Neonatal Malnutrition Impacts Fibroblast Growth Factor 21-induced Neurite Outgrowth and Growth Hormone-releasing Hormone Secretion in Neonatal Mouse Brain

Neonatal malnutrition has been suggested as a factor contributing to neurological and other disorders. However, the details of this mechanism remain unclear. We focused on fibroblast growth factor 21 (FGF21), an endocrine factor produced in the liver during lactation-the main source of nutrition during the neonatal period- and analyzed its role in the brain. From the RNA-seq analysis of mouse brains, we analyzed the genes whose expression was regulated by FGF21 and their respective functions. We found that FGF21 has two functions in the neonatal brain; FGF21 induces the production of growth hormone-releasing hormone (GHRH) in the hypothalamus and is involved in isoform determination of Kalirin, a Ras homologous guanine nucleotide exchange factor, and promotes neurite outgrowth in the brain. Furthermore, the above mechanism is regulated by SH2-containing tyrosine phosphatase (SHP2) activity downstream of the FGF receptor. Additionally, the conserved intron of the SHP2 gene, Ptpn11, shows altered activity in malnourished mouse brains. In summary, FGF21 functions in neurite outgrowth and GHRH production in the neonatal mouse brain, with the mechanism being regulated by SHP2. However, SHP2 activity depends on nutritional status. Our goal was to elucidate the mechanisms by which FGF21 is involved in the maintenance of the central nervous system during the neonatal period. This study provides new insights into the role of FGF21 in diseases caused by dysfunction due to malnutrition.