Cross-species comparison of pregnancy-induced GDF15

Abstract

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Although the exact physiological function of GDF15 is not yet fully comprehended, the significant elevation of circulating GDF15 levels during gestation suggests a potential role for this hormone in pregnancy. This is corroborated by genetic association studies in which GDF15 and the GDF15 receptor, GDNF Family Receptor Alpha Like (GFRAL) have been linked to morning sickness and hyperemesis gravidarum (HG) in humans. Here, we studied GDF15 biology during pregnancy in mice, rats, macaques, and humans. In contrast to macaques and humans, mice and rats exhibited an underwhelming induction in plasma GDF15 levels in response to pregnancy (~75-fold increase in macaques vs. ~2-fold increase in rodents). The changes in circulating GDF15 levels were corroborated by the magnitude of Gdf15 mRNA and GDF15 protein expression in placentae from mice, rats, and macaques. These species-specific findings may help guide future studies focusing on GDF15 in pregnancy and on the evaluation of pharmacological strategies to interfere with GDF15-GFRAL signaling to treat severe nausea and HG.

GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice

“…It is possible that under conditions of elevated somatic stress other than pregnancy, GDF15 plays a larger role. It is also possible that the deletion of GDF15 during mouse pregnancy is of little effect because GDF15 in circulation increases only modestly in rodents (2-fold) compared to humans and primates (75-100 fold in primates and humans, respectively) (41).…”

Identification and characterization of human GDF15 knockouts

“…This elevation suggests a biological function during fetal development. Exploring this biology in rodent models is challenging as it appears to be a largely primate-specific phenomenon 22 . GDF15 LOF carriers, including KOs, report having had children, indicating that complete functional genetic loss of GDF15 in at least one parent is compatible with life and fertility.…”