Interrupting the Vicious Cycle of Obesity and Metabolic Syndrome

中断肥胖和代谢综合症的恶性循环

基本信息

批准号：
9985360
负责人：
Kjersti Marie Aagaard
金额：
$ 152.18万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9985360
关键词：
3 year old Address Adolescent Age Alpha Cell Anatomy Animals Anti-inflammatory Antioxidants Behavior Biological Assay Birth Brain Cardiovascular Diseases Cell Count Chronic Clinical Conceptions Consumption Counseling Coupled Data Development Diabetes Mellitus Diet Dietary Intervention Eating Energy Metabolism Ethnic Origin Event Exposure to Fatty Liver Fatty acid glycerol esters Fetus Food Energy Genetic Genomics Goals Grant Health Human In Vitro Infant Inflammation Insulin Resistance Interruption Intervention Intervention Trial Investigation Knowledge Lactation Life Cycle Stages Link Liver Metabolic Metabolic Diseases Metabolic dysfunction Metabolic syndrome Mitochondria Modeling Modification Molecular Molecular Target Monoclonal Antibody R24 Morphology Mothers Muscle Muscle Mitochondria Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Overweight Pancreas Pathway interactions Physiological Physiology Pregnancy Prevalence Prevention Property Puberty Publishing Race Research Resveratrol Risk Signal Transduction Skeletal Muscle Socioeconomic Status Supplementation System Techniques Testing Thinness Third Pregnancy Trimester Time Tissues Toddler Weaning Youth base body system cell growth design dietary supplements early-onset obesity epigenome epigenomics fetal follow-up gestational weight gain good diet in vivo insight islet juvenile animal liver function maternal obesity microbiome mitochondrial dysfunction mother nutrition next generation nonhuman primate obese mothers obesity development obesity risk offspring offspring obesity postnatal postnatal period public health relevance success therapy design transcriptomics

项目摘要

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.

描述（由适用提供）：在美国，孕产妇超重和肥胖的患病率不断增加，跨越了年龄，种族和种族和社会经济地位的范围。令人震惊的是，尽管在过去的十年中，前肥胖的速度已经稳定，但十分之一的婴儿和幼儿是肥胖的，而五分之一的青年则是肥胖和危险的代谢综合症，在青春期开始之前。我们的假设是，孕妇肥胖和西方风格饮食（WSD）正在损害关键代谢系统（肝脏，肌肉和胰腺）的发展，从而改变了肥胖母亲的年轻后代的细胞和分子水平的组织功能。此外，转向健康饮食的产后动物异常的持久性表明，发育变化可能会产生永久性的影响，改变了代谢结果，将早期母体肥胖症/WSD与下一代肥胖症的长期风险和2型糖尿病联系起来。对肥胖母亲出生的人类婴儿的生活课程研究，特别是在与糖尿病和肥胖有关的组织中的分子和细胞水平上，完全缺乏。在过去的十年中，我们的小组一直在发展，此后利用具有与人类至关重要的重要发展和物理相似性的母体高脂肪/热量密集的WSD消耗的精致非人类灵长类动物（NHP）模型。这笔赠款的主要重点将放在肥胖母亲的后代基于纵向的研究上，这些肥胖母亲（包括食物摄入量和能量消耗），3个关键组织的功能和形态变化：肝脏，胰腺和骨骼肌肉以及跨组织和时间的基因组事件。在AIM 1中，肥胖或精益母亲的后代将以健康的CHOW控制饮食或继续进行WSD为断奶，而随后的动物（在青春期之前）随后随后进行。为了中断这个粘性周期，消费WSD饮食的肥胖母亲将补充白藜芦醇（AIM 2），一种具有抗炎特性的抗氧化剂或基于健康的Chow饮食（AIM 3）（AIM 3）。白藜芦醇和饮食开关母亲的后代将被研究高达14个月。年龄。此类研究将提供重要的机械洞察力，即肝脏，胰腺和骨骼肌肉的产妇饮食和代谢健康的影响，适应性和产后功能如何 - 在人类中无法访问，但具有直接的临床和翻译意义，对肥胖和2型糖尿病的发展产生了影响。我们的研究继续满足对受控的机械研究的需求，以确定孕产妇肥胖症以及在与人类直接相关的模型的后代中关键代谢系统中对关键代谢系统的相对贡献。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Maternal Western-style diet and obesity during pregnancy reduces mitochondrial Complex I-linked oxidative capacity in tandem with decreased oxidative stress in skeletal muscle of adolescent Japanese macaque offspring.

母亲的西式饮食和怀孕期间的肥胖会降低线粒体复合物 I 相关的氧化能力，同时降低日本猕猴后代骨骼肌的氧化应激。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Greyslak,KeenanT;Hetrick,Byron;Carey,Kat;McCurdy,CarrieE
通讯作者：
McCurdy,CarrieE