Cell cycle control of adipogenesis

脂肪生成的细胞周期控制

基本信息

批准号：
10668721
负责人：
Mary N Teruel
金额：
$ 49.84万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668721
关键词：
Adipocytes Adipose tissue Adolescent obesity Adult Body Weight decreased Brown Fat CDK2 gene CDK4 gene Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Differentiation process Cell division Cells Child Clonal Expansion Cyclins Ensure Fatty acid glycerol esters Functional disorder G1 Phase Genetic Goals Health Human Hypertrophy In Vitro Injections Knock-out Knockout Mice Link Maintenance Metabolic Metabolic Diseases Methods Molecular Mus Muscle Obesity Obesity Epidemic Outcome Pancreas Persons Phase Process Proliferating Publishing Reporter Research Risk Role Skeletal Muscle Testing Therapeutic Time Tissue Differentiation Tissues Work adipocyte differentiation cellular imaging experimental study imaging approach in vivo inducible gene expression inhibitor interest lipid biosynthesis live cell imaging mouse model neuron regeneration progenitor programs regenerative tissue stem cells synergism

项目摘要

Revised Abstract Recent evidence shows that creating new fat cells (adipogenesis) can counteract the harmful metabolic effects of obesity, which have been shown to originate primarily from abnormal enlargement (hypertrophy) and resulting dysfunction of existing fat cells. Thus, how to increase adipogenesis over hypertrophy is of great interest. Previous work showed that preadipocytes in vivo and in vitro must complete one or more cell cycles, a process referred to as clonal expansion, before they can differentiate into adipocytes. One of the most striking genetic examples of increased adipogenesis was demonstrated by manipulating this clonal expansion period by knocking out the cell cycle inhibitors p21 and p27. Knockout of either p21 or p27 in mice results in a 2-fold increase in adipogenesis and fat mass, but knockout of both results in a dramatic 6-fold increase. Previous work suggests that p21 and p27 are regulated by very different mechanisms and are active at different times during adipogenesis. In recent published work, we identified the molecular mechanisms that could explain the increased adipogenesis observed in the p21- knockout mouse. However, how p27 regulates adipogenesis and tissue mass and how p21 and p27 synergize are poorly understood. We hypothesize that the synergistic expression of p21 and p27 during adipogenesis is the primary mechanism that controls the number of cell divisions before differentiation, and thus controls the number the adipocytes produced per preadipocyte. We will test this hypothesis by using live-cell imaging approaches, together with a fat-pad injection mouse model. We will first use methods to inducibly express and rapidly degrade p27 to determine when and how p27 regulates cell cycle progression during adipogenesis. We will then use live cell reporters for CDK4/6 and CDK2 activity to understand when and how p27 and p21 synergize to regulate CDK4/6 and CDK2 activity and control the number of adipocytes produced. The outcome of this work will be a framework how the clonal expansion period can be controlled to significantly increase adipogenesis over hypertrophy while also ensuring that the progenitor pool is maintained. Our results will likely have broad applicability not only to the maintenance of adipose tissue, but also more generally for the maintenance and regeneration of neuronal, muscle, and other terminally differentiated tissues.

修订摘要最近的证据表明，创建新的脂肪细胞（脂肪形成）可以抵消肥胖的有害代谢作用，肥胖症已显示出主要来自异常肿大（肥大）和现有脂肪细胞功能障碍。因此，如何增加肥大的脂肪形成引起了人们的极大兴趣。先前的工作表明，在体内和体外的前脂肪细胞必须完成一个或多个细胞周期，这一过程被称为克隆膨胀，然后才能区分成脂肪细胞。通过敲除细胞周期抑制剂p21和p27来操纵这一克隆扩张期，最引人注目的掺杂发生的遗传实例之一是表现出来的。小鼠中p21或p27的敲除导致脂肪形成和脂肪质量增加2倍，但两种敲除导致6倍急剧增加。先前的工作表明，p21和p27受到非常不同的机制调节，并且在脂肪生成期间的不同时间活跃。在最近发表的工作中，我们确定了可以解释P21-敲除小鼠中观察到的脂肪形成增加的分子机制。然而，p27如何调节脂肪形成和组织质量以及p21和p27的协同作用知之甚少。我们假设脂肪生成过程中p21和p27的协同表达是控制分化前细胞分裂数量的主要机制，从而控制了每个质子细胞产生的脂肪细胞的数量。我们将通过使用活细胞成像方法以及脂肪填充小鼠模型来检验这一假设。我们将首先使用方法来诱导并迅速降解P27，以确定p27何时以及如何调节脂肪生成过程中细胞周期的进程。然后，我们将使用实时细胞记者进行CDK4/6和CDK2活性，以了解何时以及如何协同调节CDK4/6和CDK2活性并控制产生的脂肪细胞数量。这项工作的结果将是一个框架，如何控制克隆膨胀周期以显着增加肥大的脂肪形成，同时还确保保持祖细胞池的维持。我们的结果可能不仅适用于维持脂肪组织，而且更普遍地用于维持和再生神经元，肌肉和其他末端分化的组织。