Molecular Mechanism of Brown Adipose Tissue Regression

棕色脂肪组织消退的分子机制

• 批准号: 10221852
• 负责人: Daorong Feng
• 金额: $ 57.81万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221852
• 关键词: Address; Adipocytes; Adipose tissue; Adolescent; Adult; Age; Age-Months; Aging; Applications Grants; Autophagocytosis; Birth; Blood Vessels; Brown Fat; CASP1 gene; CASP3 gene; Cell Death; Cell Nucleus; Cell Survival; Cell membrane; Data; Development; Down-Regulation; Energy Metabolism; Event; Familial generalized lipodystrophy; Female; Functional disorder; Gene Expression; Genetic; Homeostasis; Human; Insulin Resistance; Knock-out; Knockout Mice; Life; Ligands; Longevity; Mediating; Mediator of activation protein; Membrane Fusion; Membrane Lipids; Membrane Proteins; Metabolic; Mitochondria; Modeling; Molecular; Mus; NTRK3 gene; Neurotrophic Tyrosine Kinase Receptor Type 3; Pathway interactions; Pharmacology; Physiological; Play; Principal Investigator; Proteins; RNA; Receptor Protein-Tyrosine Kinases; Reporting; Role; SNAP receptor; SNAP23 gene; Signal Pathway; Signal Transduction; Thermogenesis; Time; Tissues; Transgenic Mice; Transgenic Organisms; Vesicle; Weight Gain; Wild Type Mouse; adiponectin; age related; aged; base; energy balance; gene therapy; glucose metabolism; improved; inhibitor/antagonist; insulin sensitivity; interleukin-1beta-converting enzyme inhibitor; lipid biosynthesis; male; neurotropic; normal aging; obesity prevention; paracrine; preservation; prevent; receptor; syntaxin 4; target SNARE proteins; therapeutic target; therapeutically effective; trafficking; transcriptome sequencing

Abstract Our preliminary data demonstrates that in both Adipoq and UCP1-specific Stx4 knockout mice results in the activation of pyroptotic brown adipocyte cell death through the NLRP1 (NOD-like receptor protein 1) signaling pathway. In parallel, brown adipose function and to a lesser extent mass declines during aging and this age-associated decline in BAT thermogenesis occur concomitant with the induction of pyroptosis. Furthermore, in both modes the regression of BAT results in the reduction in insulin sensitivity, energy expenditure and cold tolerance that can be reversed by over expression of Stx4 in brown/beige adipocytes (UCP1-Stx4 transgenic mice) or by blocking of pyroptosis using an inhibitor of caspase 1. In addition, aged and Stx4 knockout mice have reduced protein levels of the cell survival receptors Ntrk3, a brown adipocyte selective tyrosine receptor kinase within brown adipose tissue. Based upon these data, we are proposing a multi-principal investigator (MPI) application to understand the molecular basis for the decline in brown adipose tissue mass and function during the normal development of aging and the functional/physiological consequences of preserving brown mass and function, in terms of energy balance, insulin sensitivity and metabolic homeostasis. In this proposal, we will determine 1) the specific pathways and signaling events responsible for brown adipocyte pyroptosis and functional consequences of preserving BAT using both pharmacological and genetic interventions; 2) the functional role of the neurotropic tyrosine receptor kinase Ntrk3 in regulating BAT mass, function and brown adipocyte pyroptosis; and 3) changes in tissue cellular identity and its role during age-dependent BAT dysfunction and regression. The findings obtained from this proposal will then allow to develop strategies to prevent age-dependent regression of BAT that will likely provide a more tractable and effective therapeutic approach than the induction of beige adipose tissue to improve glucose metabolism, increase energy expenditure and prevent weight gain.

摘要 我们的初步数据表明，在Adipoq和UCP 1特异性Stx 4敲除小鼠中， 通过NLRP 1（NOD样受体蛋白1）激活焦萎棕色脂肪细胞死亡 信号通路与此同时，棕色脂肪的功能和在较小程度上的质量下降， 这种与年龄相关的BAT产热下降伴随着焦亡的诱导而发生。 此外，在这两种模式中，BAT的回归导致胰岛素敏感性、能量消耗和胰岛素抵抗的降低。 棕色/米色脂肪细胞中Stx 4的过度表达可以逆转消耗和耐冷性 （UCP 1-Stx 4转基因小鼠）或通过使用半胱天冬酶1的抑制剂阻断焦亡。此外，老年人和 Stx 4基因敲除小鼠的细胞存活受体Ntrk 3（一种棕色脂肪细胞）蛋白水平降低 棕色脂肪组织内的选择性酪氨酸受体激酶。根据这些数据，我们提出了一个 多主要研究者（MPI）应用程序，以了解棕色脂肪下降的分子基础 组织质量和功能的正常发展过程中的老化和功能/生理 在能量平衡、胰岛素敏感性和胰岛素敏感性方面， 代谢平衡在这个建议中，我们将确定1）特定的途径和信号事件 负责棕色脂肪细胞焦亡和使用保存BAT的功能后果 药理学和遗传学干预; 2）亲神经性酪氨酸的功能作用 受体激酶Ntrk 3在调节BAT质量、功能和棕色脂肪细胞焦亡中的作用;和3） 组织细胞特性的变化及其在年龄依赖性BAT功能障碍和退化过程中的作用。 从这项建议中获得的结果将有助于制定战略，防止年龄依赖性疾病的发生。 BAT的回归可能提供比诱导更易处理和更有效的治疗方法 米色脂肪组织，以改善葡萄糖代谢，增加能量消耗，防止体重增加。