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 3

MKP-3 knockdown in DIO mice.

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MKP-3 knockdown in DIO mice. Male C57BL/6J DIO mice were injected with a...
Male C57BL/6J DIO mice were injected with adenoviruses expressing either shGFP or shMKP-3. A subgroup of the mice were injected with Dex at a dose of 15 mg/kg. (A) Relative Mkp-3 mRNA levels in DIO mice injected with Ad-shGFP or Ad-shMKP-3 in the fed or fasted condition with or without Dex (n = 5–6 each group). (B) MKP-3 protein expression in DIO mice injected with Ad-shGFP or Ad-shMKP-3 (n = 6 each group). (C) Body weight and blood glucose levels in DIO mice injected with Ad-shGFP or Ad-shMKP-3 in the fed or fasted condition with or without Dex (n = 5–7 each group). (D) Insulin levels in DIO mice injected with Ad-shGFP or Ad-shMKP-3 in the fed or fasted condition with or without Dex (n = 5–7 each group). (E) Pyruvate tolerance test (n = 6 each group). (F) Glucose tolerance test (n = 6 each group). (G) Insulin tolerance test (n = 7 each group). (H) Hyperinsulinemic-euglycemic clamp study (n = 3 each group). HGP, hepatic glucose production. *P < 0.05, mice injected with Ad-shGFP versus mice injected with Ad-shMKP-3.