Role of Acetate in Heavy Drinking

描述（由申请人提供）：酒精滥用和依赖是与许多合并症相关的全球健康问题。低血糖是一种合并症，尤其与酗酒有关。在正常情况下，葡萄糖是大脑能量代谢的主要燃料，因此在低血糖时，大脑越来越依赖血乳酸、酮体和醋酸盐，所有这些都通过同一种单羧酸转运体穿过血脑屏障。当饮酒时，身体将酒精转化为醋酸盐，而老鼠能够利用醋酸盐，部分替代葡萄糖的消耗。对糖尿病和饥饿中低血糖的研究表明，低血糖和单羧酸的升高会促进单羧酸的运输和利用。因此，我们假设通过反复暴露于升高的乙酸、酮、乳酸和低血糖，经历多次低血糖发作的重度饮酒者比轻度饮酒者和不饮酒者更能消耗从乙醇中提取的乙酸。如果这个项目的假设得到支持，酒精的燃料生成方面可能提供一种新的奖励机制，促进大量饮酒的持续，并有助于延长狂饮的发作时间。要回答的核心问题是：重度饮酒者是否容易运输和利用醋酸盐进行大脑能量代谢？第二个问题将得到回答：对于脑代谢，重度饮酒者比轻度/不饮酒者更容易运输和利用醋酸盐吗？这些问题将在注入[2-13C]醋酸期间以三种组分进行检查。测量将包括：(1)脑醋酸盐浓度，(2)醋酸盐氧化更快，以及(3)与轻度/不饮酒者相比，重度饮酒者的血脑运输能力。在注射[2-13C]醋酸盐期间，对10名重度饮酒者和10名轻度/不饮酒者的醋酸盐浓度和利用率进行测量。测量将利用4特斯拉的13C MRS来检测大脑中13C标记的醋酸盐、谷氨酸盐和谷氨酰胺的时间过程。

DESCRIPTION (provided by applicant): Alcohol abuse and dependence are global health concerns associated with numerous comorbidities. Hypoglycemia is a comorbidity particularly associated with binge-drinking. Under normal conditions glucose is the primary fuel for brain energy metabolism, so in hypoglycemia the brain relies increasingly on blood lactate, ketone bodies, and acetate, all of which cross the blood-brain barrier by the same monocarboxylic acid transporter. When drinking, the body converts alcohol to acetate, and rats are able to utilize the acetate, partially replacing glucose consumption. Studies of hypoglycemia in diabetes and in starvation show that the transport and utilization of monocarboxylic acids are enhanced by hypoglycemia and by elevations in monocarboxlyic acids. Therefore, we hypothesize that through repeated exposure to elevated acetate, ketones, lactate, and hypoglycemia, heavy drinkers who experience repeated episodes of hypoglycemia are more able to consume the acetate derived from ethanol than are light drinkers and non-drinkers. If the hypotheses of this project are supported, the fuel-generation aspect of alcohol may provide a novel award mechanism that promotes the continuation of heavy drinking and helps to prolong episodes of binge-drinking. The central question to be answered is this: Can heavy drinkers readily transport and utilize acetate for brain energy metabolism? A secondary question will be answered: For brain metabolism, do heavy drinkers more readily transport and utilize acetate than light/non- drinkers? These questions will be examined in three components during infusions of [2-13C]acetate. Measurements will be (1) brain acetate concentrations, (2) oxidize acetate more rapidly, and (3) blood-brain transport capacity of heavy drinkers relative to light/non-drinkers. The concentrations and rates of utilization acetate will be measured in 10 heavy drinkers and 10 light/non-drinkers during infusions of [2-13C]acetate. The measurements will utilize 13C MRS at 4 Tesla to detect the time courses of 13C-labeled acetate, glutamate, and glutamine in the brain. PUBLIC HEALTH RELEVANCE: Under most circumstances, people's brains derive nearly all their energy needs from the sugar glucose. Sometimes when people drink large quantities of alcohol, their blood sugar drops, particularly if they are not eating properly, and to survive, the brain must find alternatives to glucose. One alternative chemical that the brain can consume is acetate that the body forms from alcohol. In this study, we will determine if heavy drinkers are more able to use acetate as fuel for the brain. If they are, the possibility exists that heavy drinkers continue drinking not only for the known drug-effects of alcohol, but to provide sustenance for the brain when they do not eat properly, supporting an idea that nutrition is a key player in the ability to reduce heavy drinking or stop drinking alcohol.