Hepatokine Regulation of Thermogenesis and Metabolic Physiology

肝因子对生热和代谢生理学的调节

基本信息

批准号：
10376212
负责人：
Jiandie D Lin
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376212
关键词：
Ablation Address Adipose tissue Adrenergic Agents Attenuated Biological Models Blood Circulation Blood Coagulation Factor Body Temperature Brown Fat Data Deterioration Diet Disease Distal Endocrine Energy Metabolism Exhibits FGF21 gene Feedback Gene Expression Profiling Genetic Health Hepatic High Fat Diet Homeostasis Hormonal Human Imaging Device In Vitro Insulin Resistance Knowledge Leucine-Rich Repeat Link Lipoproteins Liver Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Molecular Genetics Mus Nature Neuraxis Neurobiology Norepinephrine Obese Mice Obesity Pathway interactions Peripheral Physiological Physiology Plasma Proteins Public Health Regulation Role Signal Transduction Source Testing Thermogenesis Three-Dimensional Imaging Tissues Viral Weight Gain base diet-induced obesity energy balance in vivo innovation insight liver function liver metabolism loss of function metabolic imaging nerve supply new therapeutic target novel nutrient metabolism obese patients obesity genetics prevent tool trait

Ablation Address Adipose tissue Adrenergic Agents Attenuated Biological Models Blood Circulation Blood Coagulation Factor Body Temperature Brown Fat Data Deterioration Diet Disease Distal Endocrine Energy Metabolism Exhibits FGF21 gene Feedback Gene Expression Profiling Genetic Health Hepatic High Fat Diet Homeostasis Hormonal Human Imaging Device In Vitro Insulin Resistance Knowledge Leucine-Rich Repeat Link Lipoproteins Liver Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Molecular Genetics Mus Nature Neuraxis Neurobiology Norepinephrine Obese Mice Obesity Pathway interactions Peripheral Physiological Physiology Plasma Proteins Public Health Regulation Role Signal Transduction Source Testing Thermogenesis Three-Dimensional Imaging Tissues Viral Weight Gain base diet-induced obesity energy balance in vivo innovation insight liver function liver metabolism loss of function metabolic imaging nerve supply new therapeutic target novel nutrient metabolism obese patients obesity genetics prevent tool trait

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项目摘要

Abstract The mammalian liver functions as a hub for nutrient and energy metabolism that helps maintain systemic homeostasis. Hepatic metabolism is highly responsive to physiological signals and undergoes drastic reprogramming in insulin resistant state. The liver also provides an important source of secreted proteins in circulation, including lipoproteins, coagulation factors, and endocrine factors (hepatokines). Upon release into circulation, hepatokines may act locally or on other peripheral tissues and the central nervous system to exert pleiotropic metabolic effects, as illustrated by recent studies on FGF21. Despite the expanding role of liver-derived secreted factors in systemic energy metabolism, the molecular nature and physiological action of the endocrine liver remains an important unsolved problem in molecular metabolism. Addressing this challenge provides a significant opportunity for the discovery of novel therapeutic targets and approaches for the treatment of metabolic disease. In preliminary studies, we identified Tsukushin (TSKU) as a novel liver-derived endocrine factor that exhibits markedly elevated levels in plasma from diet-induced and genetic obese mice. Genetic inactivation of this hepatokine stimulates thermogenesis and energy expenditure and protects mice from high-fat diet-induced obesity and metabolic disorders. Based on these exciting findings, we hypothesize that TSKU exacerbates diet-induced deterioration of metabolic health through attenuating thermogenesis and energy expenditure. We will test this hypothesis using a combination of in vivo and in vitro gain- and loss-of-function model systems. In Aim 1, we will examine the association of plasma TSKU levels with obesity in obese patients and establish the causative role of TSKU in diet-induced metabolic disorders. In Aim 2, we will dissect the role of TSKU in physiological regulation of adipose thermogenesis. In Aim 3, we will dissect the mechanisms through which TSKU modulates adipose sympathetic innovation using a combination of 3D imaging and molecular cellular tools. Successful completion of this highly innovative project will generate high-impact discoveries of significant scientific and translational value.

抽象的哺乳动物的肝脏充当营养和能量代谢的枢纽，有助于保持系统性稳态。肝代谢对生理信号并在抗胰岛素耐药状态下进行剧烈重编程。肝脏还提供了循环中分泌蛋白质的重要来源，包括脂蛋白，凝结因子和内分泌因子（肝素）。释放进入循环，肝运动可能在本地或其他周围组织和中央作用神经系统发挥了多效代谢作用，如最近的研究所示 FGF21。尽管肝脏衍生的分泌因素在全身能量中的作用不断扩大代谢，内分泌肝的分子本质和生理作用分子代谢中的一个重要问题。解决这个挑战为发现新颖的治疗靶标提供了重要的机会治疗代谢疾病的方法。在初步研究中，我们确定了 Tsukushin（tsku）是一种新颖的肝脏衍生的内分泌因子，表现出明显的表现饮食诱导和遗传肥胖小鼠血浆中血浆的水平升高。遗传这种肝动物的失活刺激了生热和能量消耗，保护小鼠免受高脂饮食诱发的肥胖症和代谢障碍。基于这些令人兴奋的发现，我们假设tsku加剧了饮食引起的通过减弱热生成和能量来恶化代谢健康支出。我们将使用体内和体外增益的组合检验这一假设。和功能丧失模型系统。在AIM 1中，我们将检查等离子体的关联肥胖患者的肥胖症水平，并确定tsku的致病作用饮食引起的代谢疾病。在AIM 2中，我们将剖析tsku的作用脂肪热发生的生理调节。在AIM 3中，我们将剖析 TSKU使用A调制脂肪交感神经创新的机制 3D成像和分子细胞工具的组合。成功完成高度创新的项目将产生大量科学和翻译价值。