The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, tens of thousands of long non-coding RNAs lncRNAs (lncRNAs) have been identified to constitute a significant portion of mammalian genomes. Interestingly, more then half of SNPs associated with diseases including metabolic disease fall in the noncoding regions suggesting that dysfunction of lncRNAs might be pathogenic. However, the pathophysiological roles of most lncRNAs remain poorly understood and their implications in metabolic disorders are largely unexplored. We have recently demonstrated that a liver-enriched lncRNA robustly regulates systemic lipid metabolism in vivo (Li et al, Cell Metabolism, 2015) and a second lncRNA regulates critical aspects of glucose metabolism in mice (Ruan et al, Cell Reports, 2016). However, it remains to be determined how many lncRNAs might regulate metabolism and what is the significance of lncRNA transcriptome to the overall metabolic regulation. Addressing this question requires identifying and characterizing functional lncRNAs in a genomewide scale, which is a challenging task given that it is extremely difficult to predict lncRNA functions. To understand the global impact of lncRNA transcriptome to energy metabolism, we have developed an integrative roadmap to identify thousands of regulated lncRNAs in metabolic disease models and to establish a catalog of 359 lncRNAs with predicted metabolic functions in vivo (Cell Metabolism, 2016 Oct 11; 24(4):627). Our findings support that lncRNAs are a bona fide component of nutrient-sensing and metabolic responses and that their significance to metabolic homeostasis is systemic and goes far beyond the scope that has currently been recognized. Furthermore, our work also establishes a framework for investigating the pathological role of lncRNAs in metabolic disorders and the potential to adapt these molecules for novel therapies.
