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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.

修订后的抽象