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 4

PGC-1α and FOXO1 are required for MKP-3–induced gluconeogenesis.

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PGC-1α and FOXO1 are required for MKP-3–induced gluconeogenesis. (A–E) E...
(A–E) Effect of PGC-1α knockdown on MKP-3–induced gluconeogenesis. MKP-3 or GFP is coexpressed with PGC-1α shRNA in rat primary hepatocytes via adenovirus-mediated gene transfer. Expression of Mkp-3 (A), Pgc1a (B), Pepck (C), and G6pase (D) genes as well as glucose output (E) were measured. *P < 0.05, MKP-3–overexpressing versus GFP-overexpressing cells in the presence/absence of PGC-1α shRNA. (F) MKP-3 and FOXO1 have an additive effect on Pgc1a transcription. The 2-kb Pgc1a promoter–driven luciferase construct was cotransfected with vector control or MKP-3 expression plasmid in the presence/absence of FOXO1. (G–K) Effect of dominant-negative (DN) FOXO1 Δ256 overexpression on MKP-3–induced gluconeogenesis. MKP-3 or GFP was coexpressed with FOXO1 Δ256 in rat primary hepatocytes via adenovirus-mediated gene transfer. Expression of Mkp-3 (G), Pgc1a (H), Pepck (I), and G6pase (J) genes as well as glucose output (K) were measured. *P < 0.05, bar 2 versus 1; bar 4 versus 3; #P < 0.05, bar 3 versus 1; bar 4 versus 2.