大影响，特别是对酒精戒断综合征和酒精对情绪的影响。代谢控制分析的方法和代谢物分析的更快速的方法预计将有助于显着的NIH路线图计划的方式相结合的酶动力学和热力学的大代谢图的定义部分的代谢组学研究。

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.