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，目前肥胖在美国的流行令人担忧。由于生命早期营养经历的改变而导致的代谢程序与肥胖和相关疾病的病因有关。我们早期的研究结果表明，高碳水化合物（HC）饮食改变会导致第一代（1-HC）大鼠的慢性高胰岛素血症和成年型肥胖（HC表型）。1-HC雌性大鼠的胎儿发育导致HC表型自发转移到后代（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。下丘脑黑素皮质素系统被认为在食欲和体重平衡的调节中起关键作用；据推测，该系统的畸变对1-HC和2-HC大鼠肥胖的发展起着重要作用。基于这一理论，Specific Aim 1假设，在大鼠出生后的神经元发育期间，对新生大鼠的HC饮食进行调整，将导致黑素皮质素系统异常，并使1- HC大鼠易患成年期肥胖。Specific Aim 2假设，1-HC雌性大鼠在不利的宫内环境（1-HC雌性大鼠代谢表型的结果）中的胎儿发育将导致2- hc后代黑素皮质素系统的编程错误，并易患成年期肥胖。Specific Aim 3假设，通过对1-HC雌性大鼠施加饮食或药物干预以减少贪食和体重增加，在正常的1-HC宫内环境中实现胎儿发育，将逆转2-HC后代的跨代效应。为了研究黑素皮质素系统异常的发展，将在1-HC和2-HC大鼠中测定(i)黑素皮质素基因表达的改变，（ii）弓形核投射的发展和（iii）对外源性瘦素的功能反应。新出生的大鼠幼崽将被人工饲养在高碳水化合物的牛奶配方中，以产生1-HC大鼠。2-HC大鼠将由1-HC雌性大鼠与正常雄性大鼠交配产生。从断奶开始，1-HC雌性大鼠将进行配对喂养和膳食补充1-硫辛酸，并监测对母鼠和后代的影响。为了研究黑素皮质素系统的改变，将在脑切片上进行原位杂交和免疫组织化学分析。这些研究的结果有望提供有价值的信息，以支持两代大鼠成年发病肥胖的机制，这些大鼠是由于在出生后立即对雌性大鼠施加高碳水化合物饮食改变而导致的，也可能逆转跨代效应。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种食物，婴儿和怀孕合并肥胖可能独立地促进肥胖的发展，这是目前在美国成人和儿童的流行病比例。我们的大鼠模型提供了一个独特的机会来研究大脑在产后和胎儿时期对成年生活中肥胖发展的编程。为预防编程错误效应而提出的干预措施可能会导致制定有效的治疗方案，以遏制人类肥胖的流行。

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.