The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.
The human genetic variant rs6190 unveils Foxc1 and Arid5a as novel pro-metabolic targets of the glucocorticoid receptor in muscle.
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人类基因变异 rs6190 揭示了 Foxc1 和 Arid5a 作为肌肉中糖皮质激素受体的新型促代谢靶点。
DOI：
10.1101/2024.03.28.586997
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Quattrocelli,
中科院分区：
文献类型：
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作者：
Prabakaran,AshokDaniel;Chung,Hyun-Jy;McFarland,Kevin;Govindarajan,Thirupugal;ElAbdellaouiSoussi,Fadoua;Durumutla,HimaBindu;Villa,Chiara;Piczer,Kevin;Latimer,Hannah;Werbrich,Cole;Akinborewa,Olukunle;Horning,Robert;Quattrocelli,
糖皮质激素受体（GR）代谢作用的遗传决定因素在很大程度上仍不清楚。这是对GR单核苷酸多态性（SNP）rs6190（p.R23K）的认识上的一个引人注目的差距，它在人类中与增强的代谢健康有关，但其作用机制仍然完全未知。我们产生了转基因敲入小鼠基因拷贝这种多态性，以阐明如何突变GR影响代谢。与非突变的同窝小鼠相比，突变小鼠对常规食物和高脂饮食的胰岛素敏感性增加，减弱了饮食诱导的肥胖和运动不耐受的不良影响。骨骼肌中RNA-seq和ChIP-seq图谱的重叠显示突变GR增加了Foxc 1和Arid 5A基因的反式激活。使用亲肌性腺相关病毒在肌肉中进行体内过表达或敲低，我们发现Foxc 1是胰岛素反应途径基因Insr和Irs 1正常表达水平所必需的，足以促进肌肉胰岛素敏感性。同时，Arid 5a是必需的，足以转录抑制脂质摄取基因Cd 36和Fabp 4，减少肌肉三酰甘油的积累。此外，肌肉中的Foxc 1和Arid 5a程序被糖皮质激素方案不同地改变，在肌肉中具有相反的代谢结果。最后，我们在UK Biobank和All of Us数据集中发现了SNP作用机制的直接人类相关性，其中rs6190 SNP与BMI、瘦体重、力量和葡萄糖控制中的促代谢变化相关。总的来说，我们的研究利用人类核受体编码变体来揭示肌肉代谢的新型表观遗传调节因子。
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 Cd36 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.