Li Yujie, Wang Laicheng, Zhou Lingyan, Song Yongfeng, Ma Shizhan, Yu Chunxiao, Zhao Jiajun, Xu Chao, Gao Ling
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Clinical Medical Center of Endocrinology and Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, 324 Jing 5 Rd Jinan, Shandong 250021, PR China.
Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 544 Jing 4 Rd Jinan, Shangdong 250021, PR China.
Mol Cell Endocrinol. 2017 May 5;446:70-80. doi: 10.1016/j.mce.2017.02.015. Epub 2017 Feb 15.
Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis.
流行病学证据表明，促甲状腺激素（TSH）与血糖异常呈正相关。我们之前报道过TSH对糖异生有直接影响。然而，其潜在的分子机制仍不清楚。在本研究中，我们在亚临床甲状腺功能减退小鼠模型（仅TSH水平升高）中观察到空腹血糖和葡萄糖生成增加。TSH通过经典的cAMP/PKA途径发挥作用，且CRTC2调节葡萄糖稳态。因此，我们探究CRTC2是否参与TSH诱导的糖异生过程。我们发现TSH通过TSHR/cAMP/PKA途径增加CRTC2表达，进而上调肝脏糖异生基因。此外，TSH刺激HepG2细胞中CRTC2去磷酸化并上调p-CREB（Ser133）。沉默CRTC2和CREB可降低TSH对磷酸烯醇式丙酮酸羧激酶荧光素酶（糖异生的限速酶）的作用。最后，TSHR的缺失降低了小鼠肝脏中CRTC2:CREB复合物的水平。本研究表明，TSH通过TSHR/cAMP/PKA途径激活CRTC2，导致CRTC2:CREB复合物形成并增加肝脏糖异生。
