Skeletal muscle–targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance
Skeletal muscle–targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance
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DOI：
10.1172/jci.insight.149969
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发表时间：
2021-09
期刊：
影响因子：
8
通讯作者：
Bo Xu;Caizhi Liu;Hong Zhang;Rong Zhang;Mengyang Tang;Yan Huang;Li Jin;Lingyan Xu;Cheng Hu;Wei Jia
中科院分区：
文献类型：
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作者：
Bo Xu;Caizhi Liu;Hong Zhang;Rong Zhang;Mengyang Tang;Yan Huang;Li Jin;Lingyan Xu;Cheng Hu;Wei Jia
肥胖是一个主要的健康问题，其特征在于包括骨骼肌在内的多个组织中的代谢异常。虽然骨骼肌代谢的失调可以强烈地影响全身能量的稳态，但其潜在机制仍不清楚。我们使用高通量测序发现肥胖个体骨骼肌中成纤维细胞生长因子6（FGF 6）的启动子高甲基化和基因表达降低。环腺苷酸反应元件结合蛋白-1（CREB 1）与高甲基化环腺苷酸反应元件（转录起始位点上游的调节元件）的结合减少，部分导致肥胖患者FGF 6的下调。Fgf 6在小鼠骨骼肌中的过表达刺激了蛋白质合成，激活了雷帕霉素通路的哺乳动物靶点，并阻止了高脂饮食喂养小鼠的体重增加和胰岛素抵抗的发展。因此，我们的研究结果强调了FGF 6在调节骨骼肌肥大和全身代谢中所起的作用，表明其在预防和治疗代谢性疾病的策略中的潜力。
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.