Developmental and Dynamic Regulation of the Crosstalk between Adipocytes and the Sympathetic Nervous System

脂肪细胞与交感神经系统之间串扰的发育和动态调节

基本信息

批准号：
10547789
负责人：
Paul Cohen
金额：
$ 42.26万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547789
关键词：
3-Dimensional Address Adipocytes Adipose tissue Adrenergic Agonists Adult Affect Aging Architecture Basic Science Biogenesis Biological Biology Blood Vessels Cell physiology Cells Chemicals Collaborations Communication Complex Data Set Development Developmental Process Diabetes Mellitus Disease Embryonic Development Exhibits Exposure to Fatty acid glycerol esters Fatty-acid synthase Female Fibroblasts Genetic Genetic Transcription Homeostasis Human Imaging Techniques Immune Knock-out Knowledge Life Mammals Maps Metabolic Diseases Methods Molecular Morbidity - disease rate Mus Nerve Neurites Neurons Obesity Outcome Pathway interactions Phenotype Physiological Physiological Processes Play Process Proteins Proteomics Regulation Research Role Semaphorins Sympathetic Nervous System Techniques Testing Therapeutic Tissue imaging Tissues United States Use of New Techniques Variant Viral adipocyte differentiation candidate identification cell type comparative density gain of function genetic manipulation in vivo insight loss of function male mortality mouse model nerve supply neuregulin-4 novel novel strategies novel therapeutics obesity treatment postnatal preference public health emergency subcutaneous therapeutic target three-dimensional visualization

项目摘要

Obesity affects more than one in three adults in the United States and contributes to the leading causes of morbidity and mortality. Addressing this public health emergency will require new approaches supported by deeper understanding of fundamental biological mechanisms. Fat cells or adipocytes have been a focus of basic research into obesity and metabolic disease. Mammals possess white adipocytes that are efficient at storing energy and thermogenic brown and beige adipocytes that can convert energy into heat. The activation of beige fat cells is associated with anti-obesity and anti-diabetes effects. Beige fat cell function is dependent on the transcriptional coregulatory protein PRDM16. While the molecular pathways governing beige adipocyte development and phenotype have been increasingly delineated, little is known about how beige adipocytes interact with other cell types within adipose tissue. We developed a novel three-dimensional whole tissue imaging technique to provide insights into cellular crosstalk within adipose tissue. We discovered a regional preference for beige fat biogenesis and a regulated interaction between beige adipocytes and the sympathetic nervous system (SNS). Employing mouse models with adipocyte-specific Prdm16 loss of function, we found that PRDM16 in adipocytes regulates sympathetic neurite projections to these cells. Here we propose to address two aims to elucidate the mechanisms underlying the crosstalk between beige adipocytes and the SNS. First, we will investigate whether sympathetic projections to adipose tissue are established during development and/or show plasticity in different physiological contexts. Second, we will test the role of several candidate pathways in modulating the communication between beige adipocytes and sympathetic neurons. In addition, we will employ a cell-type selective proteomic approach to comprehensively characterize the molecular components involved in the interaction between beige adipocytes and sympathetic projections. This proposal will provide an integrated view of adipose tissue, including its architecture and the interaction between beige adipocytes and projections from the sympathetic nervous system. These studies will produce important technical and conceptual advances that address knowledge gaps in our understanding of adipose tissue biology and will yield new mechanism-based therapeutic targets for the treatment of obesity and associated diseases.

肥胖会影响美国的三分之一以上的成年人，并为主要原因做出了贡献发病率和死亡率。解决这一公共卫生紧急情况将需要由对基本生物学机制的更深入了解。脂肪细胞或脂肪细胞一直是肥胖和代谢疾病的基础研究。哺乳动物具有有效的白色脂肪细胞存储能量和热棕色和米色脂肪细胞，可以将能量转化为热量。激活米色脂肪细胞的抗肥胖和抗糖尿病作用有关。米色脂肪细胞功能取决于在转录核调节蛋白PRDM16上。而米色脂肪细胞的分子途径开发和表型越来越多地描绘，对米色脂肪细胞的方式知之甚少与脂肪组织中的其他细胞类型相互作用。我们开发了一种新颖的三维整体组织成像技术可为脂肪组织内的细胞串扰提供见解。我们发现了一个地区偏爱米色脂肪生物发生和米色脂肪细胞与交感神经之间的相互作用神经系统（SNS）。使用脂肪细胞特异性PRDM16功能丧失的鼠标模型，我们发现脂肪细胞中的PRDM16调节对这些细胞的交感神经突变。在这里我们建议解决两个旨在阐明米色脂肪细胞和串扰的机制的旨在 SNS。首先，我们将研究是否在在不同的生理环境下发展和/或显示可塑性。其次，我们将测试几个角色调节米色脂肪细胞和交感神经元之间的通信时，候选途径。在此外，我们将采用细胞类型选择性蛋白质组学方法来全面地表征米色脂肪细胞与交感神经投影之间相互作用涉及的分子成分。这提案将提供脂肪组织的综合视图，包括其结构和之间的相互作用来自交感神经系统的米色脂肪细胞和投影。这些研究将产生重要的技术和概念的进步解决我们对脂肪组织的理解中知识差距生物学，并将产生新的基于机制的治疗靶标，以治疗肥胖症和相关性疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sensory neurons expressing calcitonin gene-related peptide α regulate adaptive thermogenesis and diet-induced obesity.

DOI：
10.1016/j.molmet.2021.101161
发表时间：
2021-03
期刊：
Molecular metabolism
影响因子：
8.1
作者：
Makwana K;Chodavarapu H;Morones N;Chi J;Barr W;Novinbakht E;Wang Y;Nguyen PT;Jovanovic P;Cohen P;Riera CE
通讯作者：
Riera CE

Early postnatal interactions between beige adipocytes and sympathetic neurites regulate innervation of subcutaneous fat.