Abstract
Fibroblast growth factor 21 (FGF21) plays an important role in the treatment of disease associated with muscle insulin resistance which is characterized by various factors, such as intramuscular triglyceride (IMT) content. Studies have also shown that FGF21 inhibits triglyceride synthesis in vivo. However, the precise mechanism whereby FGF21 regulates triglyceride metabolism in intramuscular fat (IMF), which may influence the muscle insulin sensitivity, is not clearly understood. In order to understand the role of FGF21 in IMF deposition, we performed FGF21 overexpression in IMF cells by stable transfection. Our results showed that FGF21 inhibited the key adipogenesis gene mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein (CEBP) family by reducing lysine-specific demethylase 1 (LSD1) expression which led to significant decline in lipid accumulation, and the result was confirmed by Western blot. Moreover, triggered by FGF21, parts of the adipokines—fatty acid-binding protein 4 (FABP4), glucose transporter 4 (GLUT4), adiponectin (ADIPOQ), and perilipin (PLIN1)—were also down-regulated. Furthermore, FGF21 gene expression was suppressed by transcription factor CEBP beta (CEBPB) which contributed strongly to triglyceride synthesis. Taken together, our study is the first to experimentally demonstrate FGF21 emerging as an efficient blockade of adipogenesis in IMF, thus also providing a new understanding of the mechanism whereby FGF21 improves insulin sensitivity.
Highlights
Intramuscular triglyceride (IMT), as an indispensable energy source for skeletal muscles, has been considered to be a robust indicator of muscle insulin sensitivity, which is an essential predictive factor for type 2 diabetes
In order to understand the effect on intramuscular fat (IMF), we performed Fibroblast growth factor 21 (FGF21) overexpression in IMF cells and evaluated the expression of the relative genes participating in triglyceride metabolism
We showed that there were no obvious changes observed in expression of LRP6, β-catenin and COUP-TF II, which suggested FGF21 appeared to have no effect on the Wnt/β-catenin-COUP-TF ii-peroxisome proliferator-activated receptor gamma (PPARG) pathway
Summary
Intramuscular triglyceride (IMT), as an indispensable energy source for skeletal muscles, has been considered to be a robust indicator of muscle insulin sensitivity, which is an essential predictive factor for type 2 diabetes. Ectopic fat accumulation in skeletal muscles is associated with the early pathogenesis of insulin resistance. This has inspired heightened efforts to be made to better understand the precise lipid metabolism in muscles. Wnt signal plays an important role in the regulation of adipocyte differentiation, which was first reported in the MacDougald laboratory [5]. Which promotes adipocyte differentiation [9], resulting in down-regulation of genes involved in adipogenesis [10]. FGF21 suppresses adipogenesis as assessed by oil red O staining (Figures 4 and 5). Key genes PPARG, CEBPA and CEBPD involved in adipogenesis was down-regulated dramatically in FM compared with the control, which was the same with down-regulation of the protein level. Q-PRCTR-PaCnRalaynsailsyssihsoswhoewdeCdECBEPBBPBrerdeduucceeddFFGGFF2211 mmRRNNAAlelveevle. l*.**f*orfo0r.000.10
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