Molecular Mechanism of Brown Adipose Tissue Regression

摘要 我们的初步数据表明，在ADIPOQ和UCP1特异的Stx4基因敲除小鼠中， NLRP1(结节样受体蛋白1)激活嗜酸性棕色脂肪细胞死亡 信号通路。同时，棕色脂肪的功能和重量在衰老和 这种与年龄相关的蝙蝠产热能力下降是伴随着下垂的诱发而发生的。 此外，在两种模式下，BAT的退化都会导致胰岛素敏感性、能量的降低。 棕色/米色脂肪细胞过度表达Stx4可逆转支出和耐寒性 (UCP1-Stx4转基因小鼠)或使用caspase 1抑制剂阻断下垂。此外，老年和 Stx4基因敲除小鼠降低了细胞存活受体NTRK3的蛋白水平，NTRK3是一种棕色脂肪细胞 棕色脂肪组织中的选择性酪氨酸受体激酶。基于这些数据，我们提出了一项 多主体调查者(MPI)在了解棕色脂肪减少的分子基础上的应用 衰老正常发育过程中的组织质量和功能及功能/生理 保存棕色质量和功能的后果，在能量平衡、胰岛素敏感性和 代谢动态平衡。在本提案中，我们将确定1)特定的路径和信号事件 负责棕色脂肪细胞下垂和保存BAT的功能后果 药物和遗传干预；2)嗜神经酪氨酸的功能作用 受体激酶NTRK3在调节蝙蝠体重、功能和棕色脂肪细胞下垂中的作用； 组织细胞特性的变化及其在年龄依赖性BAT功能障碍和退化中的作用。 从这项提案中获得的发现将允许制定预防年龄依赖的策略 BAT的消退可能会提供一种比诱导更容易和更有效的治疗方法 米色脂肪组织，改善葡萄糖代谢，增加能量消耗，防止体重增加。

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.