Maternal obesity together with androgen excess in mice negatively affects placental function and maternal and fetal liver function as demonstrated by increased triglyceride content with dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage. To identify changes in molecular pathways that might promote diseases in adulthood, we performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess.
After ten weeks on a control diet (CD) or high fat/high sugar-diet, dams were mated with males fed the CD. Between gestational day (GD) 16.5 and GD 18.5, mice were injected with vehicle or dihydrotestosterone (DHT) and sacrificed at GD 18.5 prior to dissection of the placentas and fetal livers. Four pools of female placentas and fetal livers were subjected to a global proteomic analysis. Total and phosphorylated proteins were filtered by ANOVA q < 0.05, and this was followed by two-way ANOVA to determine the effect of maternal obesity and/or androgen exposure.
In placenta, phosphorylated ATP-citrate synthase was decreased due to maternal obesity, and phosphorylated catechol-O-methyltransferase (COMT) was differentially expressed due to the interaction between maternal diet and DHT exposure. In fetal liver, five total proteins and 48 proteins phosphorylated in one or more sites, were differentially expressed due to maternal obesity or androgen excess. In fetal liver, phosphorylated COMT expression was higher in fetus exposed to maternal obesity.
These results suggest a common regulatory mechanism of catecholamine metabolism in the placenta and the fetal liver as demonstrated by higher phosphorylated COMT expression in the placenta and fetal liver from animals exposed to diet-induced maternal obesity and lower expression of phosphorylated COMT in animals exposed to maternal androgen excess.
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Quantitative proteomic analysis and subsequent data analysis were performed at the Proteomics Core Facility at Sahlgrenska Academy, Gothenburg University. The Proteomics Core Facility is grateful to Inga-Britt and Arne Lundbergs Forskningsstiftelse for the donation of the Orbitrap Fusion Tribrid MS instrument. This work was supported by the Swedish Medical Research Council (Project No. 2014-2775 and 2018-02435), the Adlerbert Research Foundation, the Novo Nordisk Foundation (NNF17OC0026724), the Strategic Research Programme (SRP) in Diabetes at Karolinska Institutet, and the Regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (all to ESV). The funders had no role in the study design, data collection, data analysis, preparation of the manuscript, or the decision to publish.
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Fornes, R., Manti, M., Qi, X. et al. Mice exposed to maternal androgen excess and diet-induced obesity have altered phosphorylation of catechol-O-methyltransferase in the placenta and fetal liver. Int J Obes 43, 2176–2188 (2019). https://doi.org/10.1038/s41366-018-0314-8
Medical Sciences (2019)
Nature Medicine (2019)