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：
10393046
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/10393046
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 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敲除小鼠中均导致通过NLRP1（点头样受体蛋白1）激活凋亡棕色脂肪细胞死亡信号通路。同时，棕色的脂肪功能和较小程度的质量在衰老期间下降和与诱导凋亡的诱导同时，蝙蝠热发生的这种年龄相关的下降。此外，在两种模式下，BAT的回归都会降低胰岛素敏感性，能量棕色/米色脂肪细胞中STX4的表达可以逆转的支出和冷容忍度（UCP1-STX4转基因小鼠）或使用caspase 1的抑制剂阻断凋亡。 STX4基因敲除小鼠的蛋白质水平降低了细胞存活受体NTRK3，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，我们提出了一个多权研究者（MPI）应用以了解棕色脂肪下降的分子基础组织质量和功能在衰老的正常发展和功能/生理在能量平衡，胰岛素敏感性方面保留棕色质量和功能的后果代谢稳态。在此提案中，我们将确定1）特定途径和信号事件负责使用棕色脂肪细胞凋亡和使用蝙蝠使用的功能后果药理学和遗传干预措施； 2）神经酪氨酸的功能作用受体激酶NTRK3在调节蝙蝠质量，功能和棕色脂肪细胞凋亡中； 3）组织细胞身份的变化及其在年龄依赖性蝙蝠功能障碍和回归中的作用。然后，从该提案中获得的发现将允许制定策略以防止年龄依赖于年龄比归纳米色脂肪组织以改善葡萄糖代谢，增加能量消耗并防止体重增加。