NR4A orphan nuclear receptor signalling in skeletal muscle: evidence for crosstalk with the beta-adrenergic pathway.

NR4A亚群是核激素受体(NR)超家族的孤儿成员(这些超家族都与人类疾病有关)。NRs是激素依赖的DNA结合蛋白，将营养和病理生理信号转化为基因调控。在炎症、糖尿病、血脂异常和内分泌紊乱(例如，最畅销的治疗化合物中有15%针对NRS)的背景下，与功能失调的激素信号相关的药物的多样性突显了这一可药物家族在促进和维持人类健康方面的重要性。NR4A亚群是由多种生理刺激诱导的应激反应基因，与能量过剩(暴饮暴食)和饮食诱导的肥胖的反应有关。NR4A亚群在骨骼肌中表达，骨骼肌是一种主要的周围组织，占身体质量和能量消耗的40%左右。这种瘦肉组织是脂肪氧化、胰岛素刺激的葡萄糖利用和胆固醇代谢的主要场所。因此，这个组织在胰岛素敏感性、血脂谱和能量平衡方面发挥着显著的作用。因此，肌肉在血脂异常、糖尿病和肥胖症的进展中起着重要作用。令人惊讶的是，NR4A亚组在骨骼肌代谢中的功能尚未被研究。然而，考虑到关于NR4A介导的基因调控的数据，以及用于治疗代谢性疾病的潜在治疗效用，必须确定骨骼肌对NR4A作用的贡献。相应地，这项建议的目的是研究NR4A亚组的作用，并与了解血脂异常和肥胖的基础有关。

The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabetes, dyslipidemia, and endocrine disorders (e.g ~15% of the top selling therapeutic compounds target NRs). The NR4A subgroup are stress response genes which are induced by a wide range of physiological stimuli and have been implicated in the response to energy excess (over-eating) and diet induced obesity. The NR4A subgroup are expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of the body mass and energy expenditure. This lean tissue is a major site of fat oxidation, insulin-stimulated glucose utilization and cholesterol metabolism. Therefore this tissue plays a notable role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, muscle has a significant role in the progression of dyslipidemia, diabetes and obesity. Surprisingly, the function of the NR4A subgroup in skeletal muscle metabolism has not been examined. Nevertheless, given the data on NR4A mediated gene regulation, and the potential therapeutic utility for the treatment of metabolic disease, the contribution of skeletal muscle to NR4A action must be defined. Correspondingly, the objective of this proposal is to examine the role of the NR4A subgroup and is relevant to understanding the basis of dyslipidemia and obesity.