Maternal Overweight: Consequences for Insulin Signaling in the Offspring

摘要：全球肥胖率显著上升的主要原因尚不清楚。同时，节食 组成和生活方式因素，如体力活动，无疑在决定 怀孕时的身体成分、母亲超重状态(BMI&GT；25)可能是一个关键的协同作用 因素。在临床研究中，我们发现母亲的OW状态显著增加了OW的风险(即以上百分比 第95个百分位数)在6个月大时，出生体重正常的婴儿。我们的总体目标是 调查后代在肥胖环境(食用高脂肪饮食， Hfd)和孕期母体暴露于OW。为此，我们开发了一种大鼠模型 在人类受试者中，哪些代谢和内分泌异常类似于肥胖 受孕。接触母体OW对出生体重/子代大小没有影响。然而，来自 现在，喂食HFD的母鸡变得肥胖的程度比喂食瘦弱母鸡的后代要严重得多. 同样的饮食，没有改变卡路里的摄入量。OW大鼠的后代也出现了高胰岛素血症， 脂肪组织肥大，并有成脂基因表达。根据我们的初步研究，我们 假设进入脂肪组织的葡萄糖流量增加和脂肪生成加速会导致肥胖 当喂食HFD时OW母鸡的后代。拟议的研究旨在了解潜在的 子代肥胖发生前能量平衡和胰岛素信号的差异。在……里面 具体目标1，间接量热法将被用来检查怀孕期间的OW是否降低了能量消耗 在后代身上。在特定目标2中，我们将检验母体OW导致骨骼肌的假设 后代的胰岛素抵抗，从而增加葡萄糖分配到脂肪组织，脂肪生成 和脂肪团块堆积。这将通过高胰岛素-正常血糖钳夹实验来解决，使用 标记的示踪剂，并将揭示单个组织(骨骼肌、脂肪)的胰岛素敏感性状态 和肝脏)和全身葡萄糖流量。检测脂肪组织对胰岛素反应性的研究 通过IR-PI3K-Akt信号通路增加生脂基因表达和从头合成脂质，并将 在特定目标3中执行。最后，特定目标4将在受孕前进行体力活动 干预并将检验OW大坝中增加体力活动(跑步机跑步)的假设 怀孕前将改善后代对胰岛素的敏感性，并缓解脂肪组织合成代谢的增加。 总体而言，这些研究将阐明母体OW改变子代的重要代谢机制 以及高脂肪饮食，这可能会增加肥胖的易感性。

Abstract: The major reasons underlying the remarkable global rise in obesity remain unclear. While, diet composition and life-style factors such as physical activity undoubtedly have important roles in determining body composition, maternal overweight (OW) status ( BMI > 25) at conception may be a critical synergizing factor. In clinical studies, we found that maternal OW status significantly increased risk of OW (i.e. the % above the 95th percentile) at 6 months of age, in infants born with normal body weights. Our overall objective is to investigate interactions in the offspring, between an obesegenic environment (consumption of a high-fat diet, HFD) and prior exposure to maternal OW during gestation. To this end, we have developed a rat model in which metabolic and endocrine abnormalities akin to obesity in human subjects were reproduced prior to conception. Exposure to maternal OW did not influence birth weight/size of offspring. However, offspring from OW dams when fed a HFD became obese to much greater extent compared to offspring from lean dams on the same diet, without changes in caloric intake. Offspring of OW rats also developed hyperinsulinemia, adipose tissue hypertrophy and showed lipogenic gene expression. Based on our preliminary studies, we hypothesize that increased glucose flux into adipose tissue and accelerated lipogenesis causes obesity in the offspring of OW dams when fed a HFD. The proposed studies are aimed at understanding the underlying differences in energy balance and insulin signaling prior to the development of obesity in the offspring. In Specific Aim 1, indirect calorimetry will be utilized to examine if gestational OW decreases energy expenditure in the offspring. In Specific Aim 2, we will test the hypothesis that maternal OW leads to skeletal muscle insulin resistance in the offspring, consequently increasing glucose partitioning into adipose tissue, lipogenesis and fat mass accretion. This will be addressed via hyperinsulinemic-euglycemic clamp experiments using labeled tracers, and will reveal the status of insulin sensitivity in the individual tissues (skeletal muscle, adipose and liver) and whole-body glucose flux. Studies examining responsiveness of adipose tissue to insulin signaling via IR-PI3K-Akt to increase lipogenic gene expression and de novo lipid synthesis and will be performed in Specific Aim 3. Finally, Specific Aim 4 will employ physical activity prior to conception as an intervention and will test the hypothesis that increased physical activity (treadmill running) in the OW dams prior to conception will improve offspring insulin sensitivity and mitigate increased adipose tissue anabolism. Overall, these studies will elucidate important metabolic mechanisms in the offspring altered by maternal OW and high-fat diets, which may contribute to increased susceptibility to obesity.