Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15

El Abdellaoui-Soussi, F.; Durumutla, H. B.; Latimer, H.; Prabakaran, A. D.; McFarland, K.; Miz, K.; Piczer, K.; Werbrich, C.; Jain, M. K.; Haldar, S. M.; Quattrocelli, M.

doi:10.1101/2023.12.18.572210

bioRxiv · 10.1101/2023.12.18.572210

Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15

El Abdellaoui-Soussi, F.·Durumutla, H. B.·Latimer, H.·Prabakaran, A. D.·McFarland, K.·Miz, K.·Piczer, K.·Werbrich, C.·Jain, M. K.·Haldar, S. M.·Quattrocelli, M.

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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, Kruppel-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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/572210v3_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@cf4b3corg.highwire.dtl.DTLVardef@1547db1org.highwire.dtl.DTLVardef@7f85aorg.highwire.dtl.DTLVardef@141fe94_HPS_FORMAT_FIGEXP M_FIG C_FIG Brief summaryDepending on when it is taken during the day, the drug prednisone activates the heart to

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El Abdellaoui-Soussi, F., Durumutla, H. B., Latimer, H., Prabakaran, A. D., McFarland, K., Miz, K., Piczer, K., Werbrich, C., Jain, M. K., Haldar, S. M., Quattrocelli, M.. 2023-12-18. Light-phase prednisone promotes glucose oxidation in heart through novel transactivation targets of cardiomyocyte-specific GR and KLF15. https://doi.org/10.1101/2023.12.18.572210

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