Regulation of retinoid homeostasis by the hormone FGF21

类维甲酸（维生素A（视黄醇）及其衍生物）是人体必需的微量营养素，在视觉中作为核受体的配体或光子受体参与许多生理过程。体内超过70%的类维甲酸以视黄醇酯的形式储存在特殊的肝细胞中。这些储存被动员起来，包括肝细胞对视黄醇酯的水解和视黄醇结合蛋白4 （RBP4）的分泌：视黄醇复合物。特别是在禁食期间，当脂蛋白运输的类维生素a的供应可以忽略不计时，循环RBP4是满足细胞需求的视黄醇的主要来源。在肝脏和肝外组织之间协调类视黄醇稳态的分子信号是未知的。我们做了一个令人惊讶的观察，小鼠的禁食减少了白色脂肪组织（WAT）中视黄醇酯的数量，而不是肝脏。这表明，肝脏的视黄醇动员是通过从肝外组织向肝脏的反向视黄醇运输来补充的。引人注目的是，当它们的肝视黄酰基酯储存耗尽时，小鼠表现出从肝脏中表达和分泌禁食激素成纤维细胞生长因子21 （FGF21）的增加。这与WAT中增加的脂肪分解和肝脏生酮有关，并导致葡萄糖耐量的改善，这表明FGF21在类维生素a稳态和器官间串扰中具有新的功能。因此，我们假设FGF21通过激活视黄醇酯水解酶（如激素敏感脂肪酶）诱导类维生素a从WAT重新分配到肝脏。我们认为这一途径在生理条件下（如对进食/禁食的适应）和代谢疾病（如肥胖和胰岛素抵抗）中受到干扰。在这个项目中，我们建议确定(i)空腹诱导的视黄醇从脂肪组织动员的分子事件和FGF21的需求，（ii）肝脏类视黄醇含量和FGF21表达之间的分子联系，（iii） FGF21介导的器官间串扰在代谢困难小鼠（如饮食诱导的肥胖）中的作用，以及（iv）涉及视黄醇向肝脏反向运输的器官间串扰是否，是FGF21对胰岛素敏感性有益作用的必要条件。解决这些问题将阐明RBP4/FGF21/类维甲酸轴与可能针对代谢性疾病的新型治疗干预的相关性。

Retinoids (Vitamin A (retinol) and its derivatives) are essential micronutrients and involved in a number of physiological processes by acting as ligands for nuclear receptors or as photon-acceptor in vision. More than 70% of all retinoids in the body are stored as retinyl esters in specialized liver cells. These stores are mobilized, involving the hydrolysis of retinyl esters and the secretion of the retinol binding protein 4 (RBP4):retinol complexes by hepatocytes. Especially during fasting, when the supply of lipoprotein-transported retinoids is negligible, circulating RBP4 is the principal source of retinol to meet cellular demands. The molecular signals that coordinate retinoid homeostasis between liver and extra-hepatic tissues are unknown. We made the surprising observation that fasting of mice reduced the amount of retinyl esters in white adipose tissue (WAT) but not liver. This suggests that retinol mobilization from the liver is replenished by reverse retinol transport from extrahepatic tissues back to the liver. Strikingly, when depleted of their hepatic retinyl ester stores, mice exhibited increased expression and secretion of the fasting-hormone fibroblast growth factor 21 (FGF21) from the liver. This was associated with increased lipolysis in WAT as well as hepatic ketogenesis, and led to improved glucose tolerance, suggesting a novel function of FGF21 in retinoid homeostasis and interorgan crosstalk. Thus, we hypothesize that FGF21 induces repartitioning of retinoids from WAT to the liver by activating retinyl ester hydrolases such as hormone-sensitive lipase. We propose that this pathway is relevant during physiological conditions (e.g. adaptation to feeding/fasting) and disturbed in metabolic diseases such as obesity and insulin resistance. In this project we propose to determine (i) the molecular events of fasting-induced retinol mobilization from adipose tissue and the requirement of FGF21, (ii) the molecular link between hepatic retinoid content and FGF21 expression, (iii) the role of FGF21-mediated interorgan crosstalk in metabolically-challenged mice (e.g. diet-induced obesity), and (iv) whether this interorgan crosstalk, involving reverse retinol transport to the liver, is required for the beneficial effects of FGF21 on insulin sensitivity. Addressing these aims will elucidate the relevance of the RBP4/FGF21/retinoid axis for novel therapeutic interventions that could target metabolic diseases.