Metabolic consequences of adipocyte progenitor replicative senescence: mechanism and intervention

脂肪细胞祖细胞复制衰老的代谢后果：机制和干预

基本信息

批准号：
10374142
负责人：
Mikhail G Kolonin
金额：
$ 39万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-17 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374142
关键词：
Ablation Acceleration Adipocytes Adipose tissue Aging Blood Vessels Brown Fat Caloric Restriction Cell Aging Cell Death Cell Differentiation process Cells Circadian Dysregulation Circadian Rhythms Clinical Clinical Data Competence Data Deposition Development Diabetes Mellitus Diet Dietary Intervention Fatty Acids Fatty acid glycerol esters Fibrosis Foundations Functional disorder Genetic Gluconeogenesis Glucose Glucose Intolerance Growth Health High Fat Diet Hyperplasia Hypertrophy Hypoxia Infiltration Inflammation Insulin Insulin Resistance Intervention Knock-out Knockout Mice Laboratories Length Leukocytes Life Style Link Lipids Lipolysis Liver Maintenance Measures Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Methods Mitochondria Modeling Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Nutritional Obesity Organ Outcome PDGFA gene Pancreas Pathologic Patients Pharmacology Phenotype Physiological Physiology Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor alpha Receptor Population Process Production Proliferating Regulation Reporting Signal Transduction Skeletal Muscle TGFBR2 gene Telomerase Telomere Shortening Testing Time Time-restricted feeding Tissues Triglycerides aged base cell type circadian circadian regulation diet-induced obesity energy balance exhaustion feeding innovation ketogenesis lipid biosynthesis mouse model nutritional approach obese person prevent progenitor recruit response self-renewal sex stem cell proliferation stem cells telomere translational impact

项目摘要

Under conditions of energy excess, fatty acids not utilized by the body are normally stored in white adipocytes, where they can be released and used for fuel under energy depletion by other organs. In obesity, adipocyte enlargement (hypertrophy) in white adipose tissue (AT) leads to a reduced ability of AT to contain triglycerides, causing lipid deposition in other organs, which leads to insulin resistance (IR), and type-2 diabetes (T2D) development. Obesity does not cause T2D if AT is well vascularized and composed of small white adipocytes and mitochondria-rich beige adipocytes, indicating that AT hyperplasia is the key to metabolic health. Adipocytes undergo turnover throughout aging and their pools in AT are maintained by heterogeneous adipose progenitor cells (APCs) that divide, self-renew and differentiate into preadipocytes to replace dying adipocytes in AT. Our preliminary data show that APC proliferation is under circadian control that is dysregulated upon high fat-diet feeding. PDGF receptors, PDGFRα and PDGFRβ, which signal to direct APC differentiation into beige or white adipocytes, respectively, appear to mediate this diurnal proliferation. Clinical data linking telomere shortening in AT with T2D development suggests that sustained ability of APCs to divide and give rise to new adipocytes, rather than reliance on the expansion of previously existing large, white adipocytes, explains the lack of T2D development in “healthy obese” individuals. This proposal is based on preliminary data showing that the long- term outcome of replicative APC senescence and depletion is adipocyte hypertrophy and AT fibrosis, resulting in metabolic dysfunction. Our overarching hypothesis is that APC over-proliferation in AT, aggravated by diet- induced obesity and disruption of circadian mitogenic signaling, accelerates APC replicative senescence, leading to AT metabolic dysfunction and 2TD. Here we will use genetic mouse models to analyze and manipulate APCs regulated by PDGF-A / Pdgfrα, signaling, which are skewed toward beige adipogenesis, and APCs regulated by PDGF-D / Pdgfrβ , which are skewed toward white adipogenesis. Using mouse models of accelerated telomere shortening, we will establish the consequences of replicative senescence of white and beige preadipocytes on AT and integrative physiology. In Aim 2, using mouse models of circadian dysregulation, we will investigate the mechanisms controlling white and beige adipocyte progenitor proliferation and determine the effect of circadian disruption in APC on AT function. In Aim 3, we will test approaches to nutritional control of white and beige APC exhaustion and metabolic dysfunction. Effects of dietary interventions on mitogenic signaling, APC proliferation, telomere shortening, white / beige adipocyte pools and metabolism will be analyzed. An innovation of this study is a mechanistic explanation to how depletion of APC populations in distinct AT depots due to metabolic disbalance predisposes to metabolic dysfunction. Establishing nutritional approaches to normalizing APC proliferation will have a translational impact in the field of obesity, diabetes, and aging.

在超过能量的条件下，人体未利用的脂肪酸通常存储在白色脂肪细胞中，它们可以在其他器官的能量耗竭下释放并用于燃料。在目标上，脂肪细胞白色脂肪组织（AT）中的增加（肥大）导致AT含有甘油三酸酯的能力降低，在其他器官中引起脂质沉积，这会导致胰岛素抵抗（IR）和2型糖尿病（T2D）发展。如果AT良好的血管化并由小白色脂肪细胞组成，则肥胖不会引起T2D 线粒体富含米色的脂肪细胞，表明在增生时是代谢健康的关键。脂肪细胞在整个衰老中进行流动率，其池中的AT由异质脂肪祖细胞维持分裂，自我更新和分化为前脂肪细胞的细胞（APC），以替代AT中的垂死脂肪细胞。我们的初步数据表明，APC增殖处于昼夜节律的控制下，在高脂肪diet上失调进食。 PDGF受体，PDGFRα和PDGFRβ，它们信号将APC分化为米色或白色脂肪细胞分别介导这种昼夜增殖。将端粒缩短的临床数据随着T2D的开发，APC的持续能力分裂并引起新的脂肪细胞，而不是缓解以前现有的大白脂肪细胞的扩展，而是解释了缺乏T2D 在“健康肥胖”个体中发展。该提案基于初步数据，表明长期复制性APC感应和部署的术语结果是脂肪细胞肥大，在纤维化时，由此产生在代谢功能障碍中。我们的总体假设是APC在AT中的过度增殖，由饮食汇总 - 诱导的肥胖症和昼夜节律信号的破坏，加速了APC复制感，领先到代谢功能障碍和2TD。在这里，我们将使用遗传小鼠模型来分析和操纵APC 由PDGF-A /PDGFRα调节，信号传导偏向米色脂肪形成，而APC受到APC的调节 PDGF-D /PDGFRβ，偏向白色脂肪形成。使用加速端粒的鼠标模型缩短，我们将确定白色和米色前脂肪细胞复制感的后果 AT和综合生理学。在AIM 2中，使用昼夜节律失调的小鼠模型，我们将研究控制白色和米色脂肪细胞祖细胞增殖的机制，并确定昼夜节律的影响 APC AT功能中的破坏。在AIM 3中，我们将测试白色和米色APC的营养控制方法疲惫和代谢功能障碍。饮食干预对有丝分裂信号传导，APC增殖的影响，将分析端粒缩短，白 /米色脂肪细胞池和代谢。这项研究的创新是一种机制解释，说明如何由于代谢而在沉积物中耗尽不同破坏易于代谢功能障碍。建立归一化APC的营养方法扩散将在肥胖，糖尿病和衰老领域产生翻译影响。