FGF21 is an Akt‐regulated myokine

Abstract

Fibroblast growth factor-21 (FGF21) functions as a metabolic regulator. The FGF21 transcript is reported to be abundantly expressed in liver, but little is known about the regulation of FGF21 expression in other tissues. In this study, we show that levels of FGF21 protein expression were similar in skeletal muscle and liver from fasted mice. FGF21 transcript and protein expression were upregulated in gastrocnemius muscle of skeletal muscle-specific Akt1 transgenic mice. Serum concentration of FGF21 was also increased by Akt1 transgene activation. In cultured skeletal muscle cells, FGF21 expression and secretion was regulated by insulin, Akt transduction and LY294002. These data indicate that skeletal muscle is a source of FGF21 and that its expression is regulated by a phosphatidylinosistol 3-kinase (PI3-kinase)/Akt1 signaling pathway-dependent mechanism.

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

“…The mouse monoclonal FGF21 antibody was described previously (20). The Quantikine mouse FGF21 ELISA kits (catalog no.…”

Myokines in insulin resistance and type 2 diabetes

“…Serum levels of FGF21 are significantly higher in type 2 diabetic patients than in healthy controls [113]. Izumiya et al have described FGF21 as an Akt-regulated myokine based on their findings of an insulin-mediated increase of FGF21 protein level and secretion in C2C12 myotubes, and a phosphoinositide 3-kinase inhibitormediated prevention of these effects [114]. In addition, a hyperinsulinaemic-euglycaemic clamp study in young healthy men has revealed an induction of FGF21 mRNA in skeletal muscle and increased plasma levels [115].…”

“…Based on the finding that hepatic Fgf21 mRNA expression is dramatically induced by fasting [120,121], Izumiya et al studied liver tissue and gastrocnemius muscle samples from 48 h fasted mice and reported similar levels of FGF21 protein in the two [114]. Although it is a challenge to determine the exact tissue, or even the cell type within a certain tissue, that acts as a major source of circulating proteins, the current data presume that skeletal muscle might may be an additional important source of circulating FGF21.…”

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

“…Skeletal muscle: FGF21 is produced in response to mitochondrial dysfunction FGF21 expression in muscle was first described in Akt1 transgenic mice in which the mRNA and serum levels of FGF21 were induced [39]. In normal conditions, basal expression of FGF21 in skeletal muscle is low but its expression is increased by insulin [39,40], exercise [41], mitochondrial myopathies [42], impaired mitochondrial FAO [43], muscle-specific autophagy deficiency [44] and transgenic overexpression of Akt1, perilipin-5 [45] or Ucp1 [46] in skeletal muscle.…”

“…In normal conditions, basal expression of FGF21 in skeletal muscle is low but its expression is increased by insulin [39,40], exercise [41], mitochondrial myopathies [42], impaired mitochondrial FAO [43], muscle-specific autophagy deficiency [44] and transgenic overexpression of Akt1, perilipin-5 [45] or Ucp1 [46] in skeletal muscle. The induction of FGF21 in muscle due to a metabolic dysfunction is driven by the transcription factor ATF4, which is activated by endoplasmic reticulum (ER) stress.…”