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Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine.
Am. J. Physiol. Endocrinol. Metab. 306, E469-E482 (2014)
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DOI
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UCP1-Tg mice with ectopic expression of uncoupling protein1(UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2 alpha/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, beta- klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Fibroblast Growth Factor 21 ; Browning ; Energy Metabolism ; Uncoupling-protein 1 ; Myokine; Growth-factor 21; Activated-receptor-gamma; White Adipose-tissues; Ppar-alpha; Adaptive Thermogenesis; Protein-1 Expression; Glucose-homeostasis; Insulin Sensitivity; Respiratory-chain; Lipid-metabolism
ISSN (print) / ISBN
0193-1849
e-ISSN
1522-1555
Quellenangaben
Volume: 306,
Issue: 5,
Pages: E469-E482
Publisher
American Physiological Society
Publishing Place
Bethesda
Non-patent literature
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Reviewing status
Peer reviewed