MAPK phosphatase–3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice
Zhidan Wu, Ping Jiao, Xueming Huang, Bin Feng, Yajun Feng, Shengyong Yang, Phillip Hwang, Jing Du, Yaohui Nie, Guozhi Xiao, Haiyan Xu
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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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.