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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.

在能量过剩的情况下，身体不利用的脂肪酸通常储存在白色脂肪细胞中，在那里它们可以被释放并在其他器官的能量耗尽时用作燃料。在肥胖症中，白色脂肪组织（AT）的增大（肥大）导致AT含有甘油三酯的能力降低，导致其他器官中的脂质沉积，从而导致胰岛素抵抗（IR）和2型糖尿病（T2 D）发展如果AT血管化良好且由小的白色脂肪细胞组成，则肥胖不会引起T2 D 和富含脂肪酸的米色脂肪细胞，表明AT增生是代谢健康的关键。脂肪细胞在整个衰老过程中进行周转，它们在AT中的库由异质性脂肪祖细胞维持，细胞（APC）分裂，自我更新和分化成前脂肪细胞，以取代AT中垂死的脂肪细胞。我们初步数据显示，APC增殖受昼夜节律控制，而高脂饮食则使其失调喂食PDGF受体，PDGFRα和PDGFRβ，发出信号指导APC分化为米色或白色脂肪细胞似乎分别介导这种昼夜增殖。端粒缩短的临床数据 AT与T2 D发展表明APC持续分裂和产生新脂肪细胞的能力，而不是依赖于先前存在的大的白色脂肪细胞的扩增，解释了T2 D的缺乏在“健康肥胖”个体中的发展。这项建议是基于初步数据显示，长期- 复制型APC衰老和耗竭的长期结果是脂肪细胞肥大和AT纤维化，代谢功能障碍我们的总体假设是AT中APC过度增殖，饮食加重- 诱导肥胖和破坏昼夜有丝分裂信号，加速APC复制衰老，导致 AT代谢功能障碍和2 TD。在这里，我们将使用遗传小鼠模型来分析和操纵APC 受PDGF-A / Pdgfrα调节的信号传导，其倾向于米色脂肪形成，而受PDGF-A / Pdgfrα调节的APC PDGF-D / Pdgfrβ，偏向于白色脂肪生成。使用小鼠模型的加速端粒缩短，我们将建立复制衰老的白色和米色前脂肪细胞的后果， AT和综合生理学。在目标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祖细胞增殖的机制，并确定昼夜节律的影响 APC对AT功能的破坏。在目标3中，我们将测试白色和米色APC的营养控制方法疲劳和代谢功能障碍。饮食干预对促有丝分裂信号传导、APC增殖、分析端粒缩短、白色/米色脂肪细胞池和代谢。本研究的一个创新点是是一种机制解释，如何耗尽APC人口在不同的AT仓库，由于代谢失衡易导致代谢功能障碍。建立使APC正常化的营养方法增殖将在肥胖症、糖尿病和衰老领域产生转化影响。