Hepatic FGF21 production is increased in late pregnancy in the mouse

Female mammals call on hormonally driven metabolic adaptations to meet the energy demand of late pregnancy and lactation. These maternal adaptations preserve limiting nutrients and promote their transfer to the uterus during pregnancy or mammary gland during lactation. The novel metabolic hormone fibroblast growth factor-21 (FGF21) was recently shown to increase suddenly at the onset of lactation in dairy cows, but whether FGF21 is induced during the reproductive cycle of other mammals is unknown. To start addressing this question, we studied subsets of mice when virgin (V), on day 18 of pregnancy (P18) and on lactation day 1 (L1), L5 and L14. Plasma FGF21 increased from nearly undetectable levels to over 8 ng/ml between V and P18 and returned to V levels by L1. Gene expression studies showed that liver was the major source of plasma FGF21 at P18 with little or no contribution from other known expressing tissues or from the developing placenta and mammary epithelial cells. The increased FGF21 production at P18 was dissociated from plasma nonesterified fatty acids and liver lipids, unlike that seen in fasted V mice. Changes in FGF21 signaling components in target tissues were modest except for reduced β-Klotho and FGFR1c expression in P18 adipose tissue. The placenta expressed both β-Klotho and FGFR1c, raising the possibility that it responds to FGF21. In conclusion, maternal FGF21 is increased when products of conception account for ∼ 40% of maternal weight, suggesting that FGF21 orchestrates some of the adaptations needed to meet the energy demand of late pregnancy.