Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis

Young-Sil Yoon,Seung-Hoi Koo,Dongryeol Ryu,Sungpyo Hong,Min-Woo Lee

doi:10.3858/emm.2009.41.8.063

Young-Sil Yoon, Seung-Hoi Koo + Show 3 more

Open Access

https://doi.org/10.3858/emm.2009.41.8.063

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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.

Highlights

Glucose homeostasis is tightly regulated in mam mals via hormonal or nutritional signals that govern the cellular events in various metabolic tissues
In case of TZD, it was shown that the reagent enhances production of adiponectin via activation of peroxisome proliferator activated receptor (PPAR) γ from adipose tissues, which is linked to the activation of AMP activated protein kinase (AMPK) in various tissues including liver (Nawrocki et al, 2006)
Adenovirus-mediated expression of adiponectin, an adipokine known to induce AMPK activity in liver, inhibits gluconeogenic gene expression as well as CRE luciferase activity in primary hepatocytes (Figure 1A and 1B), suggesting adiponectin is directly responsible for the regulation of CREB-dependent transcription

Summary

Introduction

Glucose homeostasis is tightly regulated in mam mals via hormonal or nutritional signals that govern the cellular events in various metabolic tissues. We report that adiponectin and TZD can act directly upon hepatocytes, and regulate hepatic AMPK activity and CRTC2-dependent transcriptional cascades to modulate glucose metabolism in liver.

Results

Conclusion