The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.
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http://dx.doi.org/10.1172/JCI96138 | DOI Listing |
Circadian entrainment and external cues can cause gene transcript abundance to oscillate throughout the day, and these patterns of diel transcript oscillation vary across genes and plant species. Less is known about within-species allelic variation for diel patterns of transcript oscillation, or about how regulatory sequence variation influences diel transcription patterns. In this study, we evaluated diel transcript abundance for 24 diverse maize inbred lines.
View Article and Find Full Text PDFAm J Physiol Gastrointest Liver Physiol
January 2025
Department of Anatomy and Physiology, theUniversity of Melbourne, Australia.
The circadian cycle is a fundamental biological rhythm that governs many physiological functions across nearly all living organisms. In the gastrointestinal tract, activities such as gut motility, hormone synthesis, and communication between the gut, central nervous system and microbiome all fluctuate in alignment with the circadian cycle. The enteric nervous system (ENS) is critical for co-ordinating many of these activities, however, how its activity is governed by the circadian cycle remains unknown.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Biology, University of Padova, Padova, Italy.
While Drosophila melanogaster serves as a crucial model for investigating both the circadian clock and gut microbiome, our understanding of their relationship in this organism is still limited. Recent analyses suggested that the Drosophila gut microbiome modulates the host circadian transcriptome to minimize rapid oscillations in response to changing environments. Here, we examined the composition and abundance of the gut microbiota in wild-type and arrhythmic per flies, under 12 h:12 h light: dark (12:12 LD) and constant darkness (DD) conditions.
View Article and Find Full Text PDFCell Biol Int
January 2025
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Teine-ku, Japan.
The transcription factor brain and muscle Arnt-like protein-1 (BMAL1) is a clock protein involved in various diseases, including atherosclerosis and cancer. However, BMAL1's involvement in kidney fibrosis and the underlying mechanisms remain largely unknown, a gap addressed in this study. Analysis through Masson's trichrome and Sirius red staining revealed that all groups exposed to unilateral ureteral obstruction showed increased BMAL1 protein expression accompanied by increased TGF-β1 expression and elevated key fibrosis markers, including α-SMA, compared with sham groups.
View Article and Find Full Text PDFCureus
December 2024
Department of Biochemistry, Era University, Era's Lucknow Medical College and Hospital, Lucknow, IND.
Purpose Fibromyalgia syndrome (FMS) presents a chronic pain condition affecting muscles and joints. Investigating circadian rhythms' disruption, integral to physiological responses, this study delves into the potential impact of gene polymorphism (rs57875989) on FMS pathogenesis. Methods In this study, we investigated gene polymorphism in 100 FMS patients and an equal number of control individuals.
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