Extensive Regulation of Diurnal Transcription and Metabolism by Glucocorticoids

Abstract

Altered daily patterns of hormone action are suspected to contribute to metabolic disease. It is poorly understood how the adrenal glucocorticoid hormones contribute to the coordination of daily global patterns of transcription and metabolism. Here, we examined diurnal metabolite and transcriptome patterns in a zebrafish glucocorticoid deficiency model by RNA-Seq, NMR spectroscopy and liquid chromatography-based methods. We observed dysregulation of metabolic pathways including glutaminolysis, the citrate and urea cycles and glyoxylate detoxification. Constant, non-rhythmic glucocorticoid treatment rescued many of these changes, with some notable exceptions among the amino acid related pathways. Surprisingly, the non-rhythmic glucocorticoid treatment rescued almost half of the entire dysregulated diurnal transcriptome patterns. A combination of E-box and glucocorticoid response elements is enriched in the rescued genes. This simple enhancer element combination is sufficient to drive rhythmic circadian reporter gene expression under non-rhythmic glucocorticoid exposure, revealing a permissive function for the hormones in glucocorticoid-dependent circadian transcription. Our work highlights metabolic pathways potentially contributing to morbidity in patients with glucocorticoid deficiency, even under glucocorticoid replacement therapy. Moreover, we provide mechanistic insight into the interaction between the circadian clock and glucocorticoids in the transcriptional regulation of metabolism.

Bidirectional crosstalk between Hypoxia-Inducible Factor and glucocorticoid signalling in zebrafish larvae

“…The use of whole animals allows us to show how these signals interact at a more global level than in cell culture, where interactions between different tissues and cell types are not easily modelled. The zebrafish offers an excellent genetic vertebrate model system for endocrine studies, and similar to humans, they are diurnal and use cortisol as the main glucocorticoid hormone (Weger et al, 2016). Importantly, unlike other teleosts, zebrafish have only a single glucocorticoid (zGr) and mineralocorticoid receptor (Mr) (zMr) isoform (Faught and Vijayan, 2018).…”

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

“…The spread of the cortisol treatment effects across multiple principal components likely reflects differing biological responses to the treatment among different experiments. That the effects are somewhat different under total dark compared with light-dark cycles is not surprising given what is known about the interplay of GC signaling and the circadian clock [33][34][35][36] . Indeed GO analysis of PC2, which segregates our previously published experiment 23 from the two reported here (accounting for 18.5% of the variance), clearly shows that effects on circadian and light-responsive gene expression (Table S7).…”

An ATF4-mediated transcriptional adaptation of electron transport chain disturbance primes progenitor cells for proliferation in vivo

“…The resulting extracts were centrifuged twice for 10 min at 4°C and 16.400 g to remove cell debris. Amino acids were derivatised with AccQ-Tag reagent (Waters) and determined as described in [45]. Total glutathione was quantified by reducing disulfides with DTT followed by thiol derivatisation with the fluorescent dye monobromobimane (Thiolyte, Calbiochem).…”