MAPK phosphatase–3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice
Zhidan Wu, … , Guozhi Xiao, Haiyan Xu
Zhidan Wu, … , Guozhi Xiao, Haiyan Xu
Published October 1, 2010
Citation Information: J Clin Invest. 2010;120(11):3901-3911. https://doi.org/10.1172/JCI43250.
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Research Article Metabolism

MAPK phosphatase–3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice

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.

Authors

Zhidan Wu, Ping Jiao, Xueming Huang, Bin Feng, Yajun Feng, Shengyong Yang, Phillip Hwang, Jing Du, Yaohui Nie, Guozhi Xiao, Haiyan Xu

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Figure 1

Overexpression of MKP-3 in lean mice.

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Overexpression of MKP-3 in lean mice. (A) Endogenous MKP-3 protein level...
(A) Endogenous MKP-3 protein levels are increased in the liver of DIO mice. MKP-3 was immunoprecipitated from liver lysates using the Exactra D system to remove IgG signals, and MKP-3 protein was detected by Western blot analysis (WS) (n = 4). Loading was indicated with tubulin content in these samples. (B) MKP-3 protein in the liver of lean mice injected with adenoviruses expressing GFP or MKP-3 (n = 4). Phospho-ERK was examined as a functional readout of MKP-3 overexpression. (C) Blood glucose levels in lean mice expressing GFP or MKP-3 (n = 3–14). *P < 0.05. (D) Plasma insulin levels in lean mice overexpressing GFP or MKP-3 (n = 3–6). *P < 0.05, MKP-3–overexpressing versus GFP-overexpressing mice. (E) Relative expression of Pepck, G6pase, and Pgc1a genes in the liver of fasted lean mice injected with adenoviruses expressing GFP or MKP-3 (n = 3–6). *P < 0.05, MKP-3 versus GFP; #P < 0.05, Dex versus vehicle.