title: Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 544 Jing 4 Rd Jinan, Shangdong 250021, PR China.
authors.forename: Laicheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Shizhan
authors.initials: S
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 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. Electronic address: doctorxuchao@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Endocrinology, Shandong Academy of Clinical Medicine, Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 544 Jing 4 Rd Jinan, Shangdong 250021, PR China. Electronic address: gaoling1@medmail.com.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D007037:Hypothyroidism / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011989:Receptors, Thyrotropin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C493245:CRTC2 protein, human; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D011989:Receptors, Thyrotropin; D014157:Transcription Factors; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: CRTC2; Gluconeogenesis; PEPCK; TSH