Integrated Systemic and Adipose Depot-Specific Regulation of Adipogenesis

项目摘要 我们对脂肪形成过程的大量理解来自于对培养的人胚胎干细胞的体外研究。 细胞系和脂肪基质成分，重点是定向前脂肪细胞分化为成熟的 富含脂质的脂肪细胞这些研究提供了丰富的知识，包括阐明一种优雅的 级联的主要转录因子，推动前脂肪细胞通过分化过程， 成熟脂肪细胞但是，我们对综合因素的认识还存在很大的知识差距 在体内引发这种脂肪生成级联反应的途径以及这些途径对 肥胖和代谢疾病。我们的建议侧重于解决这些知识差距。我们确定了一个 脂肪组织中对饮食变化有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是这一通路的关键介导因子， 决定诱导脂肪生成以响应高脂肪饮食。我们将测试和定义此功能 在调节APC分化程序启动的生理机制中，使用 分子和细胞的方法，以及小鼠模型和人类样本，我们将阐明 Adamts1通路在体内调节 脂肪生成此外，我们将揭示这一途径如何调节高脂饮食的全身刺激， 在饮食诱导的肥胖症期间在脂肪组织中产生特定于环境的反应。这些研究将 提供了一个综合的观点，这一途径如何发挥作用，以调节脂肪形成和在 肥胖的发病机制和对代谢的影响的见解。

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.