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Diabetes. 2018 Apr;67(4):624-635. doi: 10.2337/db17-0826. Epub 2018 Jan 9.

Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT.
2
Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT.
3
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT.
4
Cellular & Molecular Physiology and Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT.
5
Department of Health and Kinesiology, Purdue University, West Lafayette, IN.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, CT anton.bennett@yale.edu.

Abstract

Stress responses promote obesity and insulin resistance, in part, by activating the stress-responsive mitogen-activated protein kinases (MAPKs), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Stress also induces expression of MAPK phosphatase-1 (MKP-1), which inactivates both JNK and p38 MAPK. However, the equilibrium between JNK/p38 MAPK and MKP-1 signaling in the development of obesity and insulin resistance is unclear. Skeletal muscle is a major tissue involved in energy expenditure and glucose metabolism. In skeletal muscle, MKP-1 is upregulated in high-fat diet-fed mice and in skeletal muscle of obese humans. Mice lacking skeletal muscle expression of MKP-1 (MKP1-MKO) showed increased skeletal muscle p38 MAPK and JNK activities and were resistant to the development of diet-induced obesity. MKP1-MKO mice exhibited increased whole-body energy expenditure that was associated with elevated levels of myofiber-associated mitochondrial oxygen consumption. miR-21, a negative regulator of PTEN expression, was upregulated in skeletal muscle of MKP1-MKO mice, resulting in increased Akt activity consistent with enhanced insulin sensitivity. Our results demonstrate that skeletal muscle MKP-1 represents a critical signaling node through which inactivation of the p38 MAPK/JNK module promotes obesity and insulin resistance.

PMID:
29317435
PMCID:
PMC5860856
DOI:
10.2337/db17-0826
[Indexed for MEDLINE]
Free PMC Article

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