CTRP and Metabolic Control

代谢稳态本质上是“系统生理学”。每个组织和器官内的细胞自主过程必须紧密协调，以允许对全身代谢的综合控制。这种整合部分是通过迷走神经系统实现的，迷走神经系统将大脑与内脏器官连接起来。相反，外周的组织串扰主要由分泌的激素介导。这些外周器官通信的激素回路的中断与代谢紊乱有因果关系。然而，我们缺乏有关生理和病理条件下这种激素调节机制的基本知识。为此，我们绘制器官水平代谢回路的努力主要集中在理解我们最初描述的高度保守的分泌型C1 q/TNF相关蛋白（CTRP 1 -15）家族的功能和作用机制上。在过去的十年中，我们已经产生了许多使能工具和小鼠模型，这些工具和模型促进了对CTRP生物学及其在糖和脂肪代谢（包括疾病背景下）中所起关键作用的理解的重大进展。在这种竞争性更新应用中，我们提出了CTRP 2的集中研究，CTRP 2是一种在脂肪组织中富集的特征不佳的CTRP家族成员。使用新的小鼠模型，我们发现CTRP 2是维持全身脂质稳态所必需的。我们的初步数据表明，CTRP 2是一种新的抗脂肪分解激素内的脂肪组织，以及一个重要的调节肝脏甘油三酯，胆固醇和磷脂代谢。我们提出了两个具体的目标，以了解CTRP 2调节脂肪组织（目的1）和肝脏（目的2），其主要靶组织的脂质代谢的机制。该项目的完成将为脂肪细胞和肝细胞中由CTRP 2直接调控的代谢基因回路和信号网络提供重要见解，以控制局部和全身脂质代谢。我们的研究有可能提供基本的见解，最终为临床环境中减轻代谢疾病结局的创新策略提供信息。

Metabolic homeostasis is inherently “systems physiology”. Cell-autonomous processes within each tissue and organ must be tightly coordinated to allow for the integrative control of whole-body metabolism. This integration is achieved in part by the vagal nerve system, connecting the brain to visceral organs. Tissue crosstalk in the periphery is instead largely mediated by secreted hormones. Disruption of hormonal circuits underlying these peripheral organ communications is causally linked to metabolic disorders. Yet, we lack fundamental knowledge about mechanisms underlying this hormonal regulation in both physiologic and pathologic conditions. Toward this end, our efforts to map the organ-level metabolic circuits have largely centered on understanding the function and mechanisms of action of a family of highly conserved secreted hormones—C1q/TNF-related proteins (CTRP1-15)—that we initially described. In the last decade, we have generated numerous enabling tools and mouse models that have promoted major advances in understanding CTRP biology and the critical roles they play in sugar and fat metabolism, including in disease contexts. In this competitive renewal application, we propose focused studies of CTRP2, a poorly characterized CTRP family member that is enriched in adipose tissue. Using novel mouse models, we discovered that CTRP2 is required for maintaining systemic lipid homeostasis. Our preliminary data suggest that CTRP2 is a novel anti-lipolytic hormone within the fat tissue, as well as an important regulator of hepatic triglyceride, cholesterol, and phospholipid metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP2 regulates lipid metabolism in adipose tissue (Aim 1) and liver (Aim 2), its major target tissues. The completion of this project will provide critical insights into the metabolic gene circuits and signaling networks directly regulated by CTRP2 in adipocytes and hepatocytes to control local and systemic lipid metabolism. Our studies have the potential to provide fundamental insights that ultimately inform innovative strategies to mitigate metabolic disease outcomes in clinical settings.