CTRP and Metabolic Control

代谢动态平衡本质上是“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，以实现对全身新陈代谢的综合控制。这种整合部分是通过连接大脑和内脏器官的迷走神经系统实现的。相反，外围的组织串扰在很大程度上是由分泌的激素调节的。这些外周器官通讯背后的荷尔蒙回路中断与代谢紊乱有因果关系。然而，我们对生理和病理条件下荷尔蒙调节的潜在机制缺乏基础知识。为此，我们绘制器官水平代谢回路的努力在很大程度上集中在了解我们最初描述的一系列高度保守的分泌激素-C1q/肿瘤坏死因子相关蛋白(CTRP1-15)的功能和作用机制。在过去的十年里，我们创造了许多使能工具和小鼠模型，促进了在理解CTRP生物学及其在糖和脂肪代谢中所起的关键作用方面的重大进展，包括在疾病背景下。在这一竞争性更新应用中，我们建议对CTRP2进行重点研究，CTRP2是一个特征不佳的CTRP家族成员，富含脂肪组织。利用新的小鼠模型，我们发现CTRP2是维持全身脂质平衡所必需的。我们的初步数据表明，CTRP2是一种新的脂肪组织中的抗脂类激素，也是肝脏甘油三酯、胆固醇和磷脂代谢的重要调节因子。我们提出了两个特定的目标，以了解CTRP2调节其主要靶组织脂肪组织(Aim 1)和肝脏(Aim 2)的脂代谢的机制。该项目的完成将对CTRP2直接调控脂肪细胞和肝细胞中的代谢基因电路和信号网络以控制局部和全身脂质代谢提供关键的见解。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性疾病结果的创新战略提供参考。

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.