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MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice.
- Source :
-
Journal of Clinical Investigation . Nov2010, Vol. 120 Issue 11, p3901-3911. 11p. 1 Diagram, 6 Graphs. - Publication Year :
- 2010
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MITOGEN-activated protein kinases
*GLUCONEOGENESIS
*INSULIN resistance
*GENETIC regulation
*HYPERGLYCEMIA treatment
*TREATMENT of diabetes
*GENE expression
*LABORATORY mice
*PROTEIN metabolism
*RNA metabolism
*GLUCOSE metabolism
*ANIMAL experimentation
*BODY weight
*COMPARATIVE studies
*FASTING
*GENETIC techniques
*INSULIN
*LIVER
*RESEARCH methodology
*MEDICAL cooperation
*METABOLISM
*MICE
*TYPE 2 diabetes
*PHOSPHATASES
*PROTEINS
*RESEARCH
*RNA
*TRANSCRIPTION factors
*EVALUATION research
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 120
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 55120063
- Full Text :
- https://doi.org/10.1172/JCI43250