The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

Prabakaran, A. D.; Chung, H.-J.; McFarland, K.; Govindarajan, T.; Soussi, F. E. A.; Durumutla, H. B.; Villa, C.; Piczer, K.; Latimer, H.; Werbrich, C.; Akinborewa, O.; Horning, R.; Quattrocelli, M.

doi:10.1101/2024.03.28.586997

bioRxiv · 10.1101/2024.03.28.586997

The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.

Prabakaran, A. D.·Chung, H.-J.·McFarland, K.·Govindarajan, T.·Soussi, F. E. A.·Durumutla, H. B.·Villa, C.·Piczer, K.·Latimer, H.·Werbrich, C.·Akinborewa, O.·Horning, R.·Quattrocelli, M.

View original source ↗Export metadata ↓

Abstract

The genetic determinants of the glucocorticoid receptor (GR) metabolic action remain largely unelucidated. This is a compelling gap in knowledge for the GR single nucleotide polymorphism (SNP) rs6190 (p.R23K), which has been associated in humans with enhanced metabolic health but whose mechanism of action remains completely unknown. We generated transgenic knock-in mice genocopying this polymorphism to elucidate how the mutant GR impacts metabolism. Compared to non-mutant littermates, mutant mice showed increased insulin sensitivity on regular chow and high-fat diet, blunting the diet-induced adverse effects on adiposity and exercise intolerance. Overlay of RNA-seq and ChIP-seq profiling in skeletal muscle revealed increased transactivation of Foxc1 and Arid5A genes by the mutant GR. Using myotropic adeno-associated viruses for in vivo overexpression or knockdown in muscle, we found that Foxc1 was required and sufficient for normal expression levels of insulin response pathway genes Insr and Irs1, promoting muscle insulin sensitivity. In parallel, Arid5a was required and sufficient to transcriptionally repress the lipid uptake genes C 36 and Fabp4, reducing muscle triacylglycerol accumulation. Moreover, the Foxc1 and Arid5a programs in muscle were divergently changed by glucocorticoid regimens with opposite metabolic outcomes in muscle. Finally, we found a direct human relevance for our mechanism of SNP action in the UK Biobank and All of Us datasets, where the rs6190 SNP correlated with pro-metabolic changes in BMI, lean mass, strength and glucose control according to zygosity. Collectively, our study leveraged a human nuclear receptor coding variant to unveil novel epigenetic regulators of muscle metabolism. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/586997v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1af900borg.highwire.dtl.DTLVardef@119dcaforg.highwire.dtl.DTLVardef@e78baeorg.highwire.dtl.DTLVardef@1835427_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Prabakaran, A. D., Chung, H.-J., McFarland, K., Govindarajan, T., Soussi, F. E. A., Durumutla, H. B., Villa, C., Piczer, K., Latimer, H., Werbrich, C., Akinborewa, O., Horning, R., Quattrocelli, M.. 2024-03-31. The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.. https://doi.org/10.1101/2024.03.28.586997

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

28S-rsRNA facilitates PASMC proliferation through PKM2 β-hydroxybutyrylation

Ribosomal RNA-derived small RNAs (rsRNAs) are nucleic acid fragments originating from rRNA, the functions and roles of which in diseases remain incompletely understood. We identified 28S rsRNA-CTC_L20, an rsRNA whose expression is upregulated in hypoxic pulmonary artery smooth muscle cells (PASMCs) and in lung tissues of pulmonary hypertension (PH) models. In hypoxic cells, 28S rsRNA-CTC_L20 promotes PASMC proliferation, and its knockdown mitigates SuHx-induced pulmonary hypertension and vascular remodeling. Mechanistically, 28S rsRNA-CTC_L20 modulates {beta}-hydroxybutyrate (BHB) production by maintaining the stability of ketogenic enzyme mRNAs through its "CTGNNGG" motif. Elevated levels of BHB enhance the {beta}-hydroxybutyrylation modification at K166 of pyruvate kinase M2 (PKM2), increasing its activity and driving glycolysis to sustain proliferation. These results link ketone body metabolism to glycolysis in hypoxic cells and define an rsRNA-BHB-PKM2 {beta}-hydroxybutyrylation axis in PH. They also point to 28S rsRNA-CTC_L20 as a potential target for treating vascular remodeling.

physiology↗

bioRxiv2026

Selective activation of estrogen receptors modulates electrical activity and insulin secretion in human EndoC-βH1 cells

Estrogen receptors (ERs), ER and ER{beta} have important roles in the physiology of the endocrine pancreas in animal models, but the effects of ER activation on insulin-secreting human cells are still poorly understood. Here, we investigated the role of ER and ER{beta} as modulators of electrical activity and insulin secretion in the insulin-secreting human cell line EndoC-{beta}H1. Immunocytochemical analysis revealed a widespread cellular distribution of ER, while ER{beta} was predominantly localized outside the nucleus. We observed that both estradiol (E2) and the ER{beta} agonist diarylpropionitrile (DPN) led to a decrease in insulin secretion in the absence of stimulatory glucose concentrations, without affecting insulin content. Patch-clamp experiments revealed that a 48-hour treatment with either the ER agonist PPT or DPN resulted in depolarization of the resting membrane potential, increased action potential firing frequency, and altered the action potential waveform in EndoC-{beta}H1 cells. PPT increased voltage-dependent Ca2+ channel currents, while DPN reduced K+ and Na+ currents. These results suggest that activation of ER and ER{beta} modulates beta-cell electrical activity through distinct pathways involving ion channels. The effects of E2, PPT, and DPN were not caused by altered expression levels of ion channel genes after 48 hours of treatment. This suggests that these receptors act extranuclearly without affecting gene expression. Together, our findings demonstrate that selective activation of ER and ER{beta} modulates beta-cell excitability through distinct electrophysiological mechanisms and that E2 and DPN reduce basal insulin secretion in human EndoC-{beta}H1 cells. These results support ER and ER{beta} as potential targets for modulating human pancreatic beta-cell function.

physiology↗

bioRxiv2026

Body weight modifies the efficacy of lifespan-extending interventions in ad libitum-fed mice

Geroprotective interventions are often assessed by extension of lifespan in ad libitum-fed mice. Increased lifespan could therefore reflect rescue of adverse phenotypes of unhealthy controls. We analysed body weight and survival for 33,780 mice in the Interventions Testing Program (ITP) to test whether treatment effects varied with body weight. In males, each added standard deviation of attained adult weight made treatment 6% more favourable (HR 0.94), more apparent for interventions that lowered body weight (HR 0.90). Median lifespan increase rose from 6.2% in mice in the lightest quartile to 20.2% in the heaviest pre-dosing weight quartile among those experiments, mainly because control survival declined more steeply with weight than that of the intervention group. The effect of body weight was consistent across 13 of 14 compounds and reflected weight attained during adulthood rather than in early life. Weight-dependence of intervention effects was weak in ITP females, possibly because median survival of controls exceeded that of every sampled non-ITP female control group. Amelioration of weight-associated risk is therefore implicated as a major contributor to lifespan increases relative to heavy, short-lived controls. The geroprotective effects of these interventions may thus be less apparent in metabolically healthier mice or humans.

physiology↗