BXD strains of mice exhibit diurnal fluctuations in brain and liver iron and iron management proteins

Abstract

Restless Legs Syndrome patients frequently have a deficit in brain iron and show a significant diurnal variation in motor symptoms. Regulation of iron levels in the brain and flux of iron across the blood‐brain‐barrier are poorly understood, so the current study investigates diurnal fluctuations in plasma, liver and brain iron and in iron‐related proteins, including hepcidin and ferroportin. Plasma, spleen, liver, and ventral midbrain iron levels vary significantly between the light and dark phases of the diurnal cycle in several strains of BXD mice. The amount of variation is strain dependent (<10%‐to‐<30%) and corresponds to variations in iron management proteins (Tf, TfR, Ft). Hepatic and brain hepcidin mRNA levels also vary across the diurnal cycle and between BXD strains, suggesting a role for hepcidin regulation of iron flux at the BBB epithelial cell. Ferroportin, Ft, DMT1, and TfR are all located in these epithelial cells, and we believe one explanation for the large iron flux is an IL6 mediation of ferroportin gene expression. IL6 expression in brain is directly influenced by clock genes, putting in place a potential explanation for the novel observations of large diurnal variations in brain and liver iron. This work is supported by NIH grant P01‐AG021190.