Glucocorticoid chronopharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program
Hima Bindu Durumutla, Ashok Daniel Prabakaran, Fadoua El Abdellaoui Soussi, Olukunle Akinborewa, Hannah Latimer, Kevin McFarland, Kevin Piczer, Cole Werbrich, Mukesh K. Jain, Saptarsi M. Haldar, Mattia Quattrocelli
Hima Bindu Durumutla, Ashok Daniel Prabakaran, Fadoua El Abdellaoui Soussi, Olukunle Akinborewa, Hannah Latimer, Kevin McFarland, Kevin Piczer, Cole Werbrich, Mukesh K. Jain, Saptarsi M. Haldar, Mattia Quattrocelli
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Research Article Cardiology Metabolism

Glucocorticoid chronopharmacology promotes glucose metabolism in heart through a cardiomyocyte-autonomous transactivation program

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 cofactor, Krüppel-like factor 15 (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 the GR/KLF15 axis remain undefined. Here, we demonstrated 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, restored cardiomyocyte glucose oxidation and improved diastolic function. These effects were blocked by combined in vivo knockdown of GR and KLF15 levels in db/db hearts. In summary, this study leveraged the circadian-dependent cardioprotective effects of glucocorticoids to identify cardiomyocyte-autonomous targets for the GR/KLF15 axis in glucose metabolism.

Authors

Hima Bindu Durumutla, Ashok Daniel Prabakaran, Fadoua El Abdellaoui Soussi, Olukunle Akinborewa, Hannah Latimer, Kevin McFarland, Kevin Piczer, Cole Werbrich, Mukesh K. Jain, Saptarsi M. Haldar, Mattia Quattrocelli

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Figure 5

ZT0 glucocorticoid treatment rescues glucose oxidation and diastolic function in db/db mice.

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ZT0 glucocorticoid treatment rescues glucose oxidation and diastolic fun...
(A) Schematic showing the 12-week-long prednisone treatment of db/db and their littermate controls (db/+) at ZT0 and ZT12. (B) Representative images of pulse wave Doppler echocardiography for mitral valve flow, and quantitation of baseline defects in E/e′, stroke volume, and heart mass in db/db mice. (C) ZT0 treatment decreased E/e′ in db/db hearts to db/+-like levels, while ZT12 treatment had no sizable effects. (D) ZT0, but not ZT12, treatment increased stroke volume in both db/db and db/+ mice. (E) Cardiac hypertrophy was alleviated in db/db hearts by ZT0, but not ZT12 treatment. (F) Treatment increased glucose uptake in myocardial tissue, measured as 2DG uptake, in both db/+ and db/db hearts only with ZT0 dosing. (G) Treatment increased glucose-fueled ATP production calculated from Seahorse curves in isolated cardiomyocytes in both db/+ and db/db mice according to time of intake (ZT0 but not ZT12), increasing db/db values to control-like levels. Data are presented as mean ± SEM; histograms also show individual mouse values. n = (5 ♀ + 5 ♂)/group. ****P < 0.0001 by Welch’s t test (B) or 3-way ANOVA with Šidák’s post hoc test (C–G).