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Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity
- Publication Year :
- 2015
- Publisher :
- American Society for Clinical Investigation, 2015.
-
Abstract
- Eukaryotic translation initiation factor 4E–binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle–specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) and enhanced respiratory function. Non–cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism.
- Subjects :
- medicine.medical_specialty
Aging
FGF21
Adipose tissue
Muscle Proteins
Cell Cycle Proteins
Biology
Mechanistic Target of Rapamycin Complex 1
03 medical and health sciences
Mice
0302 clinical medicine
Oxygen Consumption
Eukaryotic initiation factor
Internal medicine
Brown adipose tissue
Myokine
medicine
Animals
Respiratory function
Obesity
Eukaryotic Initiation Factors
Muscle, Skeletal
030304 developmental biology
Adaptor Proteins, Signal Transducing
Mice, Knockout
0303 health sciences
TOR Serine-Threonine Kinases
EIF4E
Skeletal muscle
General Medicine
Phosphoproteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Fibroblast Growth Factors
medicine.anatomical_structure
Endocrinology
Diabetes Mellitus, Type 2
Organ Specificity
Multiprotein Complexes
biological phenomena, cell phenomena, and immunity
Carrier Proteins
030217 neurology & neurosurgery
Research Article
Signal Transduction
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6236935969f6019acc756b77b27d7033