Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity.
The mitogen-activated protein kinases (MAPK) play critical roles in the pathogenesis of diabetes and obesity. The MAPKs are inactivated by MAPK phosphatases (MKPs) either in the cytosol or nucleus. Here we show that mice lacking the nuclear-localized MKP, MKP-1 (mkp-1(-/-)), have enhanced Erk, p38 MAPK and c-Jun NH(2)-terminal kinase (JNK) activities in insulin-responsive tissues as compared with wild-type mice. Although JNK promotes insulin resistance, mkp-1(-/-) mice exhibited unimpaired insulin-mediated signaling and glucose homeostasis. We reconciled these results by demonstrating that in mkp-1(-/-) mice, JNK activity was increased in the nucleus, but not the cytosol. Significantly, mkp-1(-/-) mice are resistant to diet-induced obesity due to enhanced energy expenditure, but succumb to glucose intolerance on a high fat diet. These results suggest that nuclear regulation of the MAPKs by MKP-1 is essential for the management of metabolic homeostasis in a manner that is spatially uncoupled from the cytosolic actions of the MAPKs.
Wu
J Julie
JJ
Department of Pharmacology, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Roth
Rachel J
RJ
Anderson
Ethan J
EJ
Hong
Eun-Gyoung
EG
Lee
Mi-Kyung
MK
Choi
Cheol Soo
CS
Neufer
P Darrell
PD
Shulman
Gerald I
GI
Kim
Jason K
JK
Bennett
Anton M
AM
D050154:Adiposity / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1; D005260:Female; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008055:Lipids / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000517:prevention & control*; D047493:PPAR alpha / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000172:deficiency* / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D008055:Lipids; D047493:PPAR alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D005947:Glucose