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

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是营养和能量代谢的枢纽，有助于维持全身稳态。肝脏代谢高度敏感生理信号并在胰岛素抵抗状态下经历剧烈的重编程。肝脏还提供循环中分泌蛋白质的重要来源，包括脂蛋白、凝血因子和内分泌因子（肝因子）。释放后进入循环中，肝因子可能作用于局部或其他外周组织和中枢组织最近的研究表明，神经系统发挥多效代谢作用 FGF21。尽管肝源性分泌因子在全身能量中的作用不断扩大代谢、内分泌肝脏的分子性质和生理作用仍然存在分子代谢中一个重要的未解决问题。应对这一挑战为发现新的治疗靶点提供了重要的机会代谢性疾病的治疗方法。在初步研究中，我们确定 Tsukushin (TSKU) 作为一种新型肝源性内分泌因子，具有显着的作用饮食诱导和遗传性肥胖小鼠血浆中的水平升高。遗传这种肝因子的失活会刺激产热和能量消耗，保护小鼠免受高脂肪饮食引起的肥胖和代谢紊乱。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生热作用和能量而导致代谢健康恶化支出。我们将结合体内和体外增益来检验这一假设和功能丧失模型系统。在目标 1 中，我们将检查血浆的关联肥胖患者中 TSKU 水平与肥胖的关系，并确定 TSKU 在肥胖中的致病作用饮食引起的代谢紊乱。在目标 2 中，我们将剖析 TSKU 在以下方面的作用：脂肪产热的生理调节。在目标 3 中，我们将剖析 TSKU 通过以下机制调节脂肪交感神经创新： 3D 成像和分子细胞工具的结合。顺利完成本次高度创新的项目将产生重大科学和影响力的发现翻译价值。