Maternal Overweight: Consequences for Insulin Signaling in the Offspring

翻译后摘要：显着的全球肥胖症的上升的主要原因仍不清楚。同时，饮食 成分和生活方式因素，如身体活动，无疑在决定 身体组成，怀孕时的母亲超重（OW）状态（BMI > 25）可能是一个关键的协同作用， 因子在临床研究中，我们发现母亲的OW状态显著增加了OW的风险（即， 第95百分位数），出生时体重正常的婴儿。我们的总体目标是 研究后代中的相互作用，在致肥胖环境（高脂肪饮食的消耗， HFD）和妊娠期间母体OW的既往暴露。为此，我们开发了一种大鼠模型， 在人类受试者中类似于肥胖的代谢和内分泌异常在 受孕暴露于母体OW不会影响后代的出生体重/大小。然而，来自 OW母鼠在喂食HFD后，与瘦母鼠的后代相比， 同样的饮食，不改变热量摄入。OW大鼠的后代也出现高胰岛素血症， 脂肪组织肥大并显示脂肪生成基因表达。根据我们的初步研究， 假设增加的葡萄糖流入脂肪组织和加速的脂肪生成导致肥胖， 当喂食HFD时，OW母鼠的后代。拟议的研究旨在了解潜在的 在后代肥胖症发展之前，能量平衡和胰岛素信号传导的差异。在 具体目标1，将使用间接热量测定法检查妊娠期OW是否降低能量消耗 在后代中。在具体目标2中，我们将检验母体OW导致骨骼肌 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 和脂肪量增加。这将通过高胰岛素-正常血糖钳夹实验来解决， 标记的示踪剂，并将揭示在各个组织（骨骼肌，脂肪 和肝脏）和全身葡萄糖通量。检查脂肪组织对胰岛素反应性的研究 通过IR-PI 3 K-Akt信号传导以增加脂肪生成基因表达和从头脂质合成，并且将 具体目标3。最后，具体目标4将在受孕前进行身体活动， 干预，并将测试的假设，增加身体活动（跑步机运行）在OW大坝 将改善后代胰岛素敏感性并减轻脂肪组织的增加。 总之，这些研究将阐明母体OW改变后代的重要代谢机制 和高脂肪饮食，这可能会增加对肥胖的易感性。

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.