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

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