PDF(Pubmed)
Abstract：
Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.
摘要：
肥胖,一个世界性的流行病,导致各种代谢紊乱威胁着人类的健康。为了应对压力或禁食，糖皮质激素（GC）水平升高以促进食物摄入。这涉及GC通过GC受体（GR）在下丘脑弓状核（ARC）的刺鼠相关蛋白（AgRP）神经元中诱导的食欲性神经肽的表达。这里,我们报道了一种选择性GR调节剂（SGRM），它抑制GR诱导的非经典糖皮质激素反应元件（GREs）基因转录，如Agrp-GRE，但不是经典的GRES，通过这种方式可以作为一种新型的抗肥胖药物。我们已经确定了一种新的SGRM，2-O-反式-对-香豆酰基二甲酸(Zj7)，从酸枣植物中提取的三萜类化合物，在不影响经典GREs的情况下选择性抑制Agrp-GRE中的GR转录活性。Zj7在高脂饮食诱导的肥胖和遗传肥胖db/db小鼠模型中降低了ARC中食欲基因的表达，并在体重减轻方面发挥了显着的食欲效应。转录组分析表明，Zj7抑制了下丘脑中合成的GR配体地塞米松（Dex）诱导的一组食欲基因的表达，包括Agrp和Npy。一起来看,Zj7，作为选择性GR调制器，表现出有益的代谢活动，部分是通过抑制食欲基因中非经典GREs中的GR活性。这项研究表明，潜在的厌食分子可能允许GRE特异性抑制GR转录活性，这是治疗代谢紊乱的一种有前途的方法。
