CTRP and Metabolic Control

CTRP 和代谢控制

• 批准号: 9897148
• 负责人: Guang William Wong
• 金额: $ 55.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897148
• 关键词: Adipocytes; Adipose tissue; Affect; Anabolism; Biological; Biology; Blood; Brain; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Research; Communication; Complement 1q; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diet; Disease; Disease Outcome; Energy Metabolism; Exhibits; Family; Family member; Fatty Liver; Fatty acid glycerol esters; Foundations; Funding; Future; Genes; Genetic; Genetic Transcription; Hepatic; Hepatocyte; Homeostasis; Hormonal; Hormones; Human; Hydrolysis; Impairment; Infusion procedures; Insulin; Insulin deficiency; Knockout Mice; Knowledge; Link; Lipids; Lipolysis; Liver; Maps; Mediating; Membrane; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mus; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Organ; Pathologic; Pathway interactions; Peripheral; Pharmacology; Phenotype; Phospholipid Metabolism; Phospholipids; Physiological; Physiology; Plasma; Play; Process; Proteins; Recombinants; Role; Signal Transduction; System; TNF gene; Testing; Tissues; Triglyceride Metabolism; Triglycerides; Visceral; glucose metabolism; hormone regulation; in vivo; innovation; insight; lipid metabolism; metabolomics; mouse model; novel; phosphoproteomics; programs; sugar; tool; transcriptome sequencing; very low density lipoprotein triglyceride

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.

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，以实现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，将大脑与内脏器官连接起来。相反，外周组织的串扰主要是由分泌的激素介导的。这些外周器官通讯基础的激素回路的破坏与代谢紊乱有因果关系。然而，我们缺乏关于生理和病理条件下这种激素调节机制的基础知识。为此，我们绘制器官水平代谢回路的努力主要集中在了解我们最初描述的高度保守的分泌激素家族——C1q/TNF 相关蛋白 (CTRP1-15) 的功能和作用机制。在过去的十年中，我们开发了许多支持工具和小鼠模型，促进了对 CTRP 生物学及其在糖和脂肪代谢（包括在疾病背景下）中发挥的关键作用的理解的重大进展。在此竞争性更新应用中，我们建议重点研究 CTRP2，这是一种特征较差的 CTRP 家族成员，富含脂肪组织。使用新型小鼠模型，我们发现 CTRP2 是维持全身脂质稳态所必需的。我们的初步数据表明，CTRP2 是脂肪组织内的一种新型抗脂解激素，也是肝甘油三酯、胆固醇和磷脂代谢的重要调节剂。我们提出了两个具体目标，以了解 CTRP2 调节脂肪组织（目标 1）和肝脏（目标 2）（其主要靶组织）中脂质代谢的机制。该项目的完成将为脂肪细胞和肝细胞中由 CTRP2 直接调节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见解，最终为减轻临床环境中代谢疾病结果的创新策略提供信息。