Transport of FGF21 across the blood-brain barrier: mechanisms and receptor activation

Fibroblast growth factor 21 (FGF21) is a hormone mainly secreted by the liver, with pleiotropic effects on various organs, including the brain. To understand how FGF21 acts on the central nervous system (CNS), we sought to determine its mechanisms of transport across the blood–brain barrier (BBB) and subsequent activation of FGFR1. Using intracarotid cerebral perfusion (ISCP), we show that 3H-FGF21 crosses the mouse BBB with a brain transport coefficient (Clup) of 0.30 ± 0.03 µl. g−1. s−1. Perfusion of increasing concentrations of unlabeled FGF21 decreased the 3H-FGF21 uptake rate, consistent with a saturable transport mechanism. The integrity of brain FGF21 following perfusion was confirmed by ELISA. Mechanical capillary depletion of brain homogenates showed that more than 40% of 3H-FGF21 was detected in the parenchymal fractions of the brain, with the rest remaining in the cerebrovasculature. Intracarotid infusion of FGF21 led to increased phosphorylation of FGFR1 in the brain parenchyma, suggesting possible receptor activation. Inhibitors of FGFR1 phosphorylation did not impact the uptake of FGF21 but mitigated FGFR1 phosphorylation in the brain. Inhibition of P-gp alone or with BCRP increased Clup by 200% and 600%, respectively, indicating efflux transport. FGF21 uptake was uniform across brain regions and unaffected by age or sex, while co‑perfusion with BDNF reduced transport by 66%. Together, these results show that circulating FGF21 accesses the brain via a saturable transport system and activates parenchymal FGFR signaling, supporting its therapeutic potential for brain disorders. We quantified in vivo the transport of FGF21 across the blood–brain barrier and found that it is saturable, competes with BDNF, and is increased by the blockade of efflux transporters. We also provide evidence that FGFR1 is located in the brain parenchyma, where it can be activated by FGF21 injected into the carotid artery. These data highlight the relevance of using FGF21 in therapeutic strategies targeting CNS diseases.