Abstract
Lactogenic hormones (e.g., prolactin (PRL) and placental lactogens (PL) which act through the PRL receptor) drive maternal glucose adaptations during pregnancy. Dysfunction to this system contributes to the development of gestational diabetes (GDM). A Polynesian-specific gene variant, termed CREBRFR458Q, has been associated with an increase in body mass and yet, almost paradoxically, protection against GDM. The mechanisms underlying this effect are yet to be elucidated. The aim of this study was to investigate the effect of CREBRFR458Q on lactogenic hormones during mouse pregnancy. Corticosterone (CORT) was also investigated for its role in glucose metabolism. A mouse model with a ‘knock in’ (KI) of the CREBRFR457Q (murine homologue of CREBRFR458Q) gene variant was used as part of the experiments.
First, the profile of normal PRL secretion was characterised in wildtype (WT) mice during early pregnancy to better understand patterns of lactogenic activity. Serial tail tip blood samples were collected over a 24 h period during diestrous and early pregnancy and were analysed using a highly sensitive enzyme-linked immunosorbent assay (ELISA) for PRL. Second, day 16 pregnancy serum samples were obtained from a cohort of CREBRFR457Q KI and control mice on either a standard or high-fat diet to induce a model of maternal obesity. Samples were analysed using a functional live cell bioassay to measure combined lactogenic activity (PRL and PL) and an ELISA to measure circulating CORT levels to understand the broader effect of genotype and diet on glucose regulation during pregnancy.
Mouse PRL secretion follows a similar profile in WT mice during early pregnancy as it does during diestrus (Mixed-effects model: Interaction of time x physiological state p = 0.0674, AUC t-test p = 0.8426), although a significant elevation of PRL was observed in pregnant mice during daylight hours (Mixed-effects model: p = 0.0199). While prior studies identify elevated PRL levels in CREBRFR457Q KI mice in early pregnancy, during late pregnancy, CREBRFR457Q KI and control mice have similar levels of total lactogenic activity (2-way ANOVA: p = 0.2827) and CORT levels (2-way ANOVA: p = 0.6243). These findings suggest that changes in lactogenic activity and glucocorticoids are not a major component of the mechanism of the CREBRFR458Q gene variant during late pregnancy. This data does not support the hypothesis that enhanced PRL secretion during pregnancy could contribute to the protective effect of CREBRFR458Q on GDM.