Prenatal exposure to high-fat diets promotes alcohol preference in the offspring

描述（由申请人提供）：最近的研究表明，怀孕的水坝摄入过多的脂肪会导致后代表现出高脂血症，食物摄入量增加，偏好脂肪和体重增加。这些长期的生理和行为变化在一定程度上是由产后表达丙氨酸的细胞和刺激脂肪摄入的多肽的神经发生增加所驱动的。这些多肽与酒精摄入量增加有关。因此，脂肪消耗鼠后代的这些下丘脑变化可能会产生对酒精的渴望。在这里，我们建议研究产前暴露于高脂肪饮食对后代饮酒的影响。这将通过（Exp.1）复制初步结果来完成，这些初步结果表明，青春期女性在产前接触高脂肪饮食时，会比对照组消耗更多的酒精。这一发现将扩展到雄性和成年后代。在脂肪消耗母亲所生的动物中，分析年龄和性别特定的酒精摄入量趋势将使我们能够描述一种新的酒精偏好大鼠动物模型。一旦我们描述了这种行为模式，我们将（实验2）探索可能导致这种现象的肽和性激素的畸变。我们知道有一种神经回路随着增加脂肪摄入量的能力而进化；此外，它还可以被酒精吸收。同样清楚的是，饮用乙醇可以增加该回路中多肽的表达。因此，新的问题是，幼崽出生在消耗脂肪的母鼠，因此长大后，下丘脑细胞产生更高水平的促氧肽，是否会通过饮用乙醇进一步刺激这些肽的表达。这可能会对酒精滥用造成三重威胁：三倍的意义是，老鼠有更多的丙氨酸细胞，因为子宫内的编程，更多的丙氨酸表达，因为青春期的荷尔蒙，当他们开始喝酒时，更多的丙氨酸表达。实验2将讨论实验1中所见行为背后的多肽和激素的作用。最后，研究表明妊娠期间甘油三酯（TG）升高可能是实验1中所见行为和实验2中所见生理变化的原因。食用高脂肪的食物会增加怀孕公鼠的TG，从而导致幼崽的TG升高。TG的升高会增加脂肪刺激肽的表达，从而导致过量饮酒。我们的实验室发现，与对照组相比，食用高果糖玉米糖浆的动物的甘油三酯水平明显升高。因此（实验3），高果糖饮食可能导致后代酒精摄入量增加。产前饮食摄入对酒精消费的转化意义是巨大的。在当前的“快餐”文化中，母亲们可能会给孩子养成酗酒的习惯。通过了解酒精倾向行为的因果关系和机制，我们将能够更好地建议最佳的产前护理，以及对酒精倾向个体的预防和治疗。

DESCRIPTION (provided by applicant): Recent studies indicate that excessive fat intake by pregnant dams can lead to offspring that exhibit hyperlipidemia, increased food intake, preference for fat, and higher body weight. These long-term physiological and behavioral changes are driven, in part, by increased postnatal neurogenesis of galanin- expressing cells and expression of peptides that stimulate the intake of fat. These same peptides have been linked to increased alcohol intake. It follows, therefore, that these hypothalamic changes in the offspring of fat- consuming dams might create an avidity for alcohol. Here, we propose to study the effects on prenatal exposure to high-fat diet on alcohol consumption in the offspring. This will be done by (Exp.1) replicating preliminary results indicating that adolescent females, with prenatal exposure to a high-fat diet, consume significantly more alcohol than controls. This finding will be extended to males and adult offspring. Profiling age and sex specific trends in alcohol intake among animals born to fat-consuming mothers will allow us to characterize a new animal model of alcohol preferring rat. Once we have characterized this behavioral model, we will (Exp. 2) explore aberrations in peptides and sex hormones that might be driving the phenomena. We know of a neural circuit that evolved with the capability to augment fat intake; moreover, it can be co-opted by alcohol. It is also clear that drinking ethanol can increase expression of the peptides in this circuit. Therefore the new question is whether pups born to fat-consuming dams, and therefore growing up with additional hypothalamic cells producing elevated levels of orexigenic peptides, will stimulate expression of these peptides even further by drinking ethanol. This could create a triple threat for alcohol abuse: triple in the sense that the rats have, more galanin cells due to in utero programming, more galanin expression due to hormones at puberty and more galanin expression when they start drinking. Exp. 2 will address the roles of peptides and hormones underlying the behaviors seen in Exp. 1. Lastly, studies indicate that elevated triglycerides (TG) during gestation might be responsible for the behavior seen in Exp. 1 and the physiological changes seen in Exp. 2. Consumption of a high-fat diet raises TG in pregnant dams, which leads to elevated TG in the pups. This elevation of TG increases expression of fat-stimulating peptides that drive excessive intake of alcohol. Our laboratory finds that animals maintained on a diet with free access to high-fructose corn syrup show significantly elevated TG levels, as compared to controls. Therefore (Exp. 3), high dietary fructose might lead to elevated intake of alcohol in the offspring. The translational implications of prenatal dietary intake on alcohol consumption are vast. In the current "fast food" culture, mothers might be programming their offspring with a propensity for alcohol abuse. Through understanding the causation, as well as the mechanism of alcohol prone behavior, we will be better able to advise in optimal prenatal care, as well as prevention and treatment for alcohol-prone individuals. PUBLIC HEALTH RELEVANCE: In a new discovery, we find that a high-fat diet during pregnancy can program the female offspring to consume excessive amounts of alcohol during adolescence. In this proposal, the applicant plans to elucidate the mechanism of this fetal programming and its expression as a function of sex hormones, peptides and age, as well as comparing both females and males. Further, these findings will be applied to prenatal exposure of other common macronutrients, such as those found in high-fructose corn syrup. Understanding the cause and mechanism of gestational diet-induced, alcohol preference will improve prenatal care with the aim of preventing destructive, alcohol prone behavior in the next generation.