Maternal Overweight: Consequences for Insulin Signaling in the Offspring

描述(由申请人提供)：全球肥胖率显著上升的主要原因尚不清楚。虽然饮食结构和生活方式因素(如体力活动)无疑在决定身体组成方面起着重要作用，但母亲怀孕时的超重状况(BMI&GT；25)可能是一个关键的协同因素。在临床研究中，我们发现，在出生时体重正常的婴儿中，母亲的OW状态显著增加了6个月大时OW(即高于第95个百分位数的百分比)的风险。我们的总体目标是调查后代中肥胖环境(食用高脂肪饮食，HFD)与怀孕期间母亲先前接触OW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，受试者在受孕前复制了类似于肥胖的代谢和内分泌异常。接触母体OW对出生体重/子代大小没有影响。然而，在没有改变卡路里摄入量的情况下，当喂食高脂饮食时，来自OW母鸡的后代变得比来自相同饮食的瘦母鸡的后代肥胖的程度要大得多。OW大鼠的后代也出现了高胰岛素血症、脂肪组织肥大和造脂基因表达。根据我们的初步研究，我们假设，当喂食高脂饮食时，增加进入脂肪组织的葡萄糖流量和加速脂肪生成会导致OW DAMS后代肥胖。这项拟议的研究旨在了解在后代肥胖之前，能量平衡和胰岛素信号的潜在差异。在具体目标1中，将利用间接量热法来检查妊娠期OW是否降低了后代的能量消耗。在特定的目标2中，我们将检验这一假设，即母体OW导致子代骨骼肌胰岛素抵抗，从而增加葡萄糖在脂肪组织中的分配，脂肪生成和脂肪质量增加。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，并将揭示单个组织(骨骼肌、脂肪和肝脏)和全身葡萄糖流量的胰岛素敏感性状态。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肪生成基因的表达和从头合成脂肪的研究将在特定的目标3进行。最后，特定的目标4将在受孕前使用体力活动作为干预，并将检验这样的假设，即受孕前在OW母鼠中增加体力活动(跑步机跑步)将改善后代胰岛素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：怀孕期间母亲超重(OW)会显著增加子代OW的风险。虽然，潜在的原因尚不清楚，但使用一种新的母体OW模型，我们已经确认，出生后高脂肪饮食显著加剧了OW大鼠后代的肥胖发展。我们将检测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容易获得相对于肌肉质量更多脂肪的基础，从而导致肥胖。这些研究将阐明母体OW导致子代改变的机制，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.