SCFA and skeletal muscle substrate metabolism (WP4030)

Homo sapiens

The short-chain fatty acids (SCFA) acetate, propionate and butyrate can alter skeletal muscle metabolism both via direct and indirect mechanisms. Indirect mechanisms include the stimulation of glucagon like peptide 1 (GLP-1) and peptide YY (PYY) release via G-protein coupled receptor 41 (GPR41) and GPR43 signalling. Increased peripheral levels of these gut-derived satiety hormones induce the recruitment of microvasculature in skeletal muscle tissue and thereby contribute to improved insulin signalling. Furthermore SCFA induce a reduction in lipolysis in white adipose tissue (WAT), resulting in enhanced WAT lipid buffering capacity and decreased levels ectopic fat accumulation in skeletal muscle tissue. SCFA are also suggested to have direct effects on skeletal muscle metabolism, possibly via GPR41 and GPR43 signalling. SCFA induce the activation of adenosine monophosphate-activated protein kinase (AMPK), a key regulator in skeletal muscle cell metabolism. Activated AMPK induces several metabolic pathways including fatty acid oxidation and the synthesis of glycogen. Active AMPK also stimulates glucose uptake via translocation of glucose transporter type 4 (GLUT4) and decreases glycolysis. In addition to AMPK activation, SCFA might also induce peroxisome proliferator activated receptor delta (PPARD) expression, another process contributing to enhanced fat oxidation levels.


JJAJ Bastings , Marvin Martens , Denise Slenter , and Egon Willighagen


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Homo sapiens



Pathway Ontology

altered energy metabolic pathway


Label Type Compact URI Comment
Propionate Metabolite chebi:17272
Butyrate Metabolite chebi:17968
Acetate Metabolite chebi:30089
Plasma Fatty Acids Metabolite chebi:35366
Propionate Metabolite chebi:17272
Acetate Metabolite chebi:30089
GPR41 GeneProduct ensembl:ENSG00000185897
PPARD GeneProduct ensembl:ENSG00000112033
GLUT4 GeneProduct ensembl:ENSG00000181856
GPR43 GeneProduct ensembl:ENSG00000126262
GLP-1 GeneProduct ensembl:ENSG00000115263
PYY GeneProduct ensembl:ENSG00000131096
GPR41 GeneProduct ensembl:ENSG00000185897
GPR43 GeneProduct ensembl:ENSG00000126262


  1. Short-chain fatty acids in control of body weight and insulin sensitivity. Canfora EE, Jocken JW, Blaak EE. Nat Rev Endocrinol. 2015 Oct;11(10):577–91. PubMed Europe PMC Scholia