Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolism

Background:

• Epidemiological studies link elevated thyroid stimulating hormone (TSH) to abnormal glucose levels.
• Previous research indicated TSH directly influences gluconeogenesis, but the molecular pathways were unknown.

Purpose of the Study:

• To elucidate the molecular mechanism by which TSH induces hepatic gluconeogenesis.
• To investigate the role of CRTC2 (CREB-regulated transcription coactivator 2) in TSH-mediated glucose regulation.

Main Methods:

• Utilized a mouse model of subclinical hypothyroidism with elevated TSH.
• Employed HepG2 cells to study TSH effects on CRTC2 expression, phosphorylation, and CREB activation.
• Assessed the impact of CRTC2 and CREB silencing on gluconeogenic gene expression (PEPCK-luciferase).
• Examined CRTC2:CREB complex formation in mouse livers with TSH receptor (TSHR) deletion.

Main Results:

• Subclinical hypothyroidism in mice led to increased fasting blood glucose and hepatic glucose production.
• TSH stimulation upregulated CRTC2 expression and promoted CRTC2 dephosphorylation and p-CREB (Ser133) in HepG2 cells via the TSHR/cAMP/PKA pathway.
• Silencing CRTC2 or CREB attenuated TSH-induced PEPCK-luciferase activity.
• TSHR deletion in mice reduced hepatic CRTC2:CREB complex levels.

Conclusions:

• TSH activates CRTC2 through the TSHR/cAMP/PKA signaling pathway.
• Activated CRTC2 forms a complex with CREB, leading to increased hepatic gluconeogenesis.
• This pathway highlights a novel mechanism linking TSH to hyperglycemia and provides potential targets for managing glucose metabolism disorders.