Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model

Circadian time of intake determines the cardioprotective outcome of glucocorticoids in normal and infarcted hearts. The cardiomyocyte-specific glucocorticoid receptor (GR) is genetically required to preserve normal heart function in the long-term. The GR co-factor KLF15 is a pleiotropic regulator of cardiac metabolism. However, the cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted epigenetic action remain undefined. Here we report that circadian time of intake determines the activation of a transcriptional and functional glucose oxidation program in heart by the glucocorticoid prednisone with comparable magnitude between sexes. We overlayed transcriptomics, epigenomics and cardiomyocyte-specific inducible ablation of either GR or KLF15. Downstream of a light-phase prednisone stimulation in mice, we found that both factors are non-redundantly required in heart to transactivate the adiponectin receptor expression (Adipor1)and promote insulin-stimulated glucose uptake, as well as transactivate the mitochondrial pyruvate complex expression(Mpc1/2)and promote pyruvate oxidation. We then challenged this time-specific drug effect in obese diabeticdb/dbmice, where the heart shows insulin resistance and defective glucose oxidation. Opposite to dark-phase dosing, light-phase prednisone rescued glucose oxidation indb/dbcardiomyocytes and diastolic function indb/dbhearts towards control-like levels with sex-independent magnitude of effect. In summary, our study identifies novel cardiomyocyte-autonomous metabolic targets of the GR-KLF15 concerted program mediating the time-specific cardioprotective effects of glucocorticoids on cardiomyocyte glucose utilization.

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The human glucocorticoid receptor variant rs6190 promotes blood cholesterol and atherosclerosis

Durumutla,

Haller,

Noble

et al. 2024

Preprint

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Elevated cholesterol poses a significant cardiovascular risk, particularly in older women. The glucocorticoid receptor (GR), a crucial nuclear transcription factor that regulates the metabolism of virtually all major nutrients, harbors a still undefined role in cholesterol regulation. Here, we report that a coding single nucleotide polymorphism (SNP) in the gene encoding the GR, rs6190, associated with increased cholesterol levels in women according to UK Biobank and All Of Us datasets. In SNP-genocopying transgenic mice, we found that the rs6190 SNP enhanced hepatic GR activity to transactivate Pcsk9 and Bhlhe40, negative regulators of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors in liver respectively. Accordingly, in mice the rs6190 SNP was sufficient to elevate circulating cholesterol levels across all lipoprotein fractions and the risk and severity of atherosclerotic lesions on the pro-atherogenic hAPOE*2/*2 background. The SNP effect on atherosclerosis was blocked by in vivo knockdown of Pcsk9 and Bhlhe40 in liver. Remarkably, we found that this mechanism was conserved in human hepatocyte-like cells using CRISPR-engineered, SNP-genocopying human induced pluripotent stem cells (hiPSCs). Taken together, our study leverages a non-rare human variant to uncover a novel GR-dependent mechanism contributing to atherogenic risk, particularly in women.

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Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model

Cited by 4 publications

References 65 publications

Mitochondria in skeletal system-related diseases

Mitochondria in skeletal system-related diseases

Glucocorticoid chrono-pharmacology unveils novel targets for the cardiomyocyte-specific GR-KLF15 axis in cardiac glucose metabolism

The human glucocorticoid receptor variant rs6190 promotes blood cholesterol and atherosclerosis

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