Mammals experience regular cycles of fasting and feeding, leading to dynamic transcriptional changes in metabolic tissues under fluctuating nutritional conditions. However, the transcriptional regulatory mechanisms employed by the liver, the primary metabolic organ, in response to metabolic stress remain unclear. In this study, we identify CTCFL, a testis-specific paralog of chromatin architecture protein CTCF, as a key transcriptional regulator that responds to metabolic stresses. Although CTCFL is typically expressed at low levels in somatic tissues, its expression in the liver increases significantly during starvation. The elevated genome occupancy of CTCFL at genes involved in fatty acid metabolism is associated with increased chromatin accessibility and transcriptional activity of these genes. We further found that mice lacking CTCFL exhibit dysregulation of metabolic genes and prominent lipid droplet accumulation at a young age, even on a regular diet. Interestingly, the loss of CTCFL also leads to a redistribution of CTCF and cohesin and the alteration in enhancer-promoter loops, thereby affecting the expression of loop-associated genes. Collectively, our study suggests that the liver modulates chromatin accessibility and higher-order chromatin structure in response to nutritional status by regulating CTCFL expression. This highlights a previously unappreciated, pleiotropic role of CTCFL in maintaining fatty acid metabolic homeostasis.

CTCF,CTCFL,transcription regulation,genome topology,metabolism homeostasis