In utero metabolic programming of the offspring

后代的子宫内代谢编程

• 批准号: 6647617
• 负责人: Sherin U Devaskar
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-05 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647617
• 关键词: developmental nutrition; disease /disorder etiology; enzyme activity; genetic transcription; gestational diabetes mellitus; glucose metabolism; glucose transport; glucose transporter; insulin sensitivity /resistance; laboratory rat; mother /embryo /fetus nutrition; phosphatidylinositol 3 kinase; prenatal growth disorder; protein biosynthesis; protein structure function; protein transport; starvation; streptozotocin; striated muscles

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.

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综合征与宫内生长受限（IUGR）之间的关联。 为了解释这种关联背后的机制，我们研究了骨骼肌胰岛素响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相关的两种宫内极端代谢紊乱（营养过剩与限制），沿着出生后营养调整（随意限制牛奶摄入），并观察到成人骨骼肌GLUT 4功能下降。 这种变化是由不同的机制介导的，例如，通过在子宫内营养过剩的情况下抑制胰岛素诱导的GLUT 4易位到肌膜和在子宫内营养限制的情况下GLUT 4表达的转录减少。 基于现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畸变与出生后营养改变（自由摄入与限制牛奶摄入）一起沿着，并观察到成人骨骼肌GLUT 4功能下降。 这种变化是由不同的机制介导的，例如，通过在子宫内营养过剩的情况下抑制胰岛素诱导的GLUT向肌膜的移位以及在子宫内营养限制的情况下GLUT 4表达的转录降低。 根据现有的信息和我们的初步结果，我们假设，胎儿宫内发育迟缓的后代在子宫内代谢环境中的畸变与出生后的营养调整调节机制负责异常骨骼肌GLUT 4的表达，易位和功能，导致适应不良，在成人中，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具体目标来检验这一假设。 在这两种情况下，后代将有自由或限制获得牛奶摄入量 1]为了确定在宫内暴露于营养过剩和出生后营养改变的成年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和蛋白质浓度; B]胰岛素诱导的GLUT 4从细胞内低密度微粒体移位到肌膜室;某些核反式激活因子改变GLUT 4 DNA结合能力;和，d] GLUT 4从LDM到PM的胰岛素易位，以及在d2，d21，在产前饥饿或对照母亲的后代中的d 60和d180发育阶段，所述对照母亲被允许随意或限制产后乳汁摄入。 这些调查的结果将测试我们的假设，并描述不同的机制，涉及改变成人IUGR骨骼肌GLUT 4浓度/可用性和功能，由于在子宫内代谢程序修改出生后的营养影响。 明确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策略，在儿童期实施，以针对和预防成人疾病。