Hepatic nuclear receptor networks controlling responses to nutritional challenges

能量代谢是人类健康各个方面的基础。随着肥胖、糖尿病和非酒精性脂肪肝的发病率激增，了解能量代谢如何在健康和疾病中起作用是最令人关注的问题。 禁食已经实践了几千年，但直到最近，研究才揭示了它在适应性细胞反应中的作用，这些反应可以减少氧化损伤和炎症，优化能量代谢，并加强细胞保护。虽然长期禁食不能用于预防和治疗代谢性疾病，但限时喂养已被证明可以减轻各种致肥饮食引起的代谢性疾病。在啮齿动物和人类中，间歇性或周期性禁食可以预防癌症，心脏病，糖尿病，高血压等。在哺乳动物中，肝脏在适应禁食中起着核心作用。肝脏是葡萄糖的主要储存库，葡萄糖以糖原的形式储存。在禁食期间，肝细胞产生葡萄糖和酮体，其被外周组织利用。肝脏对禁食的反应的主要部分是通过引发全面的转录程序来实现的。葡萄糖异生、脂肪酸氧化和生酮在很大程度上依赖于这种禁食诱导的转录网络。肝脏对禁食的反应依赖于基因调控已经有几十年的记录，涉及许多不同的转录因子。在这些因素中，协调基因组对禁食的反应是两种核受体，即糖皮质激素受体（GR）和过氧化物酶体激活受体（PPARa）。这两种受体在肝细胞中高度表达，它们控制特定的基因网络，包括视黄醇饱和酶（RetSat）和成纤维细胞生长因子21（FGF 21），以确保全身能量稳态。我们的项目旨在了解肝脏对禁食的这种转录反应，并研究它如何影响代谢健康。目的1将应用无偏的基因组方法来确定在禁食和饮食诱导的肥胖期间PPARa和GR之间的分子串扰，以发现新的调控节点。在目标2中，我们将靶向肝细胞RetSat和Fgf21对这些代谢反应的特定贡献。随后，在目标3中，我们将研究这些受体（PPARa，GR）和转录靶点（Fgf21，RetSat）在限时喂养对饮食诱导的代谢性疾病的有益作用中的功能作用。这些目标将通过结合该联盟在通过表型分析表征遗传小鼠模型以及NGS基因组学、代谢组学和生物信息学方面的互补专业知识来实现。总之，我们将获得对禁食的基本反应的机制见解，以发现治疗肥胖和营养过剩相关代谢疾病的新治疗靶点。

Energy metabolism underlies all facets of human health. With the rates of obesity, diabetes and nonalcoholic fatty liver disease surging, understanding how energy metabolism is governed in health and disease is of the utmost concern. Fasting has been practiced for millennia, but only recently, studies have shed light on its role in adaptive cellular responses that reduce oxidative damage and inflammation, optimize energy metabolism, and bolster cellular protection. While longterm fasting cannot be used to prevent and treat metabolic diseases, time-restricted feeding has been shown to attenuate metabolic disease arising from a variety of obesogenic diets. In rodents and humans, intermittent or periodic fasting protects against cancers, heart disease, diabetes, hypertension etc.In mammals, the liver plays a central role in the adaptation to fasting. The liver serves as the main reservoir of glucose, which is stored in the form of glycogen. During fasting, hepatocytes produce glucose and ketone bodies which are used by peripheral tissues. A major part of the livers’ response to fasting is achieved by eliciting a comprehensive transcriptional program. Gluconeogenesis, fatty acid oxidation and ketogenesis are largely dependent on such fasting-induced transcriptional networks.The reliance of the hepatic response to fasting on gene regulation has been documented for decades and involves many different transcription factors. Amongst these factors orchestrating the genomic response to fasting are two nuclear receptors, namely Glucocorticoid Receptor (GR) and Peroxisome ProliferatorActivated Receptor (PPARa). Both of these receptors are highly expressed in hepatocytes where they control a specific network of genes, including Retinol Saturase (RetSat) and Fibroblast Growth Factor 21 (FGF21), to ensure systemic energy homeostasis. Our project aims at understanding this transcriptional response to fasting in the liver and at investigating how it influences metabolic health. Aim 1 will apply unbiased genomic approaches to define the molecular cross-talk between PPARa and GR during fasting and diet-induced obesity in order to discover novel regulatory nodes. In Aim 2, we will target the specific contributions of hepatocyte RetSat and Fgf21 to these metabolic responses. Subsequently, in Aim 3 we will investigate the functional role of these receptors (PPARa, GR) and transcriptional targets (Fgf21, RetSat) in the beneficial effects of time-restricted feeding for diet-induced metabolic diseases. These goals will be achieved by combining the complementary expertise of the consortium in the characterization of genetic mouse models by phenotyping as well as NGS genomics, metabolomics and bioinformatics.Altogether, we will gain mechanistic insights into the fundamental response to fasting for discovering novel therapeutic targets for the treatment of metabolic diseases associated with obesity and overnutrition.