MAPK Phosphatase-3 Promotes Hepatic Gluconeogenesis Through Dephosphorylation of Forkhead Box O1 in Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2010 Oct 6

PMID 20921625

Citations 47

Authors

Zhidan Wu

Ping Jiao

Xueming Huang

Bin Feng

Yajun Feng

Shengyong Yang

Phillip Hwang

Jing Du

Yaohui Nie

Guozhi Xiao

Haiyan Xu

Affiliations

Soon will be listed here.

Abstract

Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice. Consistent with this, adenovirus-mediated MKP-3 overexpression in lean mice promoted gluconeogenesis and increased fasting blood glucose levels. Conversely, shRNA knockdown of MKP-3 in both lean and obese mice resulted in decreased fasting blood glucose levels. In vitro experiments identified forkhead box O1 (FOXO1) as a substrate for MKP-3. MKP-3-mediated dephosphorylation of FOXO1 at Ser256 promoted its nuclear translocation and subsequent recruitment to the promoters of key gluconeogenic genes. In addition, we showed that PPARγ coactivator-1α (PGC-1α) acted downstream of FOXO1 to mediate MKP-3-induced gluconeogenesis. These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM.

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