1128 Maternal high fat diet increases weight gain in female mice without Npas2 in the liver

Abstract

Maternal high fat diet (MHFD) effects the metabolic health of offspring. We have previously demonstrated that in non-human primates, a MHFD is associated with the disruption of Npas2 in the fetal liver. We therefore developed a novel fetal hepatic Npas2 conditional knock out (cKO) mouse model to determine the role of hepatic Npas2 in adapting to the effects of a MHFD. In order to delete Npas2 during fetal life and specifically in the liver, a CreLox deletion was put under regulation of the AFP enhancer. Fetal cKO (n=70) and control mice (n=62) were thereby generated for this study from dams on either a MHFD or maternal control diet (MCD) during gestation until mice were weaned. At weaning, mice were placed onto HFD (42% fat) or a CD. To determine how a MHFD affects weight gain and adiposity mice were weighed weekly for 24 weeks and fat mass was determined by quantitative magnetic resonance (QMR). Since weight gain and adiposity can be linked to diabetes the mice were challenged with a glucose tolerance test (GTT) and an insulin tolerance test (ITT). Female fetal cKO mice exposed to a MHFD had significantly increased mass when weaned onto a CD or a HFD (Figure 1). However, female fetal cKO mice had significantly increased adiposity only when weaned onto a CD (p=0.002). Both female and male cKO mice exposed to a MHFD and weaned onto a CD had elevated blood glucose concentrations during a GTT (Figure 2). Despite these elevated glucose concentrations, no differences in glucose were measured during the ITTs. We have conditionally deleted a circadian gene (Npas2) during fetal development and have shown that a MHFD exposure alters weight gain, adiposity, and glucose response; this cannot be corrected with CD feeding in the postnatal period. These findings collectively suggest that Npas2 expression during fetal development has a role in adapting to metabolic stress during fetal and early development which has lifelong effects.View Large Image Figure ViewerDownload Hi-res image Download (PPT)