Effect of Aging on Preadipocyte Differentiation

衰老对前脂肪细胞分化的影响

• 批准号: 7907512
• 负责人: JAMES L. KIRKLAND
• 金额: $ 13.34万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907512
• 关键词: Abdomen; Adipocytes; Age; Aging; Animal Model; Animals; Atherosclerosis; Biological Models; CCAAT-Enhancer-Binding Proteins; Cell Aging; Cells; Chemotaxis; Coculture Techniques; DNA Damage; Dependence; Diabetes Mellitus; Exposure to; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Gap Junctions; Generations; Goals; Growth; Human; In Vitro; Infiltration; Inflammatory; Intervention; Life; Lipids; Liver; Longevity; Marrow; Mediating; Mediator of activation protein; Metabolic; Metabolic stress; Molecular; Morbidity - disease rate; Mus; Muscle; Obesity; Onset of illness; Organ; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Predisposition; Process; Production; Proteins; Rattus; Recording of previous events; Role; Site; Skin; Stress; TNF gene; Telomerase; Testing; Theoretical model; Thinking; Time; Tissues; Translating; Variant; Visceral; age effect; age related; base; cytokine; in vivo; lipid biosynthesis; macrophage; middle age; prevent; progenitor; public health relevance; senescence; subcutaneous; telomere

DESCRIPTION (provided by applicant): New fat cells develop from preadipocytes throughout life. Fat tissue function and distribution change dramatically with aging. After middle age, fat is redistributed from subcutaneous to metabolically deleterious visceral depots and lipid accumulates in muscle, marrow, and liver instead of fat depots, with increased predisposition to diabetes and atherosclerosis. Our hypothesis is that fat cell progenitor overutilization with aging generates senescent preadipocytes with a secretory phenotype that impairs adipogenesis. This occurs at different rates in different depots, is accelerated by repeated replication and metabolic stress, and occurs prematurely in obesity. We found preadipocyte differentiation is impaired with aging and inflammatory cytokine generation and susceptibility to metabolic stress increase. We demonstrated preadipocytes from different fat depots are inherently distinct. We found senescent preadipocytes accumulate with aging and after repeated replication in vitro and in vivo (in obesity) in a depot-dependent manner. These findings open an entirely new way of looking at fat tissue redistribution and dysfunction with aging. Aim 1 is to test the hypothesis that dysfunctional preadipocytes accumulate with aging and dissect responsible mechanisms, and test fat depot-dependence in humans. We will test cellular senescence mediators (DNA damage-associated foci/ 3-H2AX/ p53/p21 components; senescence associated foci/p16/Rb components) and distinguish between processes that potentially mediate senescent preadipocyte generation. We will perturb them by varying preadipocyte replicative history, with cytokines that increase with aging, and by eliciting metabolic stress. Aim 2 is to define the aging preadipocyte secretory phenotype, the impact of replicative history and depot origin upon it, and its effect on chemotaxis. Late passage human skin fibroblasts acquire an aberrant, pro-inflammatory secretory phenotype. We will define the secretory profile of preadipocytes from old vs. younger subjects, later vs. early passage preadipocytes in vitro, and in obesity. We will test if this aberrant secretory phenotype induces dysfunction in neighboring cells, magnifying impact. Aim 3 is to test the hypothesis that dysfunctional preadipocytes contribute to impaired adipogenesis with aging, define responsible mechanisms and, based on these, test molecular interventions. C/EBP1 and PPAR3 are essential for adipogenesis. C/EBP1 and PPAR3 expression are impaired with aging. We found exposure to preadipocytes from old animals, increased TNF1 release by preadipocytes with aging, and stress-responsive, anti-adipogenic regulators (CUGBP, CHOP) all impede adipogenesis in old rats. Co-culture and conditioned medium from preadipocytes of old subjects will be used to perturb these processes. We will define anti-adipogenic mechanisms in human aging and their relation to preadipocyte senescence. We will test if interventions that restore adipogenesis in preadipocytes from old rats do so in humans. These studies represent an entirely new way of thinking about mechanisms causing the fat redistribution and metabolic dysfunction common in old age. PUBLIC HEALTH RELEVANCE: Fat tissue function changes dramatically with aging. After middle age, fat is redistributed from regions under the skin to metabolically deleterious depots in the abdomen. Fat accumulates outside of fat tissue in muscle, marrow, the liver, and other sites. This change increases the predisposition to diabetes and atherosclerosis. The mounting evidence placing fat tissue function at the nexus of processes impacting maximum lifespan and timing of age-related disease onset in animal models has led us to ask if: 1) fat cell progenitor overutilization with aging results in dysfunctional cells that produce proteins that impede function of neighboring cells and 2) if this may underlie fat dysfunction in old age. This represents an entirely new way of thinking about mechanisms causing the fat redistribution, diabetes, and their complications so common in old age.

