Maternal Hyperinsulinemia and Fetal Programming

描述(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。由于生命早期营养体验的改变而导致的代谢编程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，新生大鼠的高碳水化合物(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雌性大鼠的胚胎发育导致HC表型自发地传递给后代(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调节食欲和体重动态平衡方面起着关键作用，推测该系统的异常在1-HC和2-HC大鼠肥胖的发生中起重要作用。基于这一原理，《特定目的1》假设，新生大鼠的HC饮食改变与大鼠出生后神经元发育时期重叠，将导致黑素皮质素系统的异常，并将使1-HC大鼠容易患上成年肥胖症。特定目的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子代的黑素皮质素系统编程错误，并容易发生成年肥胖症。具体目标3假设，通过对1-HC雌性大鼠实施饮食或药物干预以减少过度吞噬和体重增加，在正常化的1-HC宫内环境中实现的胎儿发育将逆转2-HC后代的跨代效应。为了研究黑素皮质素系统的异常发展，将在1-HC和2-HC大鼠中测定以下变化：(1)黑素皮质素基因的表达；(2)弓状核投射的发育；(3)外源性瘦素的功能反应。新生的小鼠将被人工饲养在高碳水化合物奶粉中，以产生1-HC大鼠。将1-HC雌性大鼠与正常雄性大鼠杂交产生2-HC大鼠。从断奶时起，1-HC雌性大鼠将强制进行配对喂养和补充1-硫辛酸，并对母亲和子代的后果进行监测。为了研究黑素皮质素系统的变化，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，支持两代大鼠成年后肥胖的规划，因为雌性大鼠出生后立即接受高碳水化合物饮食修改，并可能逆转跨代影响。这项拟议研究的结果可能对人类在婴儿期改变饮食习惯有一定的影响。公共卫生相关性：及早为婴儿和怀孕合并肥胖的婴儿提供第一种食物可能独立地促进肥胖的发展，肥胖在美国成年人和儿童中以流行的比例存在。我们的大鼠模型提供了一个独特的机会来研究大脑在出生后和胎儿时期的编程，以促进成年后肥胖的发展。为防止程序编制不当影响而提出的干预措施可能导致制定有效的治疗选择，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.