Decreased fasting blood glucose is associated with impaired hepatic glucose production in thyroid-stimulating hormone receptor knockout mice.

Abstract

Our previous study reported that thyroid-stimulating hormone (TSH) promotes cholesterol synthesis via the cyclic adenosine monophosphate/protein kinase A/cAMP regulatory element-binding protein (cAMP/PKA/CREB) pathway after binding to TSH receptors (TSHR) in the liver. The hepatic cAMP/PKA/CREB pathway also plays an important role in maintaining fasting glucose homeostasis. These findings implied a possible role for TSH in hepatic glucose metabolism. In this study, we used TSH receptor knockout mice (Tshr-ko mice) to clarify the effect of Tshr deletion on hepatic glucose metabolism, and investigated whether the effects of TSH directly regulate hepatic gluconeogenesis in HepG2 cells. Tshr-ko mice exhibited decreased fasting blood glucose levels, increased insulin sensitivity but normal level of fasting plasma insulin. Tshr deletion impaired hepatic glucose production by down-regulating the expression of glucose-6-phosphatase (G6P) and phosphoenolpyruvate pyruvate carboxylase (PEPCK) mRNA, two rate-limiting enzymes in hepatic gluconeogenesis, and enhancing the abundance of hepatic glucokinase (GK), the first enzyme regulating glycogen synthesis. Moreover, Tshr deletion inhibited the protein expression of hepatic phospho-CREB and increased the protein expression of hepatic phospho-AMP-activated protein kinase (p-AMPK), two up-stream regulators of PEPCK and G6P mRNA. In HepG2 cells, TSH increased the expression of G6P and PEPCK at mRNA level. These results indicated the simulative effects of TSH on hepatic glucose production in vivo and in vitro, suggesting a novel role for TSH in hepatic glucose metabolism.

• Authors: Tingting Wang, Jin Xu, Tao Bo, Xiaoming Zhou, Xiuyun Jiang, Ling Gao, Jiajun Zhao
• Journal: Endocrine journal (Endocr J) Vol. 60 Issue 8 Pg. 941-50 ( 2013) ISSN: 1348-4540 [Electronic] Japan
• PMID: 23665701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Creb1 protein, mouse
• Cyclic AMP Response Element-Binding Protein
• Insulin
• Liver Glycogen
• Receptors, Thyrotropin
• Thyrotropin
• AMP-Activated Protein Kinases
• Glucose-6-Phosphatase
• Phosphoenolpyruvate Carboxykinase (GTP)
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Blood Glucose (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Down-Regulation
• Fasting
• Gluconeogenesis (drug effects, genetics)
• Glucose (metabolism)
• Glucose-6-Phosphatase (biosynthesis)
• Hep G2 Cells
• Humans
• Insulin (blood)
• Insulin Resistance
• Liver (metabolism)
• Liver Glycogen (metabolism)
• Mice
• Mice, Knockout
• Phosphoenolpyruvate Carboxykinase (GTP) (biosynthesis)
• Receptors, Thyrotropin (deficiency)
• Thyrotropin (pharmacology)