LONG TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

新生大鼠喂食高碳水化合物（HC）牛奶配方， 哺乳期间的人工饲养系统（“杯中幼崽”模式） 高胰岛素血症持续到成年期， 肥胖高胰岛素血症/肥胖HC所生动物（第二代） 女性也会出现高胰岛素血症和肥胖症。高糖刺激 胰岛素分泌反应在HC的胰腺β细胞中改变 两代的动物。我们的长期目标是：（i）调查 特定基因改变的分子机制 转录在HC大鼠的β细胞，和（ii）调查 特定基因改变的分子机制 HC大鼠β细胞中的转录，以及（ii）研究其他品系 不同的遗传背景对这种早期的反应， 营养干预和这种“代谢”的传播 “编程”到这个后代。具体目标是：（一）调查 胰岛素基因增强的分子机制 HC大鼠胰岛中的转录（经历饮食诱导的改变） 和HC女性的后代，（ii）研究分子 负责增加这两个基因转录的机制（ 乙酰辅酶A羧化酶和丙酮酸脱氢酶α亚基基因） 其产物被认为在葡萄糖诱导的 胰岛素分泌，以及（iii）调查母体环境 导致高胰岛素血症发生的因素 高胰岛素血症HC雌性所生后代。胰岛将与 HC大鼠以及从大鼠红牛奶配方高脂肪（HF），也 自然饲养的大鼠（母鼠喂养组，MF）。实验方法 包括：转录连续测定，凝胶迁移率变动测定， 通过特异性激酶和磷酸酶修饰转录因子， 北方印迹分析，酶活性测定，双向胚胎移植 HC和MF雌性之间，饮食限制，以避免发展 肥胖症和测量血浆中的特定激素和生长因子 来自三组不同年龄的动物。这种独特的老鼠 模型有可能提供新的和重要的洞察力， 高胰岛素血症发生的分子机制 由于早期营养干预， 适应慢性高胰岛素血症环境。

Neonatal rats fed a high-carbohydrate (HC) milk formula using an artificial rearing system ("pup in a cup" model) during the suckling period experience hyperinsulinemia which persists in adult life and causes obesity. Animal (second generation) born to hyperinsulinemic/obese HC females also develop hyperinsulinemia and obesity. Glucose-stimulated insulin secretory response is altered in the pancreatic beta cells of HC animals of both generations. Our long-term goals are: (i) to investigate the molecular mechanisms responsible for alterations of specific gene transcription in beta cells of HC rat, and (ii) to investigate the molecular mechanisms responsible for alterations of specific gene transcription in beta cells of HC rat, and (ii) to study other strains with a different genetic background for their responses to this early nutritional intervention and the transmission of this "metabolic programming" to this progeny. The specific aims are: (i) to investigate the molecular mechanisms responsible for enhanced insulin gene transcription in islets of HC rats (experiencing diet-induced alterations) and the progeny of HC females, (ii) to investigate the molecular mechanisms responsible for increased transcription of the two genes (the acetyl-CoA carboxylase and pyruvate dehydrogenase alpha subunit genes) whose products are implicated to play regulatory roles in glucose-induced insulin secretion, and (iii) to investigate the maternal environmental factor(s) responsible for the development of hyperinsulinemia in the progeny born to hyperinsulinemic HC females. Islets will be isolated from HC rats as well as from rats red a milk-formula high in fat (HF) and also rats reared naturally (mother fed group, MF). Experimental approaches include: transcription run-on assay, gel mobility shift assay, modification of transcription factors by specific kinases and phosphatase, Northern blot analysis, enzyme activity assay, reciprocal embryo transfer between HC and MF females, dietary restriction to avoid the development of obesity, and measurement of specific hormones and growth factors in plasma from three different groups of animals at different ages. This unique rat model has the potential for providing new and significant insight into the molecular mechanisms responsible for the development of hyperinsulinemia due to early nutritional interventions and also on fetal pancreatic adaptations to chronic hyperinsulinemic environment.