A cross-tissue transcriptomic approach decodes glucocorticoid receptor-dependent links to human metabolic phenotypes.

Glucocorticoids, acting through the glucocorticoid receptor (GR), control metabolism, maintain homeostasis, and enable adaptive responses to environmental challenges. Their function has been comprehensively studied, leading to identification of numerous tissue-specific GR-dependent mechanisms. Abundant evidence shows that GR-triggered responses differ across tissues, however, the extent of this specificity was not comprehensively explored. It is also unknown how particular GR-induced molecular patterns are translated into profile of higher-level human traits. Here, we examine cross-tissue effects of GR activation on gene expression. We assessed changes induced by stimulation with GR agonist, dexamethasone in nine tissues (adrenal cortex, perigonadal adipose tissue, hypothalamus, liver, kidney, anterior thigh muscle, pituitary gland, spleen, and lungs) in adult male C57BL/6 mice, using whole-genome microarrays. Dexamethasone induced balanced transcriptional responses across all examined tissues with 585 identified dexamethasone-regulated transcripts, including 446 with significant treatment-tissue interaction effects. Clustering analysis revealed sixteen GR-dependent patterns, including those universal across tissues and tissue-specific. We leveraged existing gene annotations and created new annotation sets based on chromatin immunoprecipitation sequencing, recent large-scale genome-wide association studies, and human transcriptome collections. As expected, GR-dependent transcripts were associated with essential metabolic processes (glycolysis/gluconeogenesis, lipid-metabolism) and inflammation-related pathways. Beyond these, we found novel links between regulated gene patterns and human phenotypic traits, like reticulocyte count or blood triglyceride levels. Overall effects of GR stimulation are well coordinated and closely linked to biological roles of tissues and organs. Our findings provide novel insights into complex systemic and tissue-specific actions of glucocorticoids and their potential impacts on human physiology and pathology.