Interrupting the Vicious Cycle of Obesity and Metabolic Syndrome

 描述（由申请人提供）：在美国，孕产妇超重和肥胖的患病率持续增加，并且跨越年龄、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保持稳定，但十分之一的婴儿和幼儿肥胖，五分之一的青年在青春期开始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）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的年轻后代的组织功能。此外，出生后转为健康饮食的动物中异常的持续存在表明，发育变化可能具有改变代谢结果的永久性影响，将早期母体肥胖/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，特别是在与糖尿病和肥胖相关的组织中的分子和细胞水平上的研究，是完全缺乏的。在过去的十年中，我们的团队开发并利用了一种复杂的非人类灵长类动物（NHP）模型，该模型与人类具有至关重要的发育和生理相似性。这项资助的主要重点将是对肥胖母亲的后代进行详细的纵向调查，重点是青少年生理学（包括食物摄入和能量消耗），3个关键组织的功能和形态变化：肝脏，胰腺和骨骼肌，沿着组织和时间的基因组事件。在目标1中，肥胖或瘦型母亲的后代将断奶至健康的基于咀嚼物的对照饮食或继续WSD，并且动物随访至3岁（刚好在青春期之前）。为了中断这种粘性循环，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，或健康的食物饮食（Aim 3）。白藜芦醇和饮食转换母亲的后代将被研究长达14个月。年龄。这些研究将提供重要的机制见解，了解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，适应性和产后功能-这些组织在人类中无法获得，但对肥胖和2型糖尿病的发展具有直接的临床和转化意义。我们的研究继续解决需要控制，机制研究，以确定母体肥胖和断奶前和断奶后的饮食暴露对关键代谢系统的模型直接相关的后代的各自的贡献。

 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.