Maternal Overweight: Consequences for Insulin Signaling in the Offspring

描述（由申请人提供）：全球肥胖人数显著上升的主要原因尚不清楚。虽然饮食组成和生活方式因素（如体育活动）无疑在决定身体组成方面起着重要作用，但怀孕时母亲超重（OW）状态（BMI bbb25）可能是一个关键的协同因素。在临床研究中，我们发现，在出生体重正常的婴儿中，母亲OW状态显著增加6月龄时OW的风险（即高于第95百分位数的百分比）。我们的总体目标是研究后代在肥胖环境（高脂肪饮食，HFD）和妊娠期间母体OW暴露之间的相互作用。为此，我们开发了一种大鼠模型，在该模型中，在受孕之前复制了与人类肥胖相似的代谢和内分泌异常。暴露于母亲OW不影响后代的出生体重/大小。然而，在热量摄入没有变化的情况下，喂食高脂肪食物的胖鼠后代比喂食同样食物的瘦鼠后代肥胖的程度要大得多。OW大鼠后代也出现高胰岛素血症、脂肪组织肥大和增脂基因表达。根据我们的初步研究，我们假设当喂食高脂食物时，进入脂肪组织的葡萄糖通量增加和脂肪生成加速导致OW公鼠后代肥胖。拟议的研究旨在了解后代肥胖发展之前能量平衡和胰岛素信号的潜在差异。在具体目标1中，间接量热法将用于检查妊娠期OW是否会降低后代的能量消耗。在具体目标2中，我们将验证母体OW导致后代骨骼肌胰岛素抵抗的假设，从而增加葡萄糖分配到脂肪组织，脂肪生成和脂肪堆积。这将通过使用标记示踪剂的高胰岛素-正血糖钳夹实验来解决，并将揭示个体组织（骨骼肌、脂肪和肝脏）和全身葡萄糖通量中的胰岛素敏感性状态。研究通过IR-PI3K-Akt检测脂肪组织对胰岛素信号的反应性，以增加脂质基因表达和新生脂质合成，并将在Specific Aim 3中进行。最后，具体目标4将采用受孕前的身体活动作为干预措施，并将测试怀孕前增加的身体活动（跑步机跑步）可以改善后代胰岛素敏感性和减轻脂肪组织合成代谢增加的假设。总的来说，这些研究将阐明受母体OW和高脂肪饮食影响的后代的重要代谢机制，这可能有助于增加对肥胖的易感性。公共卫生相关性：怀孕期间母亲超重（OW）显著增加后代患OW的风险。虽然潜在的原因尚不清楚，但利用一种新的大鼠母性OW模型，我们已经发现，产后高脂肪饮食显著加剧了OW大鼠后代的肥胖发展。我们将研究OW后代脂肪组织中葡萄糖通量和脂肪合成的变化。这些机制可能是后代相对于肌肉质量获得更多脂肪的倾向的基础，从而导致肥胖。这些研究将阐明由于母亲OW而改变后代的机制，并为干预和预防肥胖提供新的机会。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Maternal overweight (OW) during pregnancy significantly increases the risk of OW in the offspring. While, the underlying reasons remain unclear, using a new model of maternal OW in the rat, we have identified that, post-natal high-fat diets significantly exacerbate development of obesity in offspring of OW rats. We will examine changes in glucose flux and the synthesis of fat in the adipose tissues of OW offspring. These mechanisms may underlie the predisposition of the offspring to gain more fat relative to muscle mass, leading to obesity. These studies will elucidate mechanisms that are altered in the offspring due to maternal OW and provide novel opportunities for intervention and prevention of obesity.