Maternal obesogenic diet during pregnancy and its impact on fetal hepatic function in baboons

Abstract

AbstractObjectiveMaternal obesity (MO) increases the risk of later‐life liver disease in offspring, especially in males. This may be due to impaired cytochrome P450 (CYP) enzyme activity driven by an altered maternal‐fetal hormonal milieu. MO increases fetal cortisol concentrations that may increase CYP activity; however, glucocorticoid receptor (GR)‐mediated signaling can be modulated by alternative GR isoform expression. We hypothesized that MO induces sex‐specific changes in GR isoform expression and localization that contribute to reduced hepatic CYP activity.MethodsNonpregnant, nulliparous female baboons were assigned to either an ad libitum control diet or a high‐fat, high‐energy diet (HF‐HED) at 9 months pre pregnancy. At 165 days' gestation (term = 180 days), fetal liver samples were collected (n = 6/sex/group). CYP activity was quantified using functional assays, and GR was measured using quantitative RT‐PCR and Western blot.ResultsCYP3A activity was reduced in the HF‐HED group, whereas CYP2B6 activity was reduced in HF‐HED males only. Total GR expression was increased in the HF‐HED group. Relative nuclear expression of the antagonistic GR isoform GRβ was increased in HF‐HED males only.ConclusionsReduced CYP activity in HF‐HED males may be driven in part by dampened hepatic‐specific glucocorticoid signaling via altered GR isoform expression. These findings highlight targetable mechanisms that may reduce later‐life sex‐specific disease risk.