Defining the Role of Adipogenesis in Age-Associated Adiposity

定义脂肪生成在年龄相关性肥胖中的作用

• 批准号: 10417196
• 负责人: Qiong Annabel Wang
• 金额: $ 36.08万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417196
• 关键词: Abdomen; Adipocytes; Adipose tissue; Age; Age-Months; Aging; American; Area; Biological Assay; Blood Circulation; Cardiovascular system; Cell Aging; Cell Enlargement; Cell physiology; Cells; Censuses; Chronic; Chronic Disease; Data; Diet; Exhibits; Functional disorder; Generations; Goals; Grant; Health; Human; Hypertrophy; In Vitro; Inflammatory; Insulin Resistance; Knowledge; Location; Longevity; Mus; Obesity; Persons; Play; Population; Prevention; Process; Proliferating; Research; Role; Sampling; Stains; Study models; Testing; Time; Transplantation; Visceral; adult stem cell; aged; base; cell type; experimental study; healthspan; healthy aging; human old age (65+); in vivo; insight; lipid biosynthesis; mouse model; novel; novel therapeutics; paracrine; prevent; senescence; single cell sequencing; subcutaneous

PROJECT SUMMARY/ABSTRACT The number of Americans over age 65 is 49.2 million in 2016, and it is expected to be 78 million in 2035 (U.S. Census). People over age 65 typically suffer from increased white adipose tissue (WAT) accumulation, especially in the visceral (abdominal) area. Visceral adiposity accelerates aging by promoting insulin resistance, cardiovascular dysfunction, and many other chronic health conditions, significantly shortening healthspan and lifespan. Thus, preventing or reducing adipose tissue accumulation is critical for healthy aging. Unfortunately, the relationship between aging and adipose tissue accumulation is poorly understood. Adipocytes (fat cells) undergo hypertrophy (cell enlargement) during aging, but it remains unclear if adipose tissue also expands through adipogenesis (the generation of new adipocytes), which will grant adipose tissue with unlimited potential to grow. The rate of adipogenesis is very low in young mice, similar to that in young humans. Preliminary data of this proposal show the first cellular evidence that WAT expands with age through massive adipogenesis. Thus, in contrast to most adult stem cells that exhibit a reduced ability to proliferate and differentiate, adipogenesis of preadipocytes is unlocked by aging. The goal of this R01 proposal is to determine when, where, and why does adipogenesis take place during aging. Based on the preliminary findings, the hypothesis is that aging generates new preadipocytes which undergo adipogenesis to become new adipocytes, and the stromal microenvironment generated by cellular senescence plays a key role in this process. Proposed experiments in Aim 1 will utilize the AdipoChaser mice to determine the exact age stage when adipogenesis takes place, and use MuralChaser mice to determine the percentage of new preadipocytes generated during aging and their rate of adipogenesis. Unbiased single-cell sequencing will also be used to identify preadipocyte subpopulations newly generated during aging. Proposed experiments in Aim 2 will perform both in vitro differentiation assays and in vivo transplantations to determine the contribution of cell- autonomous effect of preadipocytes, paracrine stimulation, and systemic stimulation to age-associated adipogenesis. Proposed experiments in Aim 3 will determine whether eliminating senescent cells prevents age-associated adipogenesis. The proposed research provides new scientific knowledge that adipogenesis is the major contributor to age-associated adiposity, and mechanistic insights into why adipogenesis is unlocked by aging. Successful completion of the proposed research will provide new therapeutic avenues for the prevention and treatment of age-associated adiposity and its related chronic diseases, ultimately promoting longevity and healthy aging.

项目总结/摘要 2016年65岁以上的美国人为4920万，预计2035年将达到7800万 (U.S.人口普查）。65岁以上的人通常患有增加的白色脂肪组织（WAT）积累， 特别是在内脏（腹部）区域。内脏肥胖通过促进胰岛素加速衰老 抵抗力，心血管功能障碍和许多其他慢性健康状况，显着缩短 健康和寿命。因此，预防或减少脂肪组织积累对健康衰老至关重要。 不幸的是，衰老和脂肪组织积累之间的关系知之甚少。 脂肪细胞（脂肪细胞）在衰老过程中会发生肥大（细胞增大），但目前尚不清楚脂肪细胞是否 组织也通过脂肪生成（新脂肪细胞的产生）扩张，这将使脂肪组织 具有无限的成长潜力。幼鼠的脂肪形成率很低，与幼鼠相似 人类这一提议的初步数据显示，第一个细胞证据表明，WAT随着年龄的增长而扩大， 大量脂肪生成因此，与大多数成体干细胞相比，其表现出降低的增殖能力， 分化，前脂肪细胞的脂肪形成通过衰老解锁。本R 01提案的目标是确定 在衰老过程中脂肪形成发生的时间、地点和原因。根据初步调查结果， 一种假说是，衰老产生新的前脂肪细胞，这些前脂肪细胞经历脂肪形成而成为新的 脂肪细胞，细胞衰老产生的基质微环境在其中起着关键作用。 过程目标1中提出的实验将利用AdipoChaser小鼠来确定确切的年龄阶段 并使用MuralChaser小鼠确定新的前脂肪细胞的百分比 以及它们的脂肪生成率。无偏单细胞测序也将用于 鉴定衰老过程中新产生的前脂肪细胞亚群。目标2中拟议的实验将 进行体外分化试验和体内移植，以确定细胞的贡献， 前脂肪细胞、旁分泌刺激和全身刺激对年龄相关性 脂肪生成目标3中提出的实验将确定消除衰老细胞是否能防止 与年龄相关的脂肪生成。这项拟议中的研究提供了新的科学知识，即脂肪形成是 年龄相关性肥胖的主要贡献者，以及对脂肪形成为什么被解锁的机械见解 通过老化。成功完成拟议的研究将为糖尿病患者提供新的治疗途径。 预防和治疗与年龄相关的肥胖症及其相关的慢性疾病， 长寿和健康老龄化。