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Skeletal muscle–targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance
Bo Xu, … , Cheng Hu, Weiping Jia
Bo Xu, … , Cheng Hu, Weiping Jia
Published September 7, 2021
Citation Information: JCI Insight. 2021;6(19):e149969. https://doi.org/10.1172/jci.insight.149969.
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Research Article Metabolism Muscle biology

Skeletal muscle–targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance

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Abstract

Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet–fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.

Authors

Bo Xu, Caizhi Liu, Hong Zhang, Rong Zhang, Mengyang Tang, Yan Huang, Li Jin, Lingyan Xu, Cheng Hu, Weiping Jia

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Figure 1

FGF6 promoter is hypermethylated in the skeletal muscle of participants with obesity, leading to the inhibition of CREB1-mediated transcriptional activation.

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FGF6 promoter is hypermethylated in the skeletal muscle of participants...
(A) Flow chart of the experimental design to screen differentially expressed genes in the skeletal muscle of normal-weight individuals and participants with obesity. (B) Abridged general view of the 7 pairs of age-matched skeletal muscle specimens from men subjected to MeDIP-Seq, RNA-Seq, and further analysis. (C) Comparison of relative mRNA levels of FGF6 in 35 pairs of age-matched skeletal muscle specimens from normal-weight individuals and participants with obesity. (D) Sequences of the FGF6 promoter region selected for validation by pyrosequencing in 35 pairs of skeletal muscle tissues. (E) Mean methylation level of each CpG site (n = 35 pairs). (F) Variation of methylation levels between skeletal muscles from individuals with obesity and their matched normal-weight controls (n = 35 pairs). (G) CRE in the promoter region of FGF6. (H) Luciferase activity of the WT Fgf6 reporter or the mutant Fgf6 reporter, containing the CRE deletion (Fgf6-luc del CRE), in HEK293T cells transiently expressing either an empty vector or CREB1-expressing vector, treated with forskolin (FSK) or 5-Aza; n = 3 per group. (I) ChIP analysis of phosphorylated CREB1 (p-CREB1) binding on the putative CRE identified in the Fgf6 promoter or on the β-globin promoter in mouse gastrocnemius muscle (n = 3 per group). Data information: The box plot represents data from the first quartile to the third quartile. The second quartile is the median of the data (C). Other results (E, F, H, and I) are represented as mean ± standard error of mean. Statistical analysis was done using paired and unpaired Student’s t tests or Wilcoxon’s signed rank sum tests where appropriate. *P < 0.05, **P < 0.01, ***P < 0.001.

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