LONG-TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

营养在儿童的发育和生长中起着非常重要的作用 哺乳动物。早期营养改变的影响 儿童时期肥胖及肥胖相关糖尿病的病因学研究 在生活中，人们对此知之甚少。我们目前的研究是基于 假设摄入高碳水化合物的配方奶粉 卡路里改变荷尔蒙和新陈代谢反应不仅在 出生后立即发生变化，但在成年后也会改变，因为 “印记”。我们已经用饲养的幼鼠验证了这一假设 在哺乳期间人为地使用高碳水化合物(HC)配方 句号。这种早期的营养干预会导致高胰岛素血症和 在哺乳期增加肝脏的脂肪生成能力。慢性 在断奶后持续的高胰岛素血症会导致 成年后肥胖的发展。我们现在建议 研究细胞早期适应性变化的机制 增殖(如胰岛细胞和脂肪细胞)和代谢 高胰岛素血症成年大鼠的适应(“印记”)。我们的四个人 具体目标和方法是：(一)审查“关键时期” (持续时间)和“门槛”的刺激，我们将不同的长度 处理和(HC)式中碳水化合物的浓度，(Ii) 探讨胰岛素分泌异常的机制(S) 在胰岛细胞中，我们将使用分离的灌流胰腺 胰岛、胰岛原代培养和培养的胰岛素瘤RINm5F细胞； 而葡萄糖介导的反应将在 丙酮酸脱氢酶α亚单位基因启动子区域，(III) 研究代谢反应改变的机制 在高胰岛素血症大鼠中，我们计划研究胰岛素受体 内源性底物的自磷酸化、磷酸化(Pp185)和 GLUT 4转运体在靶组织中的水平，以及(Iv)检查 高胰岛素血症对母体代谢环境改变的影响 它对后代的生长和“代谢印记”的影响，我们将 调查怀孕女性(对女性进行早期营养干预 他们的婴儿期)和他们的后代的长期后果。我们的老鼠 模型具有提供新的、重要的洞察 出生后早期营养体验对发育的影响 在晚年的肥胖和母体的非遗传转移 子代的“新陈代谢印记”。

Nutrition plays a very important role in the development and growth of mammals. The influence of nutritional modifications during early childhood on the etiology of obesity and obesity-related diabetes later in life is poorly understood. Our current studies are based on a hypothesis that the consumption of a formula high in carbohydrate calories alters the hormonal and metabolic responses not only in the immediate postnatal period but also alter in adulthood due to "imprinting". We have tested this hypothesis using rat pups reared artificially on a high-carbohydrate (HC) formula during the suckling period. This early nutritional intervention causes hyperinsulinemia and increases hepatic lipogenic capacity during the suckling period. Chronic hyperinsulinemia which persists int he postweaning period leads to the development of obesity later in adult life. We now propose to investigate the mechanisms responsible for early adaptive changes in cell proliferation (e.g. pancreatic islet cells and adipocytes) and metabolic adaptations ("imprinting") in hyperinsulinemic adult rats. Our four specific aims and approaches are: (i) to examine the "critical period" (duration) and "threshold" for the stimulus, we will vary the length of treatment and the concentration of carbohydrate in the (HC) formula, (ii) to investigate the mechanism(s) responsible for altered insulin secretion in pancreatic islet cells, we will use isolated perifused pancreatic islets, primary cultures of islets and cultured insulinoma RINm5F cells; and glucose-mediated responses will be studied at the level of the promoter region of the pyruvate dehydrogenase alpha subunit gene, (iii) to investigate the mechanisms responsible for altered metabolic responses in hyperinsulinemic rats, we plan to study insulin receptor autophosphorylation, phosphorylation of endogenous substrates (pp185) and Glut 4 transporter levels in target tissues, and (iv) to examine the effects of altered maternal metabolic milieu due to hyperinsulinemia and its effect on growth and "metabolic imprinting" in the progeny, we will investigate pregnant females (with early nutritional intervention in their infancy) and their progeny for long-term consequences. Our rat model has potential for providing new, significant insight into the impact of an early postnatal nutritional experience on the development of obesity later in life and also into a maternal non-genetic transfer of "metabolic imprinting" in the progeny.