Figure 1. Light-phase glucocorticoid stimulation improves glucose uptake and oxidation in the heart.

(A) Gene Ontology (GO) analysis revealed that ZT0 intermittent prednisone increased expression of Klf15, Adipor1, Mpc1, and Mpc2 from the enriched pathways of pyruvate transport and glucose import in the WT hearts. (B) Upregulation of KLF15 by prednisone was higher after ZT0 than ZT12 dosing, and upregulation of Adipor1, Mpc1, and Mpc2 was specific to ZT0 and blunted by ZT12 dosing. (C) Co-IPs in heart tissue showed that KLF15 interaction with GR was higher with ZT0 than ZT12 prednisone. (D) Consistent with Adipor1 upregulation, ZT0 prednisone treatment decreased myocardial ceramide levels and increased insulin-dependent 2DG uptake in the heart. (E) After ZT0, but not ZT12, treatment, cardiomyocytes increased basal glucose-fueled respiration ex vivo (arrow) and ATP production. (F) Consistent with Mpc1/2 upregulation, ZT0 treatment increased ADP-stimulated respiration (arrow) and respiratory control ratio with pyruvate in isolated mitochondria. (G) Circadian time-course qPCR analyses in myocardial tissues revealed oscillations of variable amplitude for Klf15, Adipor1, and Mpc1/2 expression. The transactivation effect by a single prednisone pulse was pronounced and prolonged over the circadian cycle with ZT0 injections, while ZT12 prednisone effects were either transient or nonsignificant. Data are presented as mean ± SEM; histograms also show individual mouse values. n = 3 ♂/group in A, n = (5 ♀ + 5 ♂)/group in B–G. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by Welch’s t test (A) or 2-way ANOVA with Šidák’s post hoc test (B–G).