Deciphering age-dependent beige adipocyte failure

解读年龄依赖性米色脂肪细胞衰竭

• 批准号: 10589822
• 负责人: Daniel Carl Berry
• 金额: $ 42.37万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589822
• 关键词: Ablation; Adipocytes; Adipose tissue; Adrenergic Agents; Age; Aging; Agreement; Automobile Driving; Biochemical; Biogenesis; Blood Glucose; Blood Vessels; Body fat; Cardiovascular Diseases; Cell Aging; Cell Communication; Cells; Cessation of life; Clinical; Communication; Consumption; Deterioration; Development; Failure; Fatty acid glycerol esters; Fostering; Functional disorder; Generations; Genetic; Genetic Models; Genetic Transcription; Glucose; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immunologics; Incidence; Individual; Interleukins; Link; Longevity; Lymphoid Cell; Mammals; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Obesity Epidemic; Output; Pathway interactions; Phenotype; Physiological; Platelet-Derived Growth Factor beta Receptor; Population; Process; Ramp; Rejuvenation; Research; Role; Signal Transduction; Signaling Molecule; Source; Testing; Therapeutic; Tissues; Type 2 diabetic; Up-Regulation; adipocyte differentiation; age related; aged; clinical efficacy; cold temperature; combat; desensitization; healthspan; improved; juvenile animal; metabolic fitness; mouse model; novel; novel therapeutics; obese patients; pharmacologic; premature; preservation; prevent; progenitor; recruit; response; senescence; stem cell function; stem cells; thermal stress; transcriptomics; young adult

PROJECT SUMMARY: Cold temperature (<15°C) exposure stimulates perivascular beige adipocyte progenitor cells (bAPCs) to generate beige adipocytes. Beige adipocytes act as cellular furnaces to burn blood glucose and free fatty acids to generate heat. Recent studies have shown the metabolic benefits of beige adipocytes, suggesting potential clinical efficacy for obese patients and type 2 diabetics. However, the potential to form cold-induced beige adipocytes declines with age, creating a pivotal challenge to the therapeutic promise for older individuals, many of whom constitute the obesity epidemic. Our studies begin to unravel how aging suppresses beige adipogenic potential and identifies new ways to rejuvenate beige fat cell biogenesis to restore metabolic fitness in aged mammals. Our previous studies have linked cellular senescence, a state of cellular arrest, of bAPCs to the age- associated decline in beige adipose tissue. In an attempt to find additional mechanisms blocking beige fat biogenesis in aged mammals, we found that the expression and signaling of platelet derived growth factor receptor beta (Pdgfrβ) is increased in aged bAPCs. Moreover, ablation of Pdgfrβ within the beige adipose lineage restored beige adipocyte generation and improved metabolic health in aged (not young) mice. Despite beige fat formation in aged Pdgfrβ-deficient mice, lineage-tracing studies revealed that auxiliary source(s) generated beige adipocytes. In agreement, senescence tests demonstrated that Pdgfrβ neither promoted nor reversed cellular senescence. Instead, we found that Pdgfrβ signaling prevents group 2 innate lymphoid cell (ILC2) recruitment and activation within iWAT depots. Mechanistically, we identified that Pdgfrβ elicits signals via Stat1 to suppress the ILC2-inducer, interleukin-33 (IL-33), to control WAT ILC2 activity. Finally, we identify sympathetic tone as a significant regulator of age-induced Pdgfrβ expression. Our aims will elucidate the physiological and cellular role of Pdgfrβ in regulating beige fat biogenesis under aging and obese conditions. We will elucidate the Pdgfrβ-Stat1 signaling mechanism in bAPCs to control ILC2 recruitment via IL-33. We uncover how sympathetic output regulates Pdgfrβ expression to drive the age-dependent beige adipogenic failure. These findings will implicate Pdgfrβ signaling as a central node in the bAPC aging process. Importantly, this application will identify factors that reverse age-dependent beige adipogenic failure with a direct clinical utility to combat excess body fat and metabolic dysfunction to extend lifespan and restore health.

项目概要： 低温（<15°C）暴露会刺激血管周围米色脂肪细胞祖细胞（bAPC） 产生米色脂肪细胞 米色脂肪细胞充当燃烧血糖和游离脂肪酸的细胞炉。 最近的研究表明米色脂肪细胞具有代谢益处，这表明其具有潜在的潜力。 对于肥胖患者和2型糖尿病的临床疗效 然而，有可能形成寒冷诱发的米色。 脂肪细胞随着年龄的增长而减少，这对老年人的治疗前景提出了关键挑战，许多人 我们的研究开始揭示衰老如何抑制米色脂肪的形成。 潜力并确定了恢复米色脂肪细胞生物发生的新方法，以恢复老年人的代谢健康 我们之前的研究已将 bAPC 的细胞衰老（一种细胞停滞状态）与年龄联系起来。 米色脂肪组织的相关减少试图找到阻止米色脂肪的其他机制。 在老年哺乳动物的生物发生中，我们发现血小板衍生生长因子的表达和信号传导 受体β (Pdgfrβ) 在老化的bAPC 中增加，此外，米色脂肪谱系中Pdgfrβ 的消融。 尽管有米色脂肪，但恢复了米色脂肪细胞的生成并改善了老年（而非年轻）小鼠的代谢健康。 在老年 Pdgfrβ 缺陷小鼠中，谱系追踪研究表明，辅助源产生 与此一致的是，衰老测试表明 Pdgfrβ 既不促进也不逆转。 相反，我们发现 Pdgfrβ 信号传导可阻止第 2 组先天淋巴细胞 (ILC2)。 iWAT 库内的招募和激活 从机制上讲，我们发现 Pdgfrβ 通过 Stat1 引发信号。 抑制 ILC2 诱导剂白细胞介素 33 (IL-33)，控制 WAT ILC2 活性 最后，我们确定了交感神经。 音调作为年龄诱导的 Pdgfrβ 表达的重要调节因子。我们的目标是阐明其生理和功能。 我们将阐明 Pdgfrβ 在衰老和肥胖条件下调节米色脂肪生物发生的细胞作用。 bAPC 中的 Pdgfrβ-Stat1 信号传导机制通过 IL-33 控制 ILC2 募集。 输出调节 Pdgfrβ 表达以驱动年龄依赖性米色脂肪形成失败。 重要的是，该应用将识别 Pdgfrβ 信号作为 bAPC 老化过程的中心节点。 逆转年龄依赖性米色脂肪形成失败的因素，具有直接临床效用，可对抗多余的身体 脂肪和代谢功能障碍，以延长寿命和恢复健康。