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

摘要 关于代谢性健康肥胖(MHO)的分类存在争议，它是否是短暂性的 心脏代谢性疾病发生之前的状态，或者这些人是否更喜欢 过剩脂肪组织的生物处理(AT)。我们已经记录了第一个自发的猴子模型 MHO和不健康肥胖(MUO)的风险。猴子的MHO和MUO的患病率几乎相同， 健康和健康的瘦人(MHL/MUL)与人类一样，是心血管疾病的优秀模型 疾病(心血管疾病)和糖尿病。猕猴MUO皮下AT(SAT)存在线粒体质量缺陷 控制和重新分布到炎症性M1-巨噬细胞。我们假设这是不充分的 SAT中的线粒体代谢导致更多的异位脂肪积累和炎症，从而推动 心脏代谢性疾病的发展。目前尚不清楚这些AT特征是否在内脏观察到 脂肪组织(增值税)，以及它是否在AT仓库和时间上保存。知识上的一个相关差距是如果AT 在MUO中，随着体重的减轻，线粒体功能得到改善，并进行了重新分配，以包括更多 抗炎的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和MHO/MHL AT仓库的脂肪特征的概括性问题 MUO/MUL，这些表型在热量限制下的稳定性，以及这些表型在 从基因上讲就是肥胖的后代。我们的目标和成果是：1.描述AT 不同健康体型的瘦猴和肥胖猴的分布和质量。手术活检的SAT、VAT和肝脏将 允许评估MHO/MHL/MUO/MUL成年猴子的AT质量措施。我们将量化 线粒体生物能量学，质量控制和结构，炎性细胞群，基因表达 概况，细胞因子，纤维化，血管，脂肪密度和在体内各部位的分布。肝脏脂肪和 还将对组织学进行测量。AT质量的差异也将与一种新的结果相关， 外周血单个核细胞(PBMC)能量学；2.表型稳定性评价及相关AT 体重减轻后心血管疾病风险和新生物标记物的变化。重复AT质量测量，PBMC 在卡路里限制前后进行生物能量学，以实现≥体重减轻10%。更改将 与脑血管病结构和功能、生物标志物和蛋氨酸的磁共振成像变化有关 得分。3.记录高危青少年肥胖前的AT特征和生物标记物。我们将评估青少年 接受上述AT质量评估的猴子(2岁和3岁；青春期≈4岁)。青少年将被重新- 体重增加后，作为青年对AT质量和健康指标进行评估。完工后，我们将拥有 解决了在相关动物模型中关于AT仓库和健康的知识差距，该模型没有受到 不同的饮食和环境影响。我们的目标是识别因果特征和独特的AT特征 这将指导未来的研究，并探索可转化为临床实践的生物标记物。

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.