CTRP and Metabolic Control

摘要 新陈代谢的综合控制需要外周组织中的器官间通信；这 相声在很大程度上是由分泌的荷尔蒙策划的。我们的长期目标是了解 荷尔蒙控制能量动态平衡。这项提议是对一项持续的 研究项目集中在我们发现的一个保守的分泌型血浆蛋白家族上， C1q/肿瘤坏死因子相关蛋白(CTRPs)。在过去的十年中，我们提供了新的和重要的 了解不同CTRP激素对全身血糖的作用和贡献 脂类代谢。在下一个预算周期中，我们将重点研究CTRP6，一种具有 与迄今具有特点的其他CTRPS相比，行动模式根本不同。我们的 CTRP6的初步研究，结合最近对CTRP家族其他成员的研究，已经 导致了阴阳概念的产生，在阴阳概念中，不同的CTRPs起着积极或消极的作用 底物代谢的调节剂。基于功能增益和损耗的中心假说 在小鼠模型中，CTRP6作为葡萄糖的负生理调节因子发挥作用 新陈代谢。我们提出了两个具体的目标来理解CTRP6 在组织(目标1)和细胞(目标2)水平负向调节葡萄糖代谢。我们预计 目标1和目标2提供对代谢基因回路和信号网络的关键见解 由CTRP6直接调节脂肪细胞、骨骼肌和肝脏控制全身能量 新陈代谢。由于CTRP6调节的通路过度激活导致肥胖相关 胰岛素抵抗和糖尿病，我们的研究有可能提供洞察力，导致 在临床环境中逆转或减轻代谢性疾病结局的创新战略。

Abstract Integrated control of metabolism requires inter-organ communication in the peripheral tissues; this crosstalk is largely orchestrated by secreted hormones. Our long-term goal is to understand hormonal control of energy homeostasis. This proposal is a competitive renewal of a continuing research project focusing on a conserved family of secreted plasma proteins we identified, the C1q/TNF-related proteins (CTRPs). In the last decade, we have provided new and important knowledge on the roles and contributions of various CTRP hormones to whole-body glucose and lipid metabolism. In the next budget cycle, we will focus our studies on CTRP6, a protein with fundamentally different modes of action compared to other CTRPs characterized to date. Our preliminary studies on CTRP6, combined with recent studies of other CTRP family members, has led to the Yin and Yang concept, in which different CTRPs function as positive or negative regulators of substrate metabolism. The central hypothesis, based on gain- and loss-of-function mouse models, is that CTRP6 functions as a negative physiological regulator of glucose metabolism. We propose two specific aims toward understanding the mechanisms by which CTRP6 negatively regulates glucose metabolism at the tissue (Aim 1) and cellular (Aim 2) levels. We expect Aim 1 and Aim 2 to provide critical insights into metabolic gene circuits and signaling networks directly regulated by CTRP6 in adipocytes, skeletal muscle, and liver to control systemic energy metabolism. Since over-activation of the CTRP6-regulated pathways contributes to obesity-linked insulin resistance and diabetes, our studies have the potential to provide insights that lead to innovative strategies to reverse or mitigate metabolic disease outcomes in clinical settings.