PMID- 20921625
OWN - NLM
STAT- MEDLINE
DCOM- 20101207
LR  - 20211020
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 120
IP  - 11
DP  - 2010 Nov
TI  - MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of 
      forkhead box O1 in mice.
PG  - 3901-11
LID - 10.1172/JCI43250 [doi]
AB  - 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 PPARgamma coactivator-1alpha 
      (PGC-1alpha) 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.
FAU - Wu, Zhidan
AU  - Wu Z
AD  - Cardiovascular and Metabolism, Novartis Institutes for BioMedical Research, 
      Cambridge, Massachusetts 02139, USA. zhidan.wu@novartis.com
FAU - Jiao, Ping
AU  - Jiao P
FAU - Huang, Xueming
AU  - Huang X
FAU - Feng, Bin
AU  - Feng B
FAU - Feng, Yajun
AU  - Feng Y
FAU - Yang, Shengyong
AU  - Yang S
FAU - Hwang, Phillip
AU  - Hwang P
FAU - Du, Jing
AU  - Du J
FAU - Nie, Yaohui
AU  - Nie Y
FAU - Xiao, Guozhi
AU  - Xiao G
FAU - Xu, Haiyan
AU  - Xu H
LA  - eng
GR  - R01 AR059647/AR/NIAMS NIH HHS/United States
GR  - R01 DK072230/DK/NIDDK NIH HHS/United States
GR  - R01 DK080746/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Insulin)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 6)
RN  - EC 3.1.3.48 (Dusp6 protein, mouse)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Body Weight
MH  - Diabetes Mellitus, Type 2/metabolism
MH  - Dual Specificity Phosphatase 6/genetics/*metabolism
MH  - Fasting
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Gluconeogenesis/*physiology
MH  - Glucose/metabolism
MH  - Insulin/metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Obese
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Trans-Activators/genetics/metabolism
MH  - Transcription Factors
MH  - Transfection
PMC - PMC2964981
EDAT- 2010/10/06 06:00
MHDA- 2010/12/14 06:00
PMCR- 2010/10/01
CRDT- 2010/10/06 06:00
PHST- 2010/04/06 00:00 [received]
PHST- 2010/08/18 00:00 [accepted]
PHST- 2010/10/06 06:00 [entrez]
PHST- 2010/10/06 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - 43250 [pii]
AID - 10.1172/JCI43250 [doi]
PST - ppublish
SO  - J Clin Invest. 2010 Nov;120(11):3901-11. doi: 10.1172/JCI43250.