描述(申请人提供)：新的脂肪细胞在一生中由前脂肪细胞发育而来。随着年龄的增长，脂肪组织的功能和分布发生了巨大的变化。中年后，脂肪从皮下重新分布到代谢有害的内脏部位，脂肪在肌肉、骨髓和肝脏而不是脂肪部位积聚，增加了患糖尿病和动脉粥样硬化的可能性。我们的假设是，随着年龄的增长，脂肪细胞前体的过度利用会产生具有分泌表型的衰老前脂肪细胞，从而损害脂肪的形成。这在不同的仓库中以不同的速度发生，由于重复复制和代谢压力而加速，并在肥胖中过早发生。我们发现，随着年龄的增长，炎性细胞因子的产生和对代谢应激的易感性增加，前脂肪细胞的分化受到损害。我们证明了来自不同脂肪库的前脂肪细胞本质上是不同的。我们发现衰老的前脂肪细胞随着年龄的增长而积累，在体外和体内(肥胖)重复复制后，以一种仓库依赖的方式积累。这些发现开启了一种全新的方式来看待脂肪组织的再分布和随着年龄增长而出现的功能障碍。目的1是验证功能失调的前脂肪细胞随着年龄的增长而积累的假说，并剖析相关的机制，并测试人类对脂肪库的依赖。我们将测试细胞衰老介质(DNA损伤相关的Foci/3-H2AX/p53/p21成分；衰老相关的Foci/p16/Rb成分)，并区分可能调节衰老前脂肪细胞生成的过程。我们将通过改变前脂肪细胞的复制历史，通过随年龄增加的细胞因子，以及通过引发代谢应激来扰乱它们。目的2确定衰老前体脂肪细胞的分泌表型，复制历史和来源对其的影响，以及其对趋化作用的影响。传代后期的人皮肤成纤维细胞获得一种异常的促炎分泌表型。我们将确定老年受试者与年轻受试者、体外传代较晚的受试者与早期传代的受试者以及肥胖者的前脂肪细胞的分泌情况。我们将测试这种异常的分泌表型是否会导致邻近细胞功能障碍，从而放大影响。目的3是验证功能失调的前脂肪细胞有助于衰老导致脂肪生成受损的假说，确定相关机制，并在此基础上测试分子干预。C/EBP1和PPAR3在脂肪形成中起重要作用。C/EBP1和PPAR3的表达随着年龄的增长而减弱。我们发现，暴露于老年动物的前脂肪细胞，随着年龄的增长，前脂肪细胞释放的TNF1增加，以及应激反应，抗成脂调节剂(CUGBP，CHOP)都阻碍了老年大鼠的脂肪生成。来自老年受试者的前脂肪细胞的共培养和条件培养液将被用来干扰这些过程。我们将确定人类衰老中的抗脂机制及其与前脂肪细胞衰老的关系。我们将测试恢复老年大鼠前脂肪细胞脂肪生成的干预措施是否对人类有效。这些研究代表了一种全新的方式来思考导致老年人常见的脂肪再分配和代谢功能障碍的机制。与公共健康相关：随着年龄的增长，脂肪组织的功能发生了巨大的变化。中年后，脂肪从皮肤下的区域重新分配到腹部代谢有害的部位。脂肪聚集在脂肪组织之外的肌肉、骨髓、肝脏和其他部位。这种变化增加了糖尿病和动脉粥样硬化的易感性。越来越多的证据表明，在动物模型中，脂肪组织功能处于影响最长寿命和年龄相关疾病发病时间的过程的连接点，这让我们问：1)随着年龄的增长，脂肪细胞前体的过度使用是否会导致细胞功能失调，从而产生阻碍邻近细胞功能的蛋白质；2)这是否可能是老年脂肪功能障碍的原因。这代表了一种全新的方式来思考导致脂肪再分配、糖尿病及其并发症在老年人中如此常见的机制。