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Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction., Author summary Adrenal glucocorticoid hormones are released in a characteristic ultradian rhythm that becomes dysregulated during chronic stress, disease, or synthetic corticosteroid treatment. Metabolic dysfunction is a comorbidity associated with all these conditions, but the role that altered glucocorticoid dynamics play is unknown. As the liver is a major site of glucocorticoid action on metabolic homeostasis regulated by the glucocorticoid receptor, we have assessed how different patterns of hormone replacement in adrenalectomised rats differentially regulate gene pathways involved in type II diabetes, cirrhosis, and fatty liver development, via altering the pattern of glucocorticoid receptor binding to regulatory sites. We believe our findings have important implications for therapies that can reproduce the endogenous glucocorticoid rhythm and thus minimize adverse metabolic side-effects in patients.