Interrupting the Vicious Cycle of Obesity and Metabolic Syndrome

 描述(由申请者提供)：在美国，母亲超重和肥胖的流行率继续上升，并跨越了年龄、种族和民族以及社会经济地位的范围。令人担忧的是，尽管青春期前肥胖率在过去十年中已经稳定下来，但每10个婴儿和蹒跚学步的儿童中就有1人肥胖，每5个年轻人中就有1人在青春期开始之前既肥胖又有患代谢综合征的风险。我们的假设是，母亲肥胖和西式饮食(WSD)正在对关键代谢系统(肝脏、肌肉和胰腺)的发育造成损害，从而在细胞和分子水平上改变肥胖母亲年轻后代的组织功能。此外，转变为健康饮食的出生后动物持续存在的异常表明，发育变化可能具有改变代谢结果的永久性影响，将早期母亲肥胖/WSD与下一代肥胖和2型糖尿病的长期风险联系起来。对肥胖母亲所生婴儿的生命过程研究，特别是与糖尿病和肥胖相关的组织的分子和细胞水平的研究，完全缺乏。在过去的十年里，我们团队一直在开发并使用一种复杂的非人类灵长类(NHP)模型，即母亲高脂肪/高热量密集WSD消费模型，该模型与人类在发育和生理上具有至关重要的相似之处。这笔赠款的主要重点将是对肥胖母亲的后代进行详细的纵向调查，重点是青少年生理(包括食物摄入量和能量消耗)、肝脏、胰腺和骨骼肌三个关键组织的功能和形态变化，以及跨组织和时间的基因组事件。在目标1中，肥胖或苗条母亲的后代将被断奶，以健康的食物为基础的控制饮食或持续的WSD，并对动物进行跟踪，直到3岁(恰好在青春期之前)。为了打破这种粘性循环，食用WSD饮食的肥胖母亲将在怀孕前补充白藜芦醇(Aim 2)，一种具有抗炎特性的抗氧化剂，或健康的以食物为基础的饮食(Aim 3)。白藜芦醇和改变饮食的母亲的后代将被研究长达14个月。年纪大了。这样的研究将为母亲的饮食和代谢健康如何影响肝脏、胰腺和骨骼肌的发育、适应性和出生后功能提供重要的机械论见解--这些组织在人类是无法获得的，但对肥胖和2型糖尿病的发展具有直接的临床和翻译意义。我们的研究继续解决受控机械性研究的需要，以确定母亲肥胖以及断奶前后饮食暴露对与人类直接相关的模型后代关键代谢系统的各自贡献。

 DESCRIPTION (provided by applicant): The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, although the rate of preadolescent obesity has stabilized over the last decade, 1 in 10 infants and toddlers are obese, and 1 in 5 youth are both obese and at-risk for metabolic syndrome prior to the onset of puberty. Our hypothesis is that maternal obesity and Western Style Diets (WSD) are causing damage to the development of key metabolic systems (liver, muscle and pancreas) thereby altering tissue function at the cellular and molecular level in young offspring of obese mothers. Furthermore, the persistence of abnormalities in postnatal animals switched to a healthy diet suggests that the developmental changes may have permanent effects that alter metabolic outcomes, linking early maternal obesity/WSD to long term risk for obesity and type 2 diabetes in the next generation. Life-course studies in human infants born to obese mothers, particularly at the molecular and cellular level in tissues relevant to diabetes and obesity, are completely lacking. Our group has spent the past decade developing and thereafter utilizing a sophisticated Non-Human Primate (NHP) model of maternal high fat/caloric dense WSD consumption that has critically important developmental and physiological similarities to humans. The major focus of this grant will be on detailed longitudinal based investigations in the offspring of obese mothers focusing on juvenile physiology (including food intake and energy expenditure), functional and morphological changes in 3 key tissues: liver, pancreas, and skeletal muscle, along with genomic events across tissues and time. In Aim 1 offspring of obese or lean mothers will be weaned to healthy chow-based control diet or continued WSD, and animals followed up to 3 years of age (just prior to puberty). To interrupt this viscous cycle, obese mothers consuming a WSD diet will be supplemented with Resveratrol (Aim 2), an antioxidant with anti-inflammatory properties, or a healthy chow based diet (Aim 3) just prior to conception. The offspring of both resveratrol and diet-switched mothers will be studied up to 14 mo. of age. Such studies will provide important mechanistic insights into how maternal diet and metabolic health impact development, adaptability and postnatal function of the liver, pancreas, and skeletal muscle--tissues that are inaccessible in humans, but with direct clinical and translational implications for the development of obesity and type 2 diabetes. Our studies continue to address the need for controlled, mechanistic studies to identify the respective contributions of maternal obesity and pre- and post-weaning diet exposures on key metabolic systems in offspring of a model directly relevant to humans.