LONG-TERM METABOLIC CONSEQUENCES OF EARLY NUTRITIONAL MODIFICATION

营养在动物的发育和生长中起着非常重要的作用。 哺乳动物 营养调整对早期妊娠的影响 儿童期肥胖的病因与肥胖相关的糖尿病后期 在生活中，人们知之甚少。 我们目前的研究是基于 假设食用高碳水化合物的配方奶粉 卡路里不仅改变了体内的激素和代谢反应， 但在成年期也会发生变化， “印记”。 我们已经用一只被饲养的幼鼠来验证这个假设， 在哺乳期间人工使用高碳水化合物（HC）配方奶 期 这种早期营养干预会导致高胰岛素血症， 在哺乳期增加肝脏脂肪生成能力。 慢性 断奶后持续的高胰岛素血症导致 成年后肥胖症的发展。 我们现建议 研究细胞早期适应性变化的机制， 增殖（例如胰岛细胞和脂肪细胞）和代谢 适应（“印记”）在高胰岛素血症的成年大鼠。 我们的四 具体目标和方法是：㈠审查“关键时期” （持续时间）和“阈值”的刺激，我们将不同的长度， 处理和（HC）配方中碳水化合物的浓度，（ii） 研究胰岛素分泌改变的机制 在胰岛细胞中，我们将使用离体灌流的胰腺 胰岛、胰岛的原代培养物和培养的胰岛素瘤RINm 5 F细胞; 和葡萄糖介导的反应将在水平上进行研究， 丙酮酸脱氢酶α亚基基因的启动子区，（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， 自磷酸化，内源性底物的磷酸化（pp 185）和 Glut 4转运蛋白在靶组织中的水平，以及（iv）检查靶组织中的Glut 4转运蛋白水平。 高胰岛素血症引起的母体代谢环境改变的影响 它对后代生长和“代谢印记”的影响，我们将 调查孕妇（早期营养干预， 他们的孩子，他们的孩子。 我们的老鼠 模型有潜力提供新的，重要的洞察力， 出生后早期营养经验对发育的影响 肥胖的风险也会转化为母亲的非基因转移 “代谢印记”的影响。

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.