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Short-chain fatty acid receptors (FFAR2 and FFAR3) (SCFA receptors)

Target: SCFA receptors
Molecular classification: G protein-coupled receptor, Receptor, Nutrient-sensing GPCR

Overview

Free fatty acid receptor 2 (FFAR2, GPR43) and Free fatty acid receptor 3 (FFAR3, GPR41) are G protein-coupled receptors that bind short-chain fatty acids (SCFAs) produced by gut microbiota fermentation. FFAR2 is primarily activated by acetate and propionate, while FFAR3 responds to propionate and butyrate. These receptors are expressed in various tissues, including gut epithelium, immune cells, and adipose tissue, and mediate diverse physiological processes involving energy homeostasis, hormone secretion, and regulation of inflammation. Their signaling is implicated in metabolic diseases, inflammatory bowel disease, and potentially cancer and infection. Pharmacological modulation of FFAR2/FFAR3 is being explored for therapeutic benefit in metabolic and inflammatory disorders, although selective clinical drugs are not yet approved. "Short-chain fatty acid receptor" should always be clarified to refer to individual targets such as Free fatty acid receptor 2 (FFAR2/GPR43) or Free fatty acid receptor 3 (FFAR3/GPR41) for precise scientific or therapeutic use, as it is not itself a unique canonical entity.

Other names: Free fatty acid receptor 2FFAR2FFA2GPR43Free fatty acid receptor 3FFAR3FFA3GPR41GPR109AHCAR2

Mechanism of action

Agonists (natural SCFAs or synthetic compounds) bind and activate FFAR2/FFAR3, leading to modulation of intracellular cAMP, calcium signaling, MAPK activation, immune modulation, hormone secretion, and anti-inflammatory effects

Biological functions

Regulation of inflammationImmune responseEnergy metabolismHormonal secretionSignal transductionGut-brain axis modulation

Disease associations

Inflammation (e.g., inflammatory bowel disease, colitis)Cancer (especially colorectal cancer)Metabolic disease (including obesity, diabetes)Immune and viral disease (host defense roles)Gut barrier functionCardiovascular effects

Safety considerations

On-target effects in multiple tissues may affect metabolism, immunity, and gut function.Potential for immune suppression or altered host defense, unclear long-term safety given involvement in host–microbiome interactions.Differences between human and mouse FFAR2/FFAR3 selectivity may complicate translation from animal studies.

Interacting drugs

No widely approved drugs are currently known to selectively target these receptors in clinical practice; several investigational selective ligands and agonists exist

Biomarkers

Expression of FFAR2/FFAR3 (by mRNA or immunoassay) in tissues (e.g., colon, immune cells)Circulating or fecal SCFA levels as a surrogate for receptor activity

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