Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity
Shihyin Tsai, … , Albert R. La Spada, Brian K. Kennedy
Shihyin Tsai, … , Albert R. La Spada, Brian K. Kennedy
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):2952-2964. https://doi.org/10.1172/JCI77361.
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Research Article Metabolism

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

Shihyin Tsai, Joanna M. Sitzmann, Somasish G. Dastidar, Ariana A. Rodriguez, Stephanie L. Vu, Circe E. McDonald, Emmeline C. Academia, Monique N. O’Leary, Travis D. Ashe, Albert R. La Spada, Brian K. Kennedy

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Figure 6

Increased FGF21 expression from 4E-BP1–activated skeletal muscle and altered expression of genes involved in fat metabolism in adipose and liver tissues.

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Increased FGF21 expression from 4E-BP1–activated skeletal muscle and alt...
(A) RT-PCR quantification of myokine genes (n = 4) and (B) Western blots of quadriceps skeletal muscles (Qm) from 6-month-old male mice fed normal chow to detect FGF21 expression. (C) Quantification of FGF21 signaling from B normalized to the housekeeping gene, HSP90. P values were calculated by 1-tailed unpaired Student’s t test. (D) Serum FGF21 level in fasted 6-month-old mice (the number of mice analyzed is indicated in bars). (E) Western blots of quadriceps muscles from 6-month-old male mice fed a normal chow diet to detect PPARγ expression in adipose tissues. WAT, white adipose tissue; BAT, brown adipose tissue. RT-PCR quantification of genes involved in fatty acid metabolism and thermogenesis in (F) white adipose tissue and (G) brown adipose tissue. P values from FGF21 ELISA and RT-PCR were assessed by 2-way ANOVA. Bonferroni post-tests were used to compare replicate means by row. *P < 0.05; ***P < 0.001. RT-PCR samples were from n = 4 per genotype.