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Adipose Mitochondial Quality Control and Cardiovascular Function in Metabolically Healthy and Unhealthy Obese Monkeys

代谢健康和不健康肥胖猴的脂肪线粒体质量控制和心血管功能

基本信息

批准号：
10541816
负责人：
Kylie Kavanagh
金额：
$ 66.87万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541816
关键词：
3 year old Address Adipose tissue Adolescent Adult African Green Monkey Animal Model Animals Anti-Inflammatory Agents Automobile Driving Bioenergetics Biological Biological Markers Biology Biopsy Blood Vessels Body Weight decreased Caloric Restriction Cardiac Cardiometabolic Disease Cardiovascular Diseases Cardiovascular Models Cardiovascular Physiology Cell Energetics Cells Cellular Structures Cercopithecus tantalus Characteristics Classification Clinical assessments Development Diabetes Mellitus Disease Drug or chemical Tissue Distribution Dual-Energy X-Ray Absorptiometry Evaluation Fatty acid glycerol esters Fibrosis Foundations Gene Expression Goals Health Health Status Heritability Histology Human Image Individual Inflammation Inflammatory Insulin Resistance Knowledge Lipids Liver Macrophage Magnetic Resonance Imaging Measures Metabolic Metabolic Diseases Metabolic syndrome Mitochondria Modeling Monitor Monkeys Mothers Obesity Operative Surgical Procedures Outcome Outcome Measure Peripheral Blood Mononuclear Cell Phenotype Population Prevalence Proteins Puberty Public Health Quality Control Research Risk Secondary to Site Structure Thinness Time Tissues Translating Visceral Weight Gain Youth arterial remodeling burden of illness cardiac magnetic resonance imaging cardiometabolism cardiovascular disorder risk clinical practice clinically relevant cytokine density dietary heart function improved magnetic resonance imaging biomarker mitochondrial metabolism novel novel marker obese person offspring prepuberty subcutaneous weight loss intervention young adult

项目摘要

Summary Controversy exists regarding the metabolically healthy obese (MHO) classification, whether it is a transient state that precedes the development of cardiometabolic disease, or whether these individuals have preferred biological handling of excess adipose tissue (AT). We have documented the first spontaneous monkey model of MHO and unhealthy (MUO) obesity. Monkeys have near identical prevalence of MHO and MUO as well as healthy and healthy lean individuals (MHL/MUL) as humans, and are an excellent model of cardiovascular disease (CVD) and diabetes. Monkey MUO subcutaneous AT (SAT) has deficits in mitochondrial quality control and redistribution towards inflammatory M1-macrophages. We hypothesize that inadequate mitochondrial metabolism in SAT leads to greater ectopic fat accumulation and inflammation which drives the development of cardiometabolic diseases. It is unknown if these AT characteristics are observed in visceral adipose tissue (VAT) and if it is conserved across AT depots and over time. A related gap in knowledge is if AT in MUO shifts with weight loss towards improved mitochondrial function and a redistribution to include more anti-inflammatory M2-type macrophages, similar to that observed in the MHO state. We aim to answer questions pertaining to the generalizability of fat characteristics across AT depots in MHO/MHL and MUO/MUL, the stability of these phenotypes under caloric restriction, and persistence of these phenotypes in offspring that are genetically programmed for obesity. Our aims and outcomes are: 1. Characterize AT distribution and quality in lean and obese health-diverse monkeys. Surgical biopsies of SAT, VAT and liver will enable assessment of AT quality measures in MHO/MHL/MUO/MUL adult monkeys. We will quantitate mitochondrial bioenergetics, quality control and structure, inflammatory cell populations, gene expression profiles, cytokines, fibrosis, vascularity, fat density and distribution across sites in the body. Liver fat and histology will be additionally measured. Differences in AT quality will also be related to a novel outcome, peripheral blood mononuclear cell (PBMC) energetics; 2. Evaluate AT phenotypic stability and relate AT changes after weight loss to CVD risk and novel biomarkers. Repeated AT quality measures, PBMC bioenergetics before and after caloric restriction to achieve ≥10% weight loss will be performed. Changes will be related to changes in magnetic resonance imaging for CVD structure and function, biomarkers and MetS scores. 3. Document pre-obesity AT characteristics and biomarkers in at-risk youth. We will evaluate juvenile monkeys (2 and 3 year olds; puberty≈4 years) with the above-listed AT quality evaluations. Juveniles will be re- assessed as young adults for AT quality and health measures after weight gain. At completion we will have addressed gaps in knowledge about AT depots and health in a relevant animal model that is un-confounded by variable dietary and environmental influences. We aim to both identify causative and unique AT characteristics that will direct future research, and explore biomarkers that can be translated into clinical practice.

总结关于代谢健康肥胖（MHO）分类存在争议，无论是短暂的，在发生心脏代谢疾病之前的状态，或者这些个体是否偏好多余脂肪组织（AT）的生物处理。我们记录了第一个自发的猴子模型不健康的肥胖（MUO）。猴的MHO和MUO患病率几乎相同，健康和健康瘦个体（MHL/穆尔）作为人类，并且是心血管疾病的极好模型。疾病（CVD）和糖尿病。猴MUO皮下AT（SAT）的线粒体质量存在缺陷控制和重新分布到炎症M1-巨噬细胞。我们假设， SAT中的线粒体代谢导致更大的异位脂肪积聚和炎症，从而导致心脏代谢疾病的发展。尚不清楚这些AT特征是否在内脏中观察到。脂肪组织（VAT）以及是否在AT库中保存并随时间推移保存。一个相关的知识差距是， MUO随着体重减轻而朝着改善线粒体功能和重新分配的方向转变，抗炎M2型巨噬细胞，类似于在MHO状态下观察到的。我们的目标是回答关于MHO/MHL中AT仓库脂肪特征的普遍性问题， MUO/穆尔，这些表型在热量限制下的稳定性，以及这些表型在遗传性肥胖的后代。我们的目标和成果是：1。表征AT 分布和质量在瘦和肥胖的健康多样化的猴子。SAT、VAT和肝脏的手术活检将能够评估MHO/MHL/MUO/穆尔成年猴的AT质量指标。我们将定量线粒体生物能量学，质量控制和结构，炎症细胞群，基因表达特征、细胞因子、纤维化、血管分布、脂肪密度和体内各部位的分布。肝脏脂肪并且将另外测量组织学。AT质量的差异也将与新的结局相关，外周血单个核细胞（PBMC）能量学; 2.评估AT表型稳定性并关联AT 体重减轻后CVD风险和新生物标志物的变化。重复AT质量指标，PBMC 将在热量限制前后进行生物能量学检查，以达到≥10%的体重减轻。变化将与CVD结构和功能、生物标志物和MetS的磁共振成像变化相关成绩. 3.记录高危青少年肥胖前期AT特征和生物标志物。我们将评估青少年猴（2岁和3奥尔兹;青春期~ 4岁）进行上述AT质量评价。青少年将重新- 在体重增加后，评估年轻成人的AT质量和健康指标。完成后，我们将有解决了在相关动物模型中关于AT贮库和健康的知识差距，该模型不受以下因素的混淆不同的饮食和环境影响。我们的目标是确定病因和独特的AT特征这将指导未来的研究，并探索可以转化为临床实践的生物标志物。