Maternal Overweight: Consequences for Insulin Signaling in the Offspring

描述（由申请人提供）：全球肥胖症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，如体力活动无疑在决定身体组成中具有重要作用，但怀孕时的母亲超重（OW）状态（BMI > 25）可能是一个关键的协同因素。在临床研究中，我们发现母亲的OW状态显著增加了出生体重正常的婴儿在6个月龄时OW的风险（即高于第95百分位数的百分比）。我们的总体目标是调查后代的相互作用，肥胖的环境（消费的高脂肪饮食，HFD）和先前暴露于母体OW妊娠期间。为此，我们开发了一种大鼠模型，在该模型中，在人类受试者中类似于肥胖的代谢和内分泌异常在受孕前重现。暴露于母体OW不会影响后代的出生体重/大小。然而，OW母鼠的后代在喂食HFD时，与相同饮食的瘦母鼠的后代相比，肥胖程度要大得多，而热量摄入量没有变化。OW大鼠的后代也出现高胰岛素血症、脂肪组织肥大和脂肪生成基因表达。基于我们的初步研究，我们假设，当喂食HFD时，增加的葡萄糖流入脂肪组织和加速的脂肪生成导致OW母鼠的后代肥胖。拟议的研究旨在了解后代肥胖症发生前能量平衡和胰岛素信号传导的潜在差异。在特定目标1中，将使用间接热量测定法检查妊娠期OW是否降低后代的能量消耗。在具体目标2中，我们将检验母体OW导致后代骨骼肌胰岛素抵抗，从而增加葡萄糖分配到脂肪组织、脂肪生成和脂肪量增加的假设。这将通过使用标记示踪剂的高胰岛素-正常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）中的胰岛素敏感性状态和全身葡萄糖通量。将在特定目标3中进行研究，检查脂肪组织对胰岛素信号传导（通过IR-PI 3 K-Akt）的反应性，以增加脂肪生成基因表达和从头脂质合成。最后，具体目标4将采用受孕前的体力活动作为干预措施，并将检验以下假设：受孕前OW母鼠增加体力活动（跑步机跑步）将改善后代胰岛素敏感性并减轻脂肪组织增加。总体而言，这些研究将阐明母亲OW和高脂肪饮食改变后代的重要代谢机制，这可能有助于增加肥胖的易感性。公共卫生相关性：孕妇在怀孕期间超重（OW）会显著增加后代患OW的风险。虽然根本原因尚不清楚，但使用大鼠中的母体OW的新模型，我们已经确定，出生后高脂肪饮食显著加剧了OW大鼠后代肥胖的发展。我们将研究葡萄糖流量的变化和脂肪的合成在脂肪组织的OW后代。这些机制可能是后代倾向于获得更多脂肪相对于肌肉质量，导致肥胖。这些研究将阐明由于母体OW而在后代中改变的机制，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.