Central FGF21 Production Regulates Memory but Not Peripheral Metabolism

Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine hormone that functions to regulate energy homeostasis and macronutrient intake. Recently, FGF21 was reported to be produced and secreted from hypothalamic tanycytes, to regulate peripheral lipid metabolism. However, rigorous investigation of FGF21 expression in the brain has yet to be accomplished. Utilizing a novel mouse model that drives CRE recombinase in FGF21-expressing cells, we demonstrate that FGF21 is not expressed in the hypothalamus, but instead is produced from the retrosplenial cortex (RSC), an essential brain region for spatial learning and memory. Furthermore, we find that central FGF21 produced in the RSC enhances spatial memory but does not regulate energy homeostasis or sugar intake. Finally, our data demonstrate that administration of FGF21 prolongs the duration of long-term potentiation in the hippocampus and enhances activation of hippocampal neurons. Thus, endogenous and pharmacological FGF21 appear to function in the hippocampus to strengthen the formation of spatial memory. Single cell suspensions derived from the hippocampus of KLB-Cre::Ai14 mice were subjected to FACs sorting and tdTomato positive cells were collected and processed for single cell RNA sequencing. Three conditions were used in this experiment to test the effects of FGF21 administriation on gene expression in the hippocampus; 1) Vehicle, 2) 1 day of FGF21 administration, and 3) 3 days of FGF21 administration.