title: Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity.
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.
authors.forename: Shihyin
authors.initials: S
authors.lastname: Tsai
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Sitzmann
authors.forename: Somasish G
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Ariana A
authors.initials: AA
authors.lastname: Rodriguez
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Vu
authors.forename: Circe E
authors.initials: CE
authors.lastname: McDonald
authors.forename: Emmeline C
authors.initials: EC
authors.lastname: Academia
authors.forename: Monique N
authors.initials: MN
authors.lastname: O'Leary
authors.forename: Travis D
authors.initials: TD
authors.lastname: Ashe
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010750:Phosphoproteins; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases