Exp Mol Med.  2009 Aug;41(8):577-583. 10.3858/emm.2009.41.8.063.

Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis

• Yoon YS
• Ryu D
• Lee MW
• Hong S
• Koo SH

• KMID: 1119323
• DOI: http://doi.org/10.3858/emm.2009.41.8.063

Abstract

During fasting periods, hepatic glucose production is enhanced by glucagon to provide fuels for other organs. This process is mediated via cAMP-dependent induction of the CREB regulated transcriptional coactivator (CRTC) 2, a critical transcriptional activator for hepatic gluconeogenesis. We have previously shown that CRTC2 activity is regulated by AMP activated protein kinase (AMPK) family members. Here we show that adiponectin and thiazolidinedione directly regulate AMPK to modulate CRTC2 activity in hepatocytes. Adiponectin or thiazolidinedione lowered glucose production from primary hepatocytes. Treatment of both reagents reduced gluconeogenic gene expression as well as cAMP-mediated induction of CRE reporter, suggesting that these reagents directly affect CREB/CRTC2- dependent transcription. Furthermore, adiponectin or thiazolidinedione mediated repression of CRE activity is largely blunted by co-expression of phosphorylation defective mutant CRTC2, underscoring the importance of serine 171 residue of this factor. Taken together, we propose that adiponectin and thiazolidinedione promote the modulation of AMPK-dependent CRTC2 activity to influence hepatic gluconeogenesis.

Keyword

adiponectin; AMP-activated protein kinases; CRTC2 protein, human; gluconeogenesis; liver; thiazolidinediones

MeSH Terms

Adiponectin/*pharmacology
Animals
Cells, Cultured
*Gene Expression Regulation
Gluconeogenesis/*drug effects
Glucose/metabolism
Hepatocytes/drug effects/*metabolism
Humans
Liver/cytology/metabolism
Male
Mice
Mice, Inbred C57BL
Protein Kinases/genetics/metabolism
Rats
Rats, Sprague-Dawley
Thiazolidinediones/*pharmacology
Transcription Factors/genetics/*metabolism