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.
Highlights
The proportion of adults with a body mass index of 25 kg/m2 or greater has substantially increased worldwide in the years between 1980 and 2013 [1]
Quantitative reverse transcription PCR results showed that skeletal muscle samples from individuals with obesity exhibited lower fibroblast growth factor 6 (FGF6) levels than those from normal-weight participants (Figure 1C)
The mass of the gastroc muscle injected with AAV9-FGF6 remained unchanged (Supplemental Figure 4A), we found that Fgf6-treated gastroc muscles showed a shift toward larger myofibers as compared with that of the control muscle (Figure 3, A and B), based on CSA measurements of H&Estained sections, indicating the occurrence of skeletal muscle hypertrophy. Quantitative reverse transcription PCR (qPCR) analysis confirmed the overexpression of Fgf6 and showed that the expression of genes critical for muscle atrophy and hypertrophy [28,29,30] was influenced by Fgf6 expression levels
Summary
The proportion of adults with a body mass index of 25 kg/m2 or greater has substantially increased worldwide in the years between 1980 and 2013 [1]. Skeletal muscle, comprising approximately 40% of total body mass in mammals, plays a critical role in the regulation of total body mass and the homeostasis of systemic metabolism [4]; it accounts for a majority of insulin-stimulated glucose disposal in humans [5, 6]. A growing body of evidence indicates that insulin resistance in skeletal muscles is strongly associated with several metabolic syndromes and T2DM [7, 8]. Saturated fatty acids and hyperglycemia have been reported to induce a decline in the mass as well as function of skeletal muscle, further aggravating metabolic abnormalities [9, 10]. Physical exercise consumes glucose and fatty acids and facilitates mitochondrial biogenesis, fiber remodeling or transformation, antioxidant defense mechanisms, and muscle hypertrophy, enhancing metabolic fitness [11]. The underlying mechanism between skeletal muscle and metabolic disturbance has not been fully elucidated
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