Meakin, A.S.Nathanielsz, P.W.Li, C.Huber, H.F.Clifton, V.L.Wiese, M.D.Morrison, J.L.2025-01-292025-01-292024Obesity, 2024; 32(10):1910-19221930-73811930-739Xhttps://hdl.handle.net/2440/143646Objective: Maternal 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. Methods: Nonpregnant, 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. Results: CYP3A 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. Conclusions: Reduced 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.en© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Maternal obesity (MO); later-life liver disease in offspringLiverFetusAnimalsPapioPrenatal Exposure Delayed EffectsObesityHydrocortisoneCytochrome P-450 Enzyme SystemReceptors, GlucocorticoidPregnancyFemaleMaleMaternal Nutritional Physiological PhenomenaDiet, High-FatObesity, MaternalPregnancy in ObesityJournal article10.1002/oby.24124706989Clifton, V.L. [0000-0002-4892-6748]