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X综合征与胎儿宫内生长受限(IUGR)之间的联系。为了破译这种联系背后的机制，我们研究了骨骼肌胰岛素反应性葡萄糖转运体(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相关的两种极端的宫内代谢扰动(营养过剩与限制)，以及出生后营养修改(临时限制乳汁摄入)，观察到成人骨骼肌过剩功能的下降。这种变化是由不同的机制介导的，例如，在宫内营养过剩的情况下，通过抑制胰岛素诱导的GLUT 4转位到肌膜，在宫内营养限制的情况下，通过抑制GLUT 4的转录表达而实现的。基于现有的信息和我们的初步结果，我们假设IUGR后代的宫内代谢环境中的异常以及出生后的营养改变(随意与限制获得乳汁的机会)，并观察到成人骨骼肌GLUT 4功能的下降。这种变化是通过不同的机制来调节的，例如，在子宫内营养过剩的情况下，通过抑制胰岛素诱导的过剩到肌膜的过量转位，在子宫内营养限制的情况下，通过抑制GLUT 4的转录表达而实现的。根据已有的信息和我们的初步结果，我们假设IUGR后代宫内代谢环境的异常与出生后营养改变单独调节骨骼肌GLUT4表达、易位和功能异常的机制，从而导致成人适应不良，导致胰岛素抵抗。我们将在链脲佐菌素诱导的母体糖尿病伴IUGR和产前饥饿伴IUGR的大鼠模型中通过以下特定目的来验证这一假设。为了确定在子宫内暴露于营养过剩和出生后营养改变的成年IUGR后代中骨骼肌Glut4表达、可用性和功能的调节机制，我们将评估：a)总Glut4mRNA和蛋白质浓度；b)胰岛素诱导的Glut4从细胞内低密度微粒子到肌膜间的移位；c)某些核反式激活因子对Glut4DNA结合能力的改变(S)；D2、D21、D60和D180发育阶段的GLUT 4从LDM到PM的胰岛素转位，以及基础和胰岛素诱导的细胞松弛素B抑制了D2、D21、D60和D180发育阶段的14C-葡萄糖的转运。这些研究的结果将检验我们的假设，并描述由于出生后营养影响而修改的宫内代谢程序所涉及的改变成年IUGR骨骼肌GLUT4浓度/可用性和功能的不同机制。明确这些异常机制将有助于深入了解NIDDM的病因学。这些研究最终将成为未来发展干预策略的推动力，以便在儿童时期实施针对和预防成人疾病的干预策略。

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.