Lartey Lattoya J, Werneck-de-Castro João Pedro, O-Sullivan InSug, Unterman Terry G, Bianco Antonio C
From the Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
the Department of Internal Medicine, Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois 60612, the Carlos Chagas Filho Biophysics Institute and School of Physical Education and Sports, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, Brazil, and.
J Biol Chem. 2015 Dec 18;290(51):30551-61. doi: 10.1074/jbc.M115.665505. Epub 2015 Oct 23.
The activity of the thyroid gland is stimulated by food availability via leptin-induced thyrotropin-releasing hormone/thyroid-stimulating hormone expression. Here we show that food availability also stimulates thyroid hormone activation by accelerating the conversion of thyroxine to triiodothyronine via type 2 deiodinase in mouse skeletal muscle and in a cell model transitioning from 0.1 to 10% FBS. The underlying mechanism is transcriptional derepression of DIO2 through the mTORC2 pathway as defined in rictor knockdown cells. In cells kept in 0.1% FBS, there is DIO2 inhibition via FOXO1 binding to the DIO2 promoter. Repression of DIO2 by FOXO1 was confirmed using its specific inhibitor AS1842856 or adenoviral infection of constitutively active FOXO1. ChIP studies indicate that 4 h after 10% FBS-containing medium, FOXO1 binding markedly decreases, and the DIO2 promoter is activated. Studies in the insulin receptor FOXO1 KO mouse indicate that insulin is a key signaling molecule in this process. We conclude that FOXO1 represses DIO2 during fasting and that derepression occurs via nutritional activation of the PI3K-mTORC2-Akt pathway.
甲状腺的活动通过瘦素诱导的促甲状腺激素释放激素/促甲状腺激素表达受食物供应的刺激。在此我们表明，食物供应还通过加速小鼠骨骼肌以及从0.1%胎牛血清过渡到10%胎牛血清的细胞模型中甲状腺素向三碘甲状腺原氨酸的转化来刺激甲状腺激素的激活。潜在机制是通过rictor基因敲低细胞中定义的mTORC2途径对DIO2进行转录去抑制。在维持于0.1%胎牛血清的细胞中，通过FOXO1与DIO2启动子结合会抑制DIO2。使用其特异性抑制剂AS1842856或组成型活性FOXO1的腺病毒感染证实了FOXO1对DIO2的抑制作用。染色质免疫沉淀研究表明，在含10%胎牛血清的培养基处理4小时后，FOXO1结合显著减少，并且DIO2启动子被激活。对胰岛素受体FOXO1基因敲除小鼠的研究表明，胰岛素是这一过程中的关键信号分子。我们得出结论，在禁食期间FOXO1抑制DIO2，而去抑制通过PI3K - mTORC2 - Akt途径的营养激活发生。
