{"doi":"10.1101/2023.12.18.572210","title":"Glucocorticoid chrono-pharmacology unveils novel targets for the cardiomyocyte-specific GR-KLF15 axis in cardiac glucose metabolism","abstract":"ABSTRACT Circadian time-of-intake gates the cardioprotective effects of glucocorticoid administration in both healthy and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) and its co-factor, Krüppel-like factor (Klf15), play critical roles in maintaining normal heart function in the long-term and serve as pleiotropic regulators of cardiac metabolism. Despite this understanding, the cardiomyocyte-autonomous metabolic targets influenced by the concerted epigenetic action of GR-Klf15 axis remain undefined. Here, we demonstrate the critical roles of the cardiomyocyte-specific GR and Klf15 in orchestrating a circadian-dependent glucose oxidation program within the heart. Combining integrated transcriptomics and epigenomics with cardiomyocyte-specific inducible ablation of GR or Klf15, we identified their synergistic role in the activation of adiponectin receptor expression ( Adipor1 ) and the mitochondrial pyruvate complex ( Mpc1/2 ), thereby enhancing insulin-stimulated glucose uptake and pyruvate oxidation. Furthermore, in obese diabetic ( db/db ) mice exhibiting insulin resistance and impaired glucose oxidation, light-phase prednisone administration, as opposed to dark-phase prednisone dosing, effectively restored cardiomyocyte glucose oxidation and improved diastolic function towards control-like levels in a sex-independent manner. Collectively, our findings uncover novel cardiomyocyte-autonomous metabolic targets of the GR-Klf15 axis. This study highlights the circadian-dependent cardioprotective effects of glucocorticoids on cardiomyocyte glucose metabolism, providing critical insights into chrono-pharmacological strategies for glucocorticoid therapy in cardiovascular disease. GRAPHICAL ABSTRACT Brief summary Depending on when it is taken during the day, the drug prednisone activates the heart to","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401989,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":897705,"name":"Ashok Daniel Prabakaran","orcid":null,"position":1,"is_corresponding":false},{"id":1177918,"name":"Fadoua El Abdellaoui Soussi","orcid":"0009-0004-7376-229X","position":2,"is_corresponding":false},{"id":1179365,"name":"Olukunle Akinborewa","orcid":"0000-0002-6735-4802","position":3,"is_corresponding":false},{"id":1177919,"name":"Hannah Latimer","orcid":"0009-0000-2233-2485","position":4,"is_corresponding":false},{"id":73595,"name":"K. S. McFarland","orcid":"0000-0001-9289-5005","position":5,"is_corresponding":false},{"id":1178255,"name":"Kevin Piczer","orcid":null,"position":6,"is_corresponding":false},{"id":1178256,"name":"Cole Werbrich","orcid":null,"position":7,"is_corresponding":false},{"id":295889,"name":"Mukesh K. Jain","orcid":"0000-0002-0975-4760","position":8,"is_corresponding":false},{"id":236209,"name":"Saptarsi M. Haldar","orcid":"0000-0001-7968-9696","position":9,"is_corresponding":false},{"id":297682,"name":"Mattia Quattrocelli","orcid":"0000-0001-7011-1740","position":10,"is_corresponding":false},{"id":833293,"name":"Hima Bindu Durumutla","orcid":"0000-0002-1646-450X","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:20:23.920156Z","pmid":"38187555","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}