Thyroid Stimulating Hormone Increases Hepatic Gluconeogenesis Via CRTC2

Presentation Number: LBSat-46
Date of Presentation: April 2nd, 2016

Yujie Li*1, Laicheng Wang Sr.2, Yongfeng Song3, Lingyan Zhou4, Shizhan Ma5, Chunxiao Yu2, Jiajun Zhao6, Chao Xu7 and Ling Gao2
1Shandong Provincial Hospital affiliated to Shandong University, 2Shandong Provincial Hospital affiliated to Shandong University, Jinan, China, 3Shandong Provincial Hospital affiliated to Shandong University, Department of Endocrinology and Metabolism, China ;, Jinan, Shandong Province, 4Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University;, 5Shandong Provincial Hospital Affiliated to Shandong University, 6Institute of Endocrinology, Shandong Academy of Clinical Medicine., Jinan, China, 7Shandong Provincial Hospital affiliated to Shandong University, Department of Endocrinology and Metabolism, China ;, Jinan, Shandong

Abstract

Background: Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. Elevated hepatic gluconeogenesis is the major contributor to fasting hyperglycemia in individuals with type 2 diabetes. Previously, using Tshr knockout mice, we reported that TSH had direct effects on gluconeogenesis. However, the mechanism remained unclear. TSH acts via the classical cAMP/PKA pathway. CRTC2 maintained glucose homeostasis through its role as a cAMP coincidence sensor. This led us to explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis.

Methods:TSH function mediated through the THS receptor (TSHR) was tested by Tshr-/- mice (supplemented with thyroxine) and HepG2 cells transfected with siRNA-TSHR. The effect of TSH on PEPCK, G6P and CRTC2 was investigated in subclinical hypothyroidism (SCH) mice model, as well as in HepG2 cells treated with different dose of TSH. Fasting blood glucose level was tested in SCH mice. The molecules of PEPCK and G6P regulation of CRTC2 mediated by TSH were measured in HepG2 cells after transfected with siRNA-CRTC2. The pathway of cAMP/PKA/CRTC2 mediated by TSH was detected in HepG2 cells.

Results: OGTT results showed that high blood glucose levels in SCH mice at different time compared with control group (p<0.05). The mRNA of PEPCK, G6P and CRTC2 was also elevated in SCH mice liver compared with control group (p<0.01). Meanwhile, the protein of CRTC2 was increased in SCH mice liver. Simultaneously, TSH promoted the mRNA and protein of CRTC2 in HepG2 cells. More importantly, TSH induced the accumulation of CRTC2 via dephosphorylation of at CRTC2 Ser 171, a site important for subcellular localization in liver cells. Interestingly, the glucose output level, the mRNA of PEPCK and G6P and the PEPCK luciferase activity were reduced in HepG2 cells after transfected with siRNA-CRTC2 even exposed to TSH. We also found that the effect of TSH on CRTC2 was decreased in Tshr-/- mice compared with Tshr+/+ mice (wild type) as well as in primary hepatocytes from Tshr-/- mice and HepG2 cells transfected with siRNA-TSHR. Furthermore, we found that the increase of TSH-induced CRTC2 was attenuated after treatment with h89 (the PKA inhibitor) in HepG2 cells.

Conclusions:we explored whether TSH modulates glucose levels via gluconeogenesis, and whether CRTC2 is involved in the induction of abnormal gluconeogenesis by TSH. This study provides a more comprehensive understanding of the pathophysiological effects of TSH on glucose metabolism and suggests that TSH might have novel therapeutic importance in preventing glucose-related metabolic diseases in SCH patients.

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Nothing to Disclose: YL, LW Sr., YS, LZ, SM, CY, JZ, CX, LG