The fine-tuning between metabolic demand and supply of metabolites is enabled by the tightly regulation of mitochondrial function both at the posttranslational and transcriptional levels. In the latter, the family of nuclear receptors is largely responsible for translating environmental signals into transcriptional modulation, being orchestrated by the antagonistic action of transcriptional co-repressors and co-activators. Using publicly available ChIP-seq data, we demonstrated that the orphan nuclear receptor Nr2f6 cistrome is enriched in genes of the oxidative metabolism pathway and a recent study corroborated with these findings, showing that Nr2f6 depletion protects mice from non-alcoholic fatty liver disease. Nonetheless, the available literature describing its function is scarce and no study has been conducted to investigate its role in muscle metabolism. Our global transcriptome profiling of Nr2f6-depleted myocytes surprisingly revealed that these cells have an enhanced myogenic potential and subsequent experiments demonstrated an increased lipid oxidation capacity and lower lactate production while maintaining cellular ATP levels, with the concomitant activation of the AMPK and AKT pathways. These phenotypes prompted us to propose the investigation of the role of Nr2f6 in muscle metabolism in vivo and to dissect the direct targets of Nr2f6 in muscle cells. Since we gathered strong pieces of evidence for an increase in lipid oxidation and activation of key pathways for the insulin signaling cascade in Nr2f6-depleted myocytes, the study of Nr2f6 cistrome and the further characterization of its function in vivo is pivotal for elucidating the transcriptional regulation of muscle biology in health and metabolic diseases, with a promising translational application, considering it explores a potentially drug-targetable protein in a novel function.
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