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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：
9894795
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894795
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 Patients Peripheral Physiological Physiology Plasma Proteins Public Health Regulation Role Signal Transduction Source Testing Thermogenesis Three-Dimensional Imaging Tissues Viral Weight Gain base energy balance in vivo innovation insight liver function liver metabolism loss of function metabolic imaging nerve supply new therapeutic target novel nutrient metabolism 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.

摘要