The insulin receptor (IR) plays critical roles in normal physiology and multiple chronic diseases through binding insulin and transducing this extracellular signal into cells as a tyrosine kinase. Although the presence of IR in the nucleus has been reported, little is known about its potential targets and biological function. Hancock et al. reported that IR at the cell surface could translocate into the nucleus upon insulin stimulation. There it forms a complex with RNA polymerase II and other factors involved in transcription to regulate the expression of genes related to insulin function. Further studies found that the association of IR with chromatin was mediated by a transcription co-regulator, host cell factor-1 (HCF-1). Knockdown of HCF-1 impaired the interaction of IR with chromatin and downstream gene expression without affecting the canonical PI3K-Akt cascades mediated by the tyrosine kinase activity of membrane-localized IR. HCF-1 knockdown mice phenocopied the effects of IR deficiency on lipid metabolism, suggesting a major role of nuclear IR in metabolic regulation. These findings reveal a new pathway for insulin signaling and add another layer of complexity to transcriptional regulation mediated by IR.