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出现高脂血症、食物摄入量增加、偏爱脂肪和更高的体重。这些长期的生理和行为变化部分是由出生后表达甘丙肽的细胞的神经发生增加和刺激脂肪摄取的多肽的表达所推动的。这些相同的多肽与酒精摄入量的增加有关。因此，由此得出的结论是，这些消耗脂肪的母鼠后代的下丘脑变化可能会产生对酒精的嗜好。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(实验1)复制初步结果来实现，该初步结果表明，出生前接触高脂肪饮食的青春期女性比对照组摄入更多的酒精。这一发现将扩展到雄性和成年后代。分析肥胖母亲所生动物的特定年龄和性别的酒精摄入量趋势，将使我们能够描述一种新的偏爱酒精的动物模型。一旦我们描述了这种行为模型，我们将(Exp.2)探索可能驱动这一现象的多肽和性激素的异常。我们知道，一种神经回路进化出了增加脂肪摄入量的能力；而且，它可以被酒精所替代。同样清楚的是，饮用酒精可以增加该回路中多肽的表达。因此，新的问题是，如果幼崽出生在消耗脂肪的水坝上，并因此伴随着额外的下丘脑细胞产生更高水平的食欲素，是否会通过饮用酒精进一步刺激这些多肽的表达。这可能会对酗酒产生三重威胁：三倍于大鼠的感觉，更多的甘丙素细胞是由于宫内编程，更多的甘丙素表达是由于青春期的激素，以及当他们开始饮酒时更多的甘丙素表达。实验2将阐述在实验中看到的行为背后的多肽和激素的作用。1.最后，研究表明，妊娠期升高的甘油三酯(TG)可能是导致实验中出现的行为的原因。1和实验中观察到的生理变化。2.高脂饮食使孕鼠的甘油三酯升高，从而导致仔鼠的甘油三酯升高。这种甘油三酯的升高增加了脂肪刺激肽的表达，从而导致过度饮酒。我们的实验室发现，与对照组相比，自由摄入高果糖玉米糖浆的动物的甘油三酯水平显著升高。因此(实验3)，高果糖饮食可能导致子代酒精摄入量增加。产前饮食摄入对酒精消费的影响是巨大的。在目前的“快餐”文化中，母亲们可能会让她们的孩子有酗酒的倾向。通过了解酒精倾向行为的原因以及机制，我们将能够更好地为酒精倾向人群的最佳产前护理以及预防和治疗提供建议。 与公共健康相关：在一项新发现中，我们发现怀孕期间的高脂肪饮食会让雌性后代在青春期过量饮酒。在这项提案中，申请人计划阐明这种胎儿编程的机制及其作为性激素、多肽和年龄的函数的表达，并对女性和男性进行比较。此外，这些发现将应用于其他常见常量营养素的产前暴露，例如高果糖玉米糖浆中的那些营养素。了解妊娠饮食诱发酒精偏好的原因和机制将改善产前护理，目的是防止下一代破坏性的酒精倾向行为。

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.