Long noncoding RNAs (lncRNAs) have recently been recognised as multifaceted regulators of gene expression across multiple cellular and developmental contexts, yet their contribution to liver energy homeostasis remains poorly understood. Using global transcriptome profiling we demonstrate that both chronic and acute nutrient challenges elicit global anticorrelative transcriptional responses of protein-coding mRNAs and lncRNAs in liver. To address if lncRNAs functionally contribute to the control of liver metabolism, we performed in vitro characterisation of regulated hepatic lncRNAs and selected metabolically-responsive lncRNAs Gm15441 and lincIRS2 for further characterisations in vivo. Through CRISPR/Cas9-mediated genome engineering we generated deletion alleles of both selected lncRNAs and verified that expression of the respective transcripts were successfully abrogated in in vivo mouse models. Finally, we show that lincIRS2 deficiency causes hyperglycemia and impaired insulin tolerance in in vivo mouse models and provide evidence that lncIRS2 is essential for proper glucose homeostasis and insulin-evoked suppression of hepatic glucose production by impacting on AKT phosphorylation and gluconeogenic and lipogenic gene expression. Collectively, we propose the concept that nutrient-sensitive lncRNA lincIRS2 is transcriptionally coupled to alterations of systemic nutrient states and functions as molecular relay controlling liver energy homeostasis
