Hepatic FGF21 production is increased in late pregnancy in the mouse

Abstract

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.

Fibroblast growth factor 21, adiposity, and macronutrient balance in a healthy, pregnant population with overweight and obesity

“…Although, after extensive qPCR experiments in term human placenta from a subset of our cohort (n=19), we were unable to quantify expression of FGF21 in the samples studieddespite detection of other genes such as SDHA and TBP. We are therefore confident the human placenta is not contributing meaningful amounts of FGF21 into the maternal circulation.Instead, considering evidence of robust elevation in hepatic FGF21 mRNA throughout pregnancy recently reported in wild-type mice 33 , we posit the elevation in circulating FGF21 observed in our human cohort is likelyresultant from the liver. Moreover, there is extensive evidence showing FGF21 synthesis and secretion by adipocytes in rodents and humans, and it may also be likelythat maternal adipocytesare contributing in part to this FGF21 elevation considering the increase in fat mass across pregnancy 14,34 .…”

Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice

“…In addition, in mice and humans, hepatic FGF21 expression is under complex nutritional regulation including protein restriction via the amino acid sensor GCN2 [34], fructose via the carbohydrate response element binding protein [35], bile acids via farnesoid X receptor [36], all-trans-retinoic acid via retinoic acid receptor β [37], α-lipoic acid via cAMP response element binding protein H [38], and resveratrol via SIRT1 [39]. During pregnancy, E2 concentrations are high [40], and late in pregnancy, hepatic FGF21 production is increased in mice, followed by a drop in the final days that matches E2 levels [41]. We show that in female mice, exogenous E2 increases FGF21 production in the fasting and fed states (thus independently from PPARα) via activation of ERα in hepatocytes, not ERβ or GPER.…”

FGF21 and Cardiac Physiopathology

“…In physiological models of cardiac hypertrophy, such as pregnancy ( 43 ), the circulating levels of FGF21 ( 44 ) as well as FGF21 expression levels in the heart are increased ( 45 ). In this physiological setting, both autocrine and endocrine cardioprotective roles of FGF21 might be at work.…”