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.

项目摘要： 冷温（<15°C）暴露刺激周围米色脂肪细胞祖细胞（BAPC）至 产生米色脂肪细胞。米色脂肪细胞充当细胞炉，可燃烧血糖和游离脂肪酸 产生热量。最近的研究表明，米色脂肪细胞的代谢益处，表明潜力 肥胖患者和2型糖尿病患者的临床效率。但是，形成冷诱导的米色的潜力 脂肪细胞随着年龄的增长而下降，对老年人的治疗承诺产生了关键的挑战，许多人 其中构成肥胖症流行。我们的研究开始揭示衰老如何抑制米色脂肪生成 潜力并确定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适应性 哺乳动物。我们以前的研究已将BAPC的细胞感受（一种细胞停滞状态）联系起来 米色脂肪组织的相关下降。试图找到阻塞米色脂肪的其他机制 老年哺乳动物的生物发生，我们发现血小板衍生生长因子的表达和信号传导 在老年BAPC中，受体β（PDGFRβ）增加。此外，在米色脂肪谱系中PDGFRβ的消融 恢复的米色脂肪细胞产生并改善了老年（不是年轻）小鼠的代谢健康。尽管米色脂肪 在老年PDGFRβ缺陷小鼠中形成，谱系追踪研究表明，辅助来源产生了 米色脂肪细胞。同意，感应测试表明PDGFRβ既没有促进也不反转 细胞感应。相反，我们发现PDGFRβ信号传导可防止2组先天淋巴样细胞（ILC2） IWAT沉积物内的招聘和激活。从机械上讲，我们确定PDGFRβ通过STAT1引起信号 为了抑制ILC2诱导剂，介体白介素33（IL-33），以控制ILC2活性。最后，我们确定同情 音调是年龄诱导的PDGFRβ表达的重要调节剂。我们的目标将阐明身体和 PDGFRβ在衰老和肥胖条件下米色脂肪生物发生的细胞作用。我们将阐明 BAPC中PDGFRβ-STAT1信号传导机制通过IL-33控制ILC2募集。我们发现了多么同情 输出调节PDGFRβ表达以驱动年龄依赖性的米色脂肪衰竭。这些发现会 在BAPC老化过程中，暗示PDGFRβ信号作为中央节点。重要的是，此应用程序将确定 逆转年龄依赖性的米色成型衰竭和直接临床实用性超过身体的因素 脂肪和代谢功能障碍可延长寿命并恢复健康。