Integrated Systemic and Adipose Depot-Specific Regulation of Adipogenesis

项目总结 我们对脂肪形成过程的大量了解来自于体外培养的 细胞系和脂肪基质组分，专注于将承诺的前脂肪细胞分化为成熟细胞 富含脂肪的脂肪细胞这些研究提供了丰富的知识，包括阐明一个优雅的 主要转录因子的级联反应，推动前脂肪细胞通过分化过程进入 成熟的脂肪细胞。然而，我们对综合因素的认识还存在很大差距。 在体内触发这一脂肪生成级联反应以及这些途径对血管生成的影响 肥胖和代谢性疾病。我们的建议的重点是解决这些知识差距。我们确定了一个 脂肪组织中响应饮食变化并调节内源性脂肪细胞前体的途径 细胞(APC)活动。我们发现，ADAMTS1是这条通路的关键中介，它可以开启特定于仓库的信号通路 决定诱导脂肪生成是对高脂肪饮食的反应。我们将测试和定义这一功能 调节APC分化程序启动的生理机制中的途径。vbl.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通路在体内调控中的作用、机制及其与人体生理学的关系 成脂作用。此外，我们还将揭示这一途径如何调节高脂饮食的系统性刺激，以 在饮食诱导的肥胖过程中，在脂肪组织中产生特定背景的反应。这些研究将 提供一个综合的视角，说明该途径如何发挥调节脂肪生成的作用 肥胖症的发病机制及其对新陈代谢的影响。

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.