IGF-I' S INFLUENCE ON PRE-ADIPOCYTES

IGF-I 对前脂肪细胞的影响

• 批准号: 7651573
• 负责人: JAMES L. KIRKLAND
• 金额: $ 37.16万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7651573
• 关键词: Abdomen; Accounting; Address; Adipocytes; Adipose tissue; Affect; Age; Aging; Animal Model; Animals; Apoptosis; Atherosclerosis; Biological Assay; CCL2 gene; Cell Aging; Cells; Cellular Stress; Cellular Stress Response; Clinical; Complement; Coupled; Data; Deposition; Development; Diabetes Mellitus; Disease; Dorsal; Fatty acid glycerol esters; Functional disorder; Gap Junctions; Gene Expression; Generations; Health; Heterozygote; Hormones; IL6 gene; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Instruction; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Investigation; Knowledge; Life; Lipids; Liver; Longevity; Mesentery; Metabolic; Metabolic stress; Morbidity - disease rate; Morphology; Mus; Mutate; Obesity; Onset of illness; Outcome; Pathology; Pathway interactions; Phenotype; Plasminogen Activator Inhibitor 1; Predisposition; Principal Investigator; Production; Proteins; Resistance; Skin; Somatotropin; Stress; TP53 gene; Testing; Time; Tissues; Visceral; Wild Type Mouse; adipokines; age related; base; biological adaptation to stress; chemokine; cytokine; factor C; insight; lipid biosynthesis; macrophage; middle age; migration; prevent; progenitor; programs; senescence; subcutaneous; tissue culture; transcription factor

Seeinstructions): Fat tissue is at the nexus of mechanisms impacting maximum lifespan, timing of age-related disease onset, and metabolic consequences of manipulating the somatotrophic axis. Clinical morbidity, altered secretory profiles, insulin resistance, fat redistribution among depots, and ectopic fat deposition with aging are strikingly delayed by reducing somatotrophic drive. New fat cells develop from their progenitors, preadipocytes, throughout life. Preadipocyte differentiation is impaired and inflammatory cytokine generation, stress responses, and preadipocyte senescence increase with aging. IGF-1 promotes preadipocyte utilization by enhancing replication and differentiation. We propose that lifelong preadipocyte utilization and metabolic stress contribute to age-related fat tissue dysfunction, particularly in subcutaneous fat. Visceral preadipocytes are resistant to IGF-1, potentially contributing to delayed age-related accumulation of visceral fat in animal models with low IGF-1. Our hypothesis is that decreasing somatotrophic drive will reduce subcutaneous preadipocyte utilization with aging, delaying loss and dysfunction, while preventing visceral preadipocyte development into fat, delaying redistribution. We predict interventions that decrease IGF-1 exposure will delay declines in adipogenesis, increases in stress responses, preadipocyte inflammatory cytokine generation, and senescent cell accumulation. Using the unique animal models in this Project, we will dissect contributions of IGF-1 vs. GH and local fat tissue vs. systemic IGF-1. In Aim 1, we will test if decreasing IGF-1 will: 1) reduce subcutaneous preadipocyte utilization with aging, preserving adipogenic capacity and delaying stress-responsive anti-adipogenic factor expression, and 2) impair visceral preadipocyte development into fat. Aim 2 is to test if reducing IGF-1 exposure will delay age-related development of a metabolically unfavorable preadipocyte secretory profile with increased inflammatory cytokine, chemokine, and matrix remodeling protein production. Aim 3 is to test if generation of senescent preadipocytes, which we found accumulate with aging, particularly in subcutaneous fat, and which may reflect progenitor overutilization and metabolic stress, is delayed by reducing life-long IGF-1 exposure. These studies will address critical knowledge gaps in aging and fat tissue function, pave the way for further analysis, and suggest potential mechanism-based interventions. RELEVANCE (See instructions): Fat tissue is at the nexus of mechanisms impacting maximum lifespan and timing of age-related disease onset. Age-related disease, insulin resistance, and fat redistribution are delayed by reducing growth hormone or insulin-like growth factor-1. Our hypothesis is that decreasing these hormones delays loss and dysfunction of skin fat with aging due to reduced fat cell progenitor dysfunction, while preventing development of progenitors into fat within the abdomen, delaying redistribution. These studies will address critical knowledge gaps in aging and fat tissue function and suggest potential mechanism-based treatments.

see Instructions）： 脂肪组织处于影响最大寿命的机制的联系，与年龄相关疾病发作的时机， 操纵躯体轴的代谢后果。临床发病率，分泌物改变 轮廓，胰岛素抵抗，仓库之间的脂肪再分配以及与老化的异位脂肪沉积为 通过减少营养性驱动而大大延迟了。新的脂肪细胞从祖细胞发展， 前一生。前脂肪细胞分化受损，炎症性细胞因子产生， 压力反应和前脂肪细胞衰老随老化的增加。 IGF-1促进前脂肪细胞 通过增强复制和分化来利用。我们提出了终生的前脂肪细胞利用和 代谢应激有助于年龄相关的脂肪组织功能障碍，特别是在皮下脂肪中。内脏 前脂肪细胞对IGF-1具有抗性，有可能导致内脏年龄相关的延迟积累 IGF-1低的动物模型中的脂肪。我们的假设是，减少嗜性驱动会减少 衰老，延迟损失和功能障碍，同时防止内脏，延迟损失和功能障碍 脂肪细胞发育成脂肪，延迟重新分布。我们预测降低IGF-1的干预措施 暴露会延迟脂肪生成的下降，压力反应增加，前炎性炎症 细胞因子产生和衰老细胞积累。使用该项目中独特的动物模型，我们 将剖析IGF-1与GH和局部脂肪组织与全身IGF-1的贡献。在AIM 1中，我们将测试是否 减少IGF-1将：1）降低皮下前脂肪细胞的利用率，并保留脂肪性 容量和延迟应力响应性抗辅助因子的表达，2）损害内脏 脂肪细胞发育成脂肪。 AIM 2是测试减少IGF-1暴露是否会延迟与年龄有关 炎症增加的代谢前分泌概况的发展 细胞因子，趋化因子和基质重塑蛋白产生。目标3是测试是否产生衰老 前脂肪细胞，我们发现它们会随着衰老而累积，尤其是皮下脂肪，可能 反映祖细胞过度利用和代谢应激，通过减少终身IGF-1暴露来延迟。 这些研究将解决衰老和脂肪组织功能的关键知识差距，为进一步的道路铺平道路 分析，并提出基于机制的潜在干预措施。 相关性（请参阅说明）： 脂肪组织处于影响最大寿命和与年龄相关疾病的时间的机制的联系 发作。与年龄有关的疾病，胰岛素抵抗和脂肪再分配通过减少生长延迟 激素或胰岛素样生长因子1。我们的假设是减少这些激素会延迟损失和 由于脂肪细胞祖细胞功能障碍降低，皮肤脂肪功能障碍与衰老，同时防止 将祖细胞发展成腹部脂肪，从而延迟重新分布。这些研究将解决 衰老和脂肪组织功能的关键知识差距，并提出潜在的基于机制的治疗方法。