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枢纽，这有助于 维持全身动态平衡。肝脏新陈代谢对 生理信号，并在胰岛素抵抗状态下经历剧烈的重新编程。 肝脏也是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(肝素)。在释放到 循环中，肝细胞因子可作用于局部或其他外周组织和中枢 神经系统发挥多效性代谢作用，如最近对 FGF21.尽管肝源性分泌因子在全身能量中的作用不断扩大 内分泌肝脏残留物的代谢、分子性质和生理作用 这是分子新陈代谢中一个尚未解决的重要问题。应对这一挑战 为发现新的治疗靶点和 代谢性疾病的治疗方法。在初步研究中，我们发现 筑巢蛋白(TSKU)作为一种新的肝源性内分泌因子，表现出明显的 饮食诱导和遗传性肥胖小鼠的血浆水平升高。遗传 这种肝细胞因子的失活刺激了产热和能量消耗，并 保护小鼠免受高脂饮食引起的肥胖和代谢紊乱的影响。基于 这些令人兴奋的发现，我们假设TSKU加剧了饮食诱导 通过减弱生热和能量而使代谢健康恶化 支出。我们将使用体内和体外收获相结合的方法来检验这一假设- 和功能丧失模型系统。在目标1中，我们将研究血浆与 肥胖患者TSKU水平与肥胖的关系及TSKU在肥胖中的作用 饮食引起的新陈代谢紊乱。在目标2中，我们将剖析TSKU在 脂肪生热的生理调控。在目标3中，我们将剖析 TSKU调节脂肪交感神经创新的机制 3D成像和分子细胞工具的结合。成功完成这项工作 高度创新的项目将产生重大科学和技术方面的重大发现 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.