Short-Chain Fatty Acid Receptor Signaling in Metabolic Health

Short-chain fatty acids (SCFAs) are aliphatic carboxylic acids with fewer than six carbon atoms, chiefly acetate, propionate and butyrate, generated by gut microbial fermentation of dietary fibre. Once released into the lumen of the large intestine, SCFAs engage specific G-protein-coupled receptors (GPCRs), notably free fatty acid receptor 2 (FFA2/GPR43) and free fatty acid receptor 3 (FFA3/GPR41). Activation of these receptors on enteroendocrine cells, adipocytes and immune cells orchestrates a broad spectrum of metabolic responses, including the secretion of anorexigenic gut hormones such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), regulation of energy homeostasis, modulation of inflammation and maintenance of intestinal barrier function. Ligand-receptor binding initiates intracellular pathways involving G-protein subunits, second messengers and kinase cascades, as well as epigenetic regulation via histone deacetylase (HDAC) inhibition. Collectively, SCFA receptor signalling constitutes a vital communication axis between the host and its microbiota, influencing glucose and lipid metabolism, appetite control and systemic immune function. Research in this area has revealed potential targets for dietary interventions and pharmacological modulation to prevent or treat metabolic disorders such as obesity, insulin resistance and inflammatory bowel disease.

Research from Nature Portfolio

A foundational study in human intestinal cell models demonstrated that propionate and butyrate markedly enhance the production and secretion of peptide YY via both HDAC inhibition and engagement of FFA2/GPR43, highlighting a species-specific transcriptional regulation absent in murine tissues. This work established the dual mechanism by which SCFAs elevate anorexigenic hormone levels, offering a mechanistic basis for dietary fibre’s role in satiety and glucose regulation.

Short-Chain Fatty Acid Receptor Signaling in Metabolic Health publication trend

The graph below shows the total number of articles in short-chain fatty acid receptor signaling in metabolic health across all publications each year (not limited to Nature Index journals).

Technical terms

Short-chain fatty acids (SCFAs): Carboxylic acids of two to five carbons produced by gut microbial fermentation of fibre.

G-protein-coupled receptors (GPCRs): Seven-transmembrane receptors that transduce extracellular signals via heterotrimeric G proteins.

Free fatty acid receptor 2 (FFA2/GPR43): A GPCR activated by acetate, propionate and butyrate, involved in gut hormone release and immune modulation.

Free fatty acid receptor 3 (FFA3/GPR41): A GPCR selective for propionate and butyrate, regulating energy balance and autonomic function.

Histone deacetylases (HDACs): Enzymes that remove acetyl groups from histones, influencing chromatin structure and gene transcription.

Peptide YY (PYY): A gut-derived hormone that inhibits appetite and slows gastrointestinal motility.

Glucagon-like peptide-1 (GLP-1): An incretin hormone that enhances insulin secretion and promotes satiety.

References

1. Host metabolic benefits of prebiotic exopolysaccharides produced by Leuconostoc mesenteroides. Gut Microbes (2023).
2. Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism. International Journal of Molecular Sciences (2020).
3. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Scientific Reports (2018).