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

产前接触高脂肪饮食会促进后代对酒精的偏好

• 批准号: 8320773
• 负责人: Miriam E. Bocarsly
• 金额: $ 2.69万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2013-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320773
• 关键词: Accounting; Address; Adolescence; Adolescent; Adult; Adult Children; Age; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Animals; Automobile Driving; Avidity; Behavior; Behavioral; Behavioral Model; Biological Assay; Birth; Blood; Body Weight; Cells; Consumption; Data; Diet; Dietary Component; Dietary Fats; Dietary intake; Eating; Equilibrium; Estrogens; Ethanol; Etiology; Exhibits; Exposure to; Fatty acid glycerol esters; Female; Female Adolescents; Fructose; Galanin; Gonadal Steroid Hormones; Heavy Drinking; Hormones; Hydrolysis; Hyperlipidemia; Hypertriglyceridemia; Hypothalamic structure; In Situ Hybridization; Individual; Injection of therapeutic agent; Intake; Laboratory Finding; Lead; Life; Link; Macronutrients Nutrition; Measures; Messenger RNA; Mothers; Ovarian hormone; Peptides; Physiological; Pregnancy; Prenatal care; Prevention; Production; Progesterone; Puberty; Radioimmunoassay; Rat-1; Rattus; Risk Factors; Role; Serum; Site; Steroids; System; Testing; Training; Triglycerides; Water; alcohol abuse therapy; alcohol measurement; alcohol preferring rats; alcohol seeking behavior; drinking; fast food; feeding; fetal; fetal programming; improved; in utero; male; neural circuit; neurochemistry; neurogenesis; next generation; novel; offspring; peptide hormone; postnatal; preference; pregnant; prenatal; prenatal exposure; prevent; programs; public health relevance; pup; sex; trend; underage drinking

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.

描述（由申请方提供）：最近的研究表明，妊娠母鼠摄入过量脂肪可导致后代表现出高脂血症、摄食量增加、偏爱脂肪和体重增加。这些长期的生理和行为变化部分是由甘丙肽表达细胞的出生后神经发生增加和刺激脂肪摄入的肽的表达所驱动的。这些相同的肽与酒精摄入量增加有关。因此，在消耗脂肪的母鼠的后代中，这些下丘脑的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（实验1）复制初步结果来完成，初步结果表明，产前暴露于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。分析脂肪消耗母亲所生动物的酒精摄入量的年龄和性别特异性趋势，将使我们能够描述一种新的酒精偏好大鼠动物模型。 一旦我们描述了这个行为模型，我们将（Exp。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进化出了增加脂肪摄入的能力;此外，它还可以被酒精所吸收。同样清楚的是，饮用乙醇可以增加该回路中肽的表达。因此，新的问题是，由消耗脂肪的母鼠所生的幼崽，以及因此伴随着额外的下丘脑细胞产生高水平的食欲肽而成长的幼崽，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：三重意义上的大鼠，由于子宫内编程，更多的甘丙肽细胞，青春期激素导致更多的甘丙肽表达，以及当他们开始饮酒时更多的甘丙肽表达。Exp. 2将解决的作用，肽和激素的基础上看到的行为实验。1. 最后，研究表明，妊娠期间甘油三酯（TG）升高可能是实验中观察到的行为的原因。1和实验中观察到的生理变化。2.高脂肪饮食的消费增加了妊娠母鼠的TG，这导致了幼崽的TG升高。这种TG的升高增加了脂肪刺激肽的表达，从而导致过量摄入酒精。我们的实验室发现，与对照组相比，保持饮食自由获得高果糖玉米糖浆的动物显示出显着升高的TG水平。因此（Exp。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影响是巨大的。在当前的“快餐”文化中，母亲可能会给后代设定酗酒的倾向。通过了解原因，以及酒精倾向行为的机制，我们将能够更好地建议在最佳的产前护理，以及预防和治疗酒精倾向的个人。 公共卫生相关性：在一项新的发现中，我们发现怀孕期间的高脂肪饮食会使女性后代在青春期摄入过量的酒精。在该提案中，申请人计划阐明这种胎儿编程的机制及其作为性激素、肽和年龄的函数的表达，以及比较雌性和雄性。此外，这些发现将应用于产前暴露于其他常见的常量营养素，例如在高果糖玉米糖浆中发现的常量营养素。了解妊娠期饮食诱导的酒精偏好的原因和机制将改善产前护理，目的是防止下一代的破坏性酒精倾向行为。

项目成果

Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa.

• DOI: 10.1016/j.neuropharm.2011.11.010
• 发表时间: 2012-07
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Avena NM;Bocarsly ME
• 通讯作者: Bocarsly ME