Integrated Systemic and Adipose Depot-Specific Regulation of Adipogenesis

脂肪生成的综合系统和脂肪库特异性调节

基本信息

批准号：
10163160
负责人：
Brian J Feldman
金额：
$ 41.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2019-03-05 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163160
关键词：
ADAMTS1 gene Address Adipocytes Adipose tissue Adult Body Weight decreased Cell Line Cells Consumption Data Development Diabetes Mellitus Diet Glucocorticoids Health High Fat Diet Hormones Human In Vitro Kinetics Knockout Mice Knowledge Life Lipids Maps Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Metalloproteases Molecular Monitor Mus Obesity Outcome Pathogenesis Pathway interactions Pattern Physiological Physiology Population Process Proteins Regulation Reporter Research Role Sampling Signal Transduction Site Stimulus Testing Tissues Weight Gain adipocyte differentiation conditional knockout diet-induced obesity dietary restriction extracellular human subject in vivo insight lipid biosynthesis mouse model novel novel therapeutic intervention obesity development precursor cell programs reconstitution response stem cells transcription factor

项目摘要

PROJECT SUMMARY A great deal of our understanding of the process of adipogenesis has come from in vitro studies on cultured cell lines and adipose stromal fractions, focusing on the differentiation of committed preadipocytes into mature lipid-laden adipocytes. These studies have provided a wealth of knowledge, including elucidating an elegant cascade of mostly transcription factors that propels preadipocytes through the differentiation process into mature adipocytes. However, there is still a large knowledge gap in our understanding of the integrated factors that trigger this adipogenesis cascade in vivo and the influence of these pathways on the development of obesity and metabolic disease. Our proposal is focused on addressing these knowledge gaps. We identified a pathway in adipose tissue that is responsive to changes in diet and regulates endogenous adipocyte precursor cell (APC) activity. We found that ADAMTS1 is a critical mediator of this pathway that gates a depot-specific decision to induce adipogenesis in response to high-fat diet. We will test and define the function of this pathway in physiological mechanisms that regulate the initiation of the differentiation program in APCs. Using molecular and cellular approaches, as well as mouse models and samples from humans, we will elucidate the roles, mechanisms and relevance to human physiology of the Adamts1 pathway in the in vivo regulation of adipogenesis. In addition, we will reveal how this pathway modulates the systemic stimulus of high-fat diet to generate context-specific responses in the adipose tissue during diet-induced obesity. These studies will provide an integrated perspective on how this pathway functions to regulate adipogenesis and in the pathogenesis of obesity and insights into the implications for metabolism.

项目概要我们对脂肪生成过程的大部分了解都来自于培养的体外研究细胞系和脂肪基质组分，重点关注定向前脂肪细胞分化为成熟细胞充满脂质的脂肪细胞。这些研究提供了丰富的知识，包括阐明了一种优雅的主要是转录因子的级联，推动前脂肪细胞通过分化过程成为成熟的脂肪细胞。然而，我们对综合因素的认识还存在很大的知识差距触发体内脂肪生成级联反应以及这些途径对脂肪生成的影响肥胖和代谢疾病。我们的建议重点是解决这些知识差距。我们确定了一个脂肪组织中对饮食变化做出反应并调节内源性脂肪细胞前体的途径细胞（APC）活性。我们发现 ADAMTS1 是该通路的关键介体，可门控仓库特异性决定诱导脂肪生成以应对高脂肪饮食。我们将测试并定义这个函数调节 APC 分化程序启动的生理机制途径。使用分子和细胞方法，以及小鼠模型和人类样本，我们将阐明 Adamts1 通路在体内调节中的作用、机制及其与人体生理学的相关性脂肪生成。此外，我们将揭示该途径如何调节高脂肪饮食的全身刺激在饮食引起的肥胖期间，脂肪组织会产生特定的反应。这些研究将提供关于该途径如何发挥调节脂肪生成作用以及在肥胖的发病机制及其对代谢影响的见解。