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.

项目摘要/摘要 65岁以上的美国人的人数在2016年为4920万，预计在2035年为7800万 （美国人口普查）。 65岁以上的人通常会遭受白色脂肪组织（WAT）积累增加的苦难， 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 阻力，心血管功能障碍以及许多其他慢性健康状况，明显缩短 HealthSpan和寿命。因此，预防或减少脂肪组织的积累对于健康衰老至关重要。 不幸的是，衰老与脂肪组织积累之间的关系知之甚少。 脂肪细胞（脂肪细胞）在衰老期间会肥大（细胞肿大），但尚不清楚脂肪是否是否脂肪 组织还通过脂肪形成（新脂肪细胞的产生）扩展，该脂肪细胞将授予脂肪组织 具有无限的生长潜力。年轻小鼠的脂肪生成速率非常低，类似于年轻小鼠 人类。该提案的初步数据显示了第一个蜂窝证据，即WAT随着年龄的增长而扩展 大规模的成生成。因此，与大多数成年干细胞相反，这些干细胞表现出降低的增殖能力和 区分，前脂肪细胞的脂肪形成通过衰老解锁。该R01提案的目标是确定 何时，何地以及为什么在衰老期间发生脂肪形成。根据初步发现 假设是衰老会产生新的前脂肪细胞，从而经历脂肪形成成为新的 脂肪细胞和细胞衰老产生的基质微环境在此起着关键作用 过程。 AIM 1中的拟议实验将利用脂肪体小鼠确定确切的年龄阶段 当发生脂肪生成并使用毛刺小鼠确定新的前脂肪细胞的百分比 在衰老及其成生成率期间产生。公正的单细胞测序也将用于 确定在衰老期间新产生的前脂肪细胞亚群。 AIM 2中的拟议实验将 同时进行体外分化测定和体内移植以确定细胞的贡献 前脂肪细胞，旁分泌刺激和与年龄相关的全身刺激的自主作用 脂肪形成。 AIM 3中提出的实验将决定消除衰老细胞是否阻止 与年龄相关的脂肪形成。拟议的研究提供了新的科学知识，即脂肪形成是 与年龄相关的肥胖性的主要贡献者，以及关于脂肪形成为什么解锁为什么的机械见解 通过衰老。成功完成拟议的研究将为该研究提供新的治疗途径 预防和治疗与年龄相关的肥胖及其相关慢性疾病，最终促进 寿命和健康衰老。