Fibroblast growth factor receptor 1c (FGFR1c) (FGFR1c)

Fibroblast growth factor receptor 1c (FGFR1c) is a specific splice variant of the FGFR1 receptor tyrosine kinase that plays a critical role in systemic metabolic regulation [UniProt P11362]. Unlike other FGFRs that primarily mediate developmental and proliferative signals via paracrine FGFs, FGFR1c functions as a primary receptor for endocrine FGFs, particularly Fibroblast Growth Factor 21 (FGF21), when complexed with the obligate co-receptor beta-Klotho (KLB) [PubMed 15997090]. This signaling axis is predominantly active in adipose tissue and the liver, where it enhances insulin sensitivity, promotes glucose uptake, and stimulates lipid oxidation and energy expenditure [PubMed 32415111]. In the context of metabolic diseases such as Type 2 diabetes and metabolic dysfunction-associated steatohepatitis (MASH), pharmacological activation of the FGFR1c/KLB complex using FGF21 analogs or FGF19-derived mimetics has shown significant therapeutic potential in reducing liver fat, improving glycemic control, and reversing fibrosis [PubMed 33055231, PubMed 37354915]. However, therapeutic development must balance metabolic benefits against potential safety concerns, including effects on bone mineral density and gastrointestinal tolerability [PubMed 25043175].

Other names

FGFR1 isoform IIIcFGFR1-IIIcFibroblast growth factor receptor 1 isoform cFGF21-FGFR1c-KLB complexFGF family ligands driving FGFR1c signaling

Agonism of the FGFR1c/beta-Klotho complex to activate downstream signaling pathways, including MAPK/ERK and PI3K/Akt, which regulate metabolic gene expression and cellular responses.