Molecular Mechanism of Brown Adipose Tissue Regression

棕色脂肪组织消退的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的我们的初步数据表明，在 Adipoq 和 UCP1 特异性 Stx4 敲除小鼠中，结果通过 NLRP1（NOD 样受体蛋白 1）激活焦亡棕色脂肪细胞死亡信号通路。与此同时，棕色脂肪的功能和质量在衰老和较小程度上下降。这种与年龄相关的 BAT 生热作用下降与细胞焦亡的诱导同时发生。此外，在这两种模式中，BAT 的退化都会导致胰岛素敏感性、能量和能量的降低。棕色/米色脂肪细胞中 Stx4 的过度表达可以逆转消耗和耐冷性（UCP1-Stx4 转基因小鼠）或通过使用 caspase 1 抑制剂阻断细胞焦亡。此外，衰老和 Stx4 基因敲除小鼠的细胞存活受体 Ntrk3（一种棕色脂肪细胞）的蛋白质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，我们提出多学科研究者（MPI）应用来了解棕色脂肪下降的分子基础衰老正常发展过程中的组织质量和功能以及功能/生理保留棕色物质和功能在能量平衡、胰岛素敏感性和功能方面的后果代谢稳态。在本提案中，我们将确定 1) 具体途径和信号事件负责棕色脂肪细胞焦亡和使用 BAT 保存的功能后果药理学和遗传干预； 2）亲神经酪氨酸的功能作用受体激酶 Ntrk3 调节 BAT 质量、功能和棕色脂肪细胞焦亡；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。从该提案中获得的研究结果将有助于制定预防年龄依赖性的策略 BAT 的回归可能会提供比诱导更容易处理和更有效的治疗方法米色脂肪组织可改善葡萄糖代谢，增加能量消耗并防止体重增加。