Maternal Hyperinsulinemia and Fetal Programming

描述（由申请人提供）：由于与肥胖相关的临床并发症，目前美国的肥胖流行是一个令人担忧的问题。由于生命早期营养经验的改变而导致的代谢程序化与肥胖和相关疾病的病因学有关。我们早期的研究结果表明，高碳水化合物（HC）的饮食改变新生大鼠的慢性高胰岛素血症和成年发病肥胖（HC表型）的第一代（1-HC）大鼠。1-HC雌性大鼠的胎仔发育导致HC表型自发转移至后代（2-HC大鼠）（跨代效应）。这项拨款提案的重点是研究支持1-HC和2-HC大鼠肥胖发展的机制。下丘脑黑皮质素系统被认为在调节食欲和体重稳态中起关键作用;假设该系统中的畸变显著促进1-HC和2-HC大鼠肥胖的发展。基于这一基本原理，特定目标1假设新生大鼠幼仔的HC饮食改变与大鼠的出生后神经元发育期重叠，将导致黑皮质素系统异常，并使1- HC大鼠易于发生成年型肥胖。特定目的2假设1-HC雌性大鼠在不利的宫内环境中的胎儿发育（1-HC雌性大鼠代谢表型的结果）将导致2-HC后代中黑皮质素系统编程不良和成年型肥胖的易感性。具体目的3假设，通过对1-HC雌性大鼠实施饮食或药物干预以减少摄食过多和体重增加，在正常化1-HC宫内环境中实现的胎仔发育将逆转2-HC后代的跨代效应。为了研究黑皮质素系统中异常的发展，将在1-HC和2-HC大鼠中测定（i）黑皮质素基因的表达、（ii）弓状核投射的发展和（iii）对外源性瘦素的功能反应的改变。新生大鼠幼仔将使用高碳水化合物配方奶人工饲养，以生成1-HC大鼠。将通过1-HC雌性大鼠与正常雄性大鼠交配产生2-HC大鼠。从断奶时起，将对1-HC雌性大鼠实施配对喂养和1-硫辛酸膳食补充，并将监测对母体和子代的影响。为了研究黑皮质素系统的改变，将在脑切片中进行原位杂交和免疫组织化学分析。这些研究的结果预计将提供有价值的信息，机制，支持编程的成年发病肥胖症在两代大鼠由于高碳水化合物饮食的修改强加于雌性大鼠在其出生后的生活，也可能逆转的跨代效应。拟议研究的结果可能对婴儿期人类饮食习惯的改变有影响。公共卫生相关性：早期引入婴儿的第一食物，婴儿和妊娠合并肥胖症可能独立地导致肥胖症的发展，这在美国的成人和儿童中以流行病的比例存在。我们的大鼠模型提供了一个独特的机会，以调查在出生后和胎儿时期的大脑编程，在成年后的肥胖发展。为预防编程不良效应而提出的干预措施可能会导致开发有效的治疗方案，以遏制人类肥胖症的流行。

DESCRIPTION (provided by applicant): The current obesity epidemic in the United States is a source of concern due to the clinical complications associated with obesity. Metabolic programming due to altered nutritional experiences in early periods of life is implicated in the etiology of obesity and related disorders. Our earlier results showed that a high carbohydrate (HC) dietary modification in new born rats results in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) in first generation (1-HC) rats. Fetal development in the 1-HC female rats results in spontaneous transfer of the HC phenotype to the offspring (2-HC rats) (transgenerational effect). The focus of this grant proposal is to investigate mechanisms supporting the development of obesity in 1-HC and 2-HC rats. The hypothalamic melanocortin system is considered to play a critical role in the regulation of appetite and body weight homeostasis; it is hypothesized that aberrations in this system contribute significantly towards the development of obesity in 1-HC and 2-HC rats. Based on this rationale, Specific Aim 1 hypothesizes that the HC dietary modification in new born rat pups overlapping with the period of postnatal neuronal development in the rat will result in abnormalities in the melanocortin system and will predispose 1- HC rats for adult-onset obesity. Specific Aim 2 hypothesizes that fetal development in the adverse intrauterine environment (a consequence of the metabolic phenotype of the 1-HC female rat) in the 1-HC female rat will result in malprogramming of the melanocortin system in the 2-HC offspring and predisposition to adult-onset obesity. Specific Aim 3 hypothesizes that fetal development in the normalized 1-HC intrauterine environment, achieved by dietary or pharmacological interventions imposed on 1-HC female rats to reduce hyperphagia and body weight gain, will reverse the transgenerational effect for 2-HC offspring. To investigate the development of abnormalities in the melanocortin system, alterations in (i) the expression of the melanocortin genes, (ii) the development of arcuate nucleus projections and (iii) the functional responses to exogenous leptin will be determined in 1-HC and 2-HC rats. New born rat pups will be artificially reared on a high carbohydrate milk formula for generation of 1-HC rats. 2-HC rats will be generated by breeding 1-HC female rats with normal male rats. Pair-feeding and dietary supplementation with 1-lipoic acid will be enforced in the 1-HC female rats from the time of weaning and consequences for both the mother and the progeny will be monitored. For investigation of alterations in the melanocortin system, in situ hybridization and immunohistochemical analyses will be carried out in brain sections. The results from these studies are expected to provide valuable information on the mechanisms that support programming for adult-onset obesity in two generations of rats due to a high carbohydrate dietary modification imposed on the female rats in their immediate postnatal life and also on the possible reversal of the transgenerational effect. The results from the proposed studies may have implications for the altered dietary practices in humans during infancy. PUBLIC HEALTH RELEVANCE: Early introduction of babies' first foods for infants and pregnancy complicated with obesity may independently contribute to the predisposition for development of obesity which is present in epidemic proportions in adults and children in the United States. Our rat model presents a unique opportunity to investigate the programming of the brain during the immediate postnatal and fetal periods for the development of obesity in adult life. Intervention measures proposed for the prevention of the malprogramming effects may lead to development of effective treatment options for curbing the human obesity epidemic.