Hepatic nuclear receptor networks controlling responses to nutritional challenges

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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.