LONG TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

新生大鼠喂食高碳水化合物(HC)配方奶粉 哺乳过程中的人工饲养系统(“杯中幼崽”模式) 持续在成人生活中的高胰岛素血症时期及其原因 肥胖。高胰岛素血症/肥胖HC所生动物(第二代) 女性还会患上高胰岛素血症和肥胖。葡萄糖刺激 HC胰岛β细胞的胰岛素分泌反应发生改变 两个世代的动物。我们的长期目标是：(一)调查 特异性基因改变的分子机制 在HC大鼠的β细胞中转录，以及(Ii)研究 特定基因改变的分子机制 在HC大鼠的β细胞中转录，以及(Ii)研究其他菌株 有不同的遗传背景，它们对这种早期的反应 营养干预和这种“新陈代谢”的传播 编程。具体目标是：(I)调查 胰岛素基因增强的分子机制 HC大鼠胰岛转录(经历饮食诱导的改变) 和HC雌体的后代，(II)分子研究 导致这两个基因转录增加的机制( 乙酰辅酶A羧基酶和丙酮酸脱氢酶α亚单位基因) 谁的产物被认为在葡萄糖诱导的过程中发挥调节作用 胰岛素分泌，以及(Iii)调查产妇的环境 高胰岛素血症的发病因素(S) 高胰岛素血症HC雌性所生的后代。小岛将与 HC大鼠以及来自大鼠的高脂配方奶粉(HF)和 自然饲养大鼠(母饲组，MF)。实验方法 包括：转录运行试验、凝胶迁移率改变试验、 通过特定的激酶和磷酸酶修饰转录因子， Northern印迹分析、酶活性分析、相互胚胎移植 在HC和MF女性之间，限制饮食以避免发生 肥胖与血浆中特定激素和生长因子的测定 来自三组不同年龄的动物。这只独特的老鼠 模型有可能为我们提供对 高胰岛素血症发生的分子机制 由于早期的营养干预以及对胎儿胰腺的影响 对慢性高胰岛素环境的适应。

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.