Sensing fluctuations in nutrient levels is essential for life. Therefore, mammals have evolved distinct mechanisms to sense the abundance of lipids, amino acids and glucose. Nutrient-sensing pathways stimulate anabolism and storage, when food is abundant, whereas scarcity induces homeostatic processes, such as the mobilization of internal energy stores. Transcription factors, in particular members of the nuclear receptor superfamily, are the proteins through which nutrients can directly influence gene expression. Many nuclear receptors bind micro- and macronutrients or their metabolites, such as fatty acids to PPARs, oxysterols to liver X receptors (LXRs), bile acids to farnesoid X receptor (FXR) and vitamin D metabolites to VDR. In particular in metabolic organs, such as liver, pancreas, intestine and adipose tissue, nuclear receptors respond to nutrient changes and specifically activate hundreds of their target genes. Moreover, also the immune system is triggered in its inflammatory and antigen response by nuclear receptors and their ligands. In addition, nuclear receptors belong to those transcription factors that play a central role in managing the molecular clock both in the CNS as well as in metabolic organs.
In this chapter, we will discuss nutrient sensing mechanisms via membrane receptors, metabolic enzymes, regulatory kinases and transcription factors. We will get insight into the central role of nuclear receptors in the translation of nutrient fluctuations into responses of the genome. We will use the nuclear receptors PPARs, LXR and FXR as examples, in order to understand their important function in controlling fatty acid, cholesterol and bile acids transport and metabolism. Furthermore, we will demonstrate the impact of vitamin D and its receptor VDR on the function of both the innate and the adaptive immune system. Finally, we will integrate the knowledge on nutrient sensing with information on circardian processes controlling anabolism and catabolism.