Hepatokine Regulation of Thermogenesis and Metabolic Physiology

摘要 哺乳动物的肝脏是营养和能量代谢的中心， 维持系统内稳态。肝脏代谢对 生理信号，并在胰岛素抵抗状态下经历剧烈的重编程。 肝脏还提供了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（肝细胞因子）。在释放到 在血液循环中，肝细胞因子可局部作用或作用于其他外周组织和中枢神经系统。 神经系统发挥多效性的代谢作用，如最近的研究所示， 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的问题。应对这一挑战 为发现新的治疗靶点提供了重要的机会， 治疗代谢性疾病的方法。在初步研究中，我们发现 Tsukushin（Tsukushin）是一种新的肝源性内分泌因子， 饮食诱导和遗传性肥胖小鼠血浆中的水平升高。遗传 这种肝因子的失活刺激产热和能量消耗， 保护小鼠免受高脂饮食诱导的肥胖和代谢紊乱。基于 这些令人兴奋的发现，我们假设TdR加剧了饮食诱导的 通过减少产热和能量而使代谢健康恶化 支出我们将使用体内和体外增益的组合来测试这一假设- 和丧失功能的模型系统。在目标1中，我们将研究血浆 肥胖患者中睾酮水平与肥胖的关系，并确定睾酮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Tactics在 脂肪产热的生理调节。在目标3中，我们将剖析 通过这种机制，Teptide调节脂肪交感神经的创新， 结合了3D成像和分子细胞工具。成功完成本 高度创新项目将产生重大科学发现， 翻译价值

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.