CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY

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PROJECT SUMMARY Glucocorticoid steroids are conserved pleiotropic hormones regulating the circadian cycle of energy utilization and storage in virtually all our organs. Nutrient metabolism in the heart is critical to adapt the high energy demand to circadian oscillations and/or diseased states like diabetic cardiomyopathy. Glucocorticoids exert their effects through the glucocorticoid receptor (GR), which is required for normal heart function. Indeed, synthetic glucocorticoids are routinely used to rescue cardiac conditions of metabolic acidosis and depressed function, such as low cardiac output syndrome. However, chronic GR over-stimulation with synthetic glucocorticoids promotes metabolic syndrome and cardiovascular diseases. Thus, the molecular and circadian effects of synthetic glucocorticoids and their receptor on cardiac metabolism are still unresolved. Using dystrophic mice as model of chronic striated muscle injury, I discovered that intermittent dosing (once-weekly) of glucocorticoids boosts nutrient utilization and insulin sensitivity in dystrophic muscle and heart. Here I postulate that intermittent glucocorticoids improve cardiometabolic health beyond the dystrophic heart and can be exploited to combat diabetic cardiomyopathy. In mice, oscillations of endogenous corticosterone and circadian clock factors create a critical time window for acute GR responsiveness to pharmacological activation in the early diurnal phase. Indeed, I found that diurnal – but not nocturnal – regimens of intermittent prednisone improved cardiac function and metabolism in wildtype hearts. Diurnal administration was critical for the prednisone-driven GR program to boost mitochondrial capacity and activate the metabolic regulators KLF15 and AMPK. Also, diurnal prednisone reduced 3-hydroxyisobutyrate (3-HIB), biomarker of impaired catabolism of branched chain amino acids (BCAA) and insulin resistance in diabetes. Thus, I hypothesize that chrono- pharmacology with diurnal glucocorticoids promotes cardiometabolic health through GR, KLF15 and AMPK activation, and reduces 3-HIB as biomarker of metabolic rescue in diabetic cardiomyopathy. To test this hypothesis, we will articulate the project to test three complementary mechanisms: in Aim 1, we will test the requirement for GR and the clock factor BMAL in the effects of diurnal prednisone on mitochondrial capacity in heart; in Aim 2, we will define requirement and epigenomic mechanisms for the GR-activated KLF15 in reshaping nutrient utilization in cardiomyocytes in response to prednisone chrono-dosing; in Aim 3, we will determine the role of AMPK and BCAA oxidation in mediating the effects of diurnal intermittent prednisone on metabolic flexibility and 3-HIB levels in diabetic cardiomyopathy. This proposal charts a novel path to cardiometabolic rescue by exploiting the circadian-gated response to synthetic glucocorticoids in heart. Defining unprecedented mechanisms of interplay between glucocorticoid cascades and circadian clock, the project will provide evidence for time-restricted intermittent dosing as “flip switch” of glucocorticoid action in heart metabolism, converting these drugs from “pro-diabetic” to “anti-diabetic” in cardiometabolic health.