In utero metabolic programming of the offspring

《成人疾病的围产期起源》描述了以胰岛素抵抗、肥胖、血脂异常、高血压和冠状动脉疾病为特征的成人疾病综合征X与宫内生长受限（IUGR）之间的关系。为了解释这种关联背后的机制，我们研究了骨骼肌胰岛素反应性葡萄糖转运蛋白（GLUT 4），它介导了胰岛素信号级联中的关键限速步骤。我们使用了与IUGR相关的两种子宫内极端代谢扰动（营养过剩与限制），以及产后营养改变（随意限制牛奶摄入），观察到成人骨骼肌GLUT - 4功能的下降。这种变化是由不同的机制介导的，例如，在子宫内营养过剩的情况下，胰岛素诱导的GLUT - 4转运到肌膜受到抑制，而在子宫内营养限制的情况下，GLUT - 4的转录表达减少。基于现有信息和我们的初步结果，我们假设IUGR后代的子宫内代谢环境异常以及产后营养改变（随机对照限制牛奶摄入）并观察到成年骨骼肌GLUT - 4功能的下降。这种变化是由不同的机制介导的，例如，在子宫内营养过剩的情况下，胰岛素诱导的GLUT向肌膜转运受到抑制，而在子宫内营养限制的情况下，GLUT 4的转录表达减少。基于现有信息和我们的初步结果，我们假设IUGR后代的子宫内代谢环境异常与产后营养改变调节了骨骼肌GLUT4异常表达、易位和功能的机制，从而导致成人的适应不良，从而导致胰岛素抵抗。我们将通过以下特定目的在链脲佐菌素诱导的IUGR孕妇糖尿病和IUGR产前饥饿大鼠模型中验证这一假设。在这两种情况下，后代将有自由或限制的牛奶摄入[1]，以确定在子宫内暴露于营养过剩和产后营养改变的成年IUGR后代中调节骨骼肌GLUT 4表达、可用性和功能的机制，我们将评估：a]总GLUT 4 mRNA和蛋白浓度；b]胰岛素诱导的GLUT 4从细胞内低密度微粒体转移到肌层室；c]某些核反式激活因子对glut4 dna结合性的改变；以及，d]在产前饥饿或限制母乳摄入的对照母亲的后代中，在d2， d21， d60和d180发育阶段，glut4从LDM到PM的胰岛素易位，以及基础和胰岛素诱导的细胞松弛素B抑制14C-葡萄糖运输。这些研究的结果将验证我们的假设，并描述由于产后营养影响改变的子宫内代谢程序而改变成人IUGR骨骼肌GLUT4浓度/可用性和功能的不同机制。确定这些异常机制将有助于深入了解NIDDM的病因。这些研究最终将推动未来制定干预战略，在儿童时期实施，以瞄准和预防成人疾病。

Perinatal Origins of Adult Disease describes the association between the adult disease Syndrome X characterized by insulin resistance, obesity, dyslipidemia, hypertension and coronary artery disease, and intrauterine growth restriction (IUGR). To decipher the mechanism behind this association we examined the skeletal muscle insulin responsive glucose transporter (GLUT 4), that mediates the critical rate-limiting step in the insulin signaling cascade. We used two in-utero extremes of metabolic perturbations (nutrient excess versus restriction) associated with IUGR, along with postnatal nutrient modifications (ad lib restricted access to milk intake) and observed a decline in the adult skeletal muscle GLUT 4 function. This change was mediated by divergent mechanisms, e.g., by suppression of insulin-induced GLUT 4 translocation to the sarcolemma in the case of in-utero nutrient excess and a transcriptional decrease in GLUT 4 expression in the case of in-utero nutrient restriction. Based on the available information and our preliminary results, we hypothesize that aberrations in the in-utero metabolic environment of the IUGR progeny along with postnatal nutritional modifications (ad lib versus restricted access to milk intake) and observed a decline in the adult skeletal muscle GLUT 4 function. This change was mediated by divergent mechanisms, e.g., by suppression of insulin- induced GLUT translocation to the Sarcolemma in the case of in-utero nutrient excess and transcriptional decrease in GLUT 4 expression in the case of in-utero nutrient restriction. Based on the available information and our preliminary results, we hypothesize that aberrations in the in-utero metabolic environment of the IUGR progeny alone with postnatal nutritional modifications regulate mechanisms responsible for aberrant skeletal muscle GLUT4 expression, translocation, and function which cause a maladaptation in the adult that leads to insulin resistance. We will test this hypothesis by the following specific aims in rat models of streptozotocin-induced maternal diabetes with IUGR and prenatal starvation with IUGR. In both cases the offsprings will have ad lib or restricted access to milk intake 1] to determine the mechanisms regulating skeletal muscle GLUT 4 expression, availability, and function in the adult IUGR progeny exposed in-utero to nutrient excess and postnatal nutritional modifications, we will assess: a] total GLUT 4 mRNA and protein concentrations; b] the insulin-induced translocation of GLUT 4 from the intracellular, low-density microsomes to the sarcolemmal compartment; c] the alteration(s) in GLUT 4 DNA-bindability by certain nuclear trans-activating factors; and, d] the insulin translocation of GLUT 4 from LDM to PM, and the basal and insulin-induced cytochalasin B inhibitable 14C- glucose transport at d2, d21, d60 and d180 developmental stages in the progeny of the prenatally starved or control mothers who are allowed either ad lib or restricted postnatal milk intake. The results of these investigations will test our hypothesis and characterize the divergent mechanisms involved that alter the adult IUGR skeletal muscle GLUT4 concentrations/availability and function due to an in-utero metabolic program modified by postnatal nutritional influences. Defining these aberrant mechanisms will provide insights into the etiology of NIDDM. These studies will ultimately server as an impetus for the future development of interventional strategies to implement in childhood to target and prevent adult disease.