Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine

被引:183
作者
Keipert, Susanne [1 ,3 ]
Ost, Mario [1 ]
Johann, Kornelia [1 ]
Imber, Francine [1 ]
Jastroch, Martin [3 ]
van Schothorst, Evert M. [2 ]
Keijer, Jaap [2 ]
Klaus, Susanne [1 ]
机构
[1] German Inst Human Nutr, Potsdam, Germany
[2] Wageningen Univ, Dept Human & Anim Physiol, NL-6700 AP Wageningen, Netherlands
[3] Helmholtz Zentrum Munchen, Inst Diabet & Obes, D-85748 Munich, Germany
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2014年 / 306卷 / 05期
关键词
fibroblast growth factor 21; browning; energy metabolism; uncoupling-protein; 1; myokine; GROWTH-FACTOR; 21; PPAR-ALPHA; PROTEIN-1; EXPRESSION; ANTIDIABETIC ACTIONS; INSULIN SENSITIVITY; LIPID-METABOLISM; TRANSGENIC MICE; BETA-KLOTHO; AUTOPHAGY; OBESITY;
D O I
10.1152/ajpendo.00330.2013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:E469 / E482
页数:14
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