NURR1 activation in skeletal muscle controls systemic energy homeostasis (RNA-seq). NURR1 activation in skeletal muscle controls systemic energy homeostasis (RNA-seq)

Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1 and transgenic overexpression of NURR1 in skeletal muscle confers an endurance phenotype in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities. Overall design: RNA-seq experiment between 6 different conditions in mice.

骨骼肌在代谢调控与运动耐力维持中发挥核心作用。我们对小鼠运动后激活的肌肉增强子开展分析，发现孤儿核受体NURR1/NR4A2是运动响应性增强子的关键组成部分。本研究证实，运动可上调NURR1的表达；在骨骼肌中通过转基因手段过表达NURR1，可使小鼠获得耐力表型。骨骼肌中NURR1的表达还可通过促进肌肉葡萄糖摄取与糖原储存，有效预防高血糖与肝脂肪变性。进一步研究显示，给肥胖小鼠施用潜在的NURR1激动剂，可提升能量消耗、改善葡萄糖耐量，并诱导产生瘦体表型，模拟运动的生理效应。上述研究明确了NURR1在骨骼肌葡萄糖代谢调控中的关键作用，并揭示了运动与代谢之间的转录调控关联。本研究同时发现，NURR1激动剂可作为潜在的运动模拟剂，有望用于改善肥胖及其他代谢异常病症。整体实验设计：针对小鼠6种不同实验条件开展RNA测序（RNA-seq）实验。