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- Title
Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance.
- Authors
Lawan, Ahmed; Min, Kisuk; Lei Zhang; Canfran-Duque, Alberto; Jurczak, Michael J.; Camporez, Joao Paulo G.; Yaohui Nie; Gavin, Timothy P.; Shulman, Gerald I.; Fernandez-Hernando, Carlos; Bennett, Anton M.; Zhang, Lei; Nie, Yaohui
- 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.
- Subjects
RNA metabolism; ANIMAL experimentation; CELLULAR signal transduction; COMPARATIVE studies; DIET; ENERGY metabolism; INSULIN resistance; RESEARCH methodology; MEDICAL cooperation; MICE; MITOCHONDRIA; OBESITY; PHOSPHATASES; RESEARCH; RESEARCH funding; TRANSFERASES; EVALUATION research; OXYGEN consumption; SKELETAL muscle
- Publication
Diabetes, 2018, Vol 67, Issue 4, p624
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-0826