Role of Acetate in Heavy Drinking

描述（由申请人提供）：酒精滥用和依赖是与多种合并症相关的全球健康问题。低血糖症是一种与暴饮暴食特别相关的合并症。在正常情况下，葡萄糖是大脑能量代谢的主要燃料，因此在低血糖症中，大脑越来越依赖于血乳酸、酮体和乙酸盐，所有这些都通过相同的单羧酸转运蛋白穿过血脑屏障。当饮酒时，身体将酒精转化为乙酸盐，大鼠能够利用乙酸盐，部分替代葡萄糖消耗。对糖尿病和饥饿中低血糖的研究表明，低血糖和一元羧酸的升高可增强一元羧酸的转运和利用。因此，我们假设，通过反复暴露于升高的乙酸盐、酮、乳酸盐和低血糖，反复发生低血糖的重度饮酒者比轻度饮酒者和非饮酒者更能消耗来自乙醇的乙酸盐。如果该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，促进酗酒的继续，并有助于延长酗酒的发作。需要回答的核心问题是：重度饮酒者是否能够容易地运输和利用乙酸盐进行大脑能量代谢？第二个问题将得到回答：对于大脑代谢，重度饮酒者比轻度/非饮酒者更容易运输和利用乙酸盐吗？在输注[2- 13 C]醋酸盐期间，将在三个组分中检查这些问题。测量将是（1）大脑乙酸盐浓度，（2）氧化乙酸盐更快，和（3）相对于轻度/非饮酒者，重度饮酒者的血脑转运能力。在输注[2- 13 C]醋酸盐期间，将在10名重度饮酒者和10名轻度/非饮酒者中测量醋酸盐的浓度和利用率。测量将利用4特斯拉的13 C MRS检测大脑中13 C标记的乙酸盐、谷氨酸盐和谷氨酰胺的时间过程。 公共卫生相关性：在大多数情况下，人们的大脑几乎所有的能量需求都来自葡萄糖。有时，当人们喝大量的酒精，他们的血糖下降，特别是如果他们没有正确饮食，为了生存，大脑必须找到葡萄糖的替代品。大脑可以消耗的另一种化学物质是身体从酒精中形成的乙酸盐。在这项研究中，我们将确定重度饮酒者是否更能够使用醋酸盐作为大脑的燃料。如果是的话，那么酗酒者继续喝酒的可能性就存在了，不仅是因为酒精的已知药物作用，而且是为了在他们饮食不当时为大脑提供营养，这支持了营养是减少酗酒或停止饮酒的关键因素的观点。

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.