Journal article
Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity
Cell metabolism, Vol.4(1), pp.61-73
2006
DOI: 10.1016/j.cmet.2006.05.010
PMID: 16814733
Abstract
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.
Details
- Title: Subtitle
- Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity
- Creators
- J. Julie Wu - Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520Rachel J Roth - Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520Ethan J Anderson - Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520Eun-Gyoung Hong - Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520Mi-Kyung Lee - Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520Cheol Soo Choi - Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520P. Darrell Neufer - Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520Gerald I Shulman - Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520Jason K Kim - Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520Anton M Bennett - Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.4(1), pp.61-73
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.cmet.2006.05.010
- PMID
- 16814733
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Language
- English
- Date published
- 2006
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health and Human Physiology
- Record Identifier
- 9984065314602771
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