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：
10317054
负责人：
Kylie Kavanagh
金额：
$ 66.64万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317054
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 Confounding Factors (Epidemiology)Development Diabetes Mellitus 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 Magnetic Resonance Imaging Measurable Measures Metabolic Metabolic Diseases Metabolic syndrome Mitochondria Modeling Monitor Monkeys Mothers Obesity Operative Surgical Procedures Outcome 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 macrophage 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.

概括关于代谢健康的肥胖（MHO）分类存在争议，是否是短暂的指出，在心脏代谢疾病的发展之前，或这些人是否偏爱过量脂肪组织的生物处理（AT）。我们已经记录了第一个赞助的猴子模型 MHO和不健康（MUO）肥胖。猴子的MHO和MUO的患病率几乎相同健康健康的精益个体（MHL/MUL）作为人类，是心血管的出色模型疾病（CVD）和糖尿病。猴子Muo皮下（SAT）已定义了线粒体质量控制和重新分布炎症M1巨噬细胞。我们假设这不足 SAT中的线粒体代谢会导致更大的生态脂肪积累和炎症，从而驱动驱动心脏代谢性疾病的发展。未知是否在内脏中观察到这些特征脂肪组织（增值税），如果它在沉积物和随着时间的流逝时进行了配置。知识的相关差距是在在MUO转移中，体重减轻朝着改善的线粒体功能和重新分布，以包括更多抗炎M2型巨噬细胞，类似于MHO状态下的巨噬细胞。我们的目标是回答与MHL/MHL和 MUO/MUL，这些表型在热量限制下的稳定性，以及这些表型的持久性用于对象性的基因编程的后代。我们的目标和结果是：1。精益和肥胖的健康多样性猴子的分布和质量。 SAT，VAT和肝脏的手术活检将启用MHO/MHL/MUO/MUL成人猴子中的AT质量度量评估。我们将定量线粒体生物能学，质量控制和结构，炎症细胞种群，基因表达剖面，细胞因子，纤维化，血管性，脂肪密度和分布跨体内。肝脂肪和组织学将进一步测量。 AT质量的差异也将与新的结果有关，外周血单核细胞（PBMC）能量学； 2。在表型稳定性上进行评估体重减轻后变化为CVD风险和新型生物标志物。以质量措施重复，PBMC 热量限制之前和之后的生物能量将进行≥10％的体重减轻。更改将与CVD结构和功能，生物标志物和MetS的磁共振成像的变化有关分数。 3。记录处于高危青年特征和生物标志物的肥胖。我们将评估少年猴子（2岁和3岁；青春期约4年），上述质量评估。少年将重新体重增加后，评估为年轻人的质量和健康措施。完成后，我们将有在相关的动物模型中解决有关存款和健康知识的差距可变的饮食和环境影响。我们旨在确定特征的因果关系和独特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。