Maternal obesity programs white and brown adipose tissue transcriptome and lipidome in offspring in a sex-dependent manner

Abstract

The prevalence of overweight and obesity among children has drastically increased during the last decades and maternal obesity has been demonstrated as one of the ultimate factors. Nutrition-stimulated transgenerational epigenetic regulation of key metabolic genes is fundamental to the developmental origins of the metabolic syndrome. Fetal nutrition may differently influence female and male offspring. In this work, we investigated the sex-dependent programming of maternal obesity in visceral, subcutaneous and brown adipose tissues of offspring using magnetic resonance imaging and spectroscopy and a lipidomic approach combined with a Smart-Seq2 differential sequencing analysis. We show that the triglyceride profile varies between adipose depots, sexes and maternal diet. Our results demonstrate for the first time that a sex-dependent gene programming exists in visceral, subcutaneous and brown adipose tissues. Maternal obesity differentially programs gene expression in adipose depots of female and male offspring, which may contribute to the sex-dependent metabolic complications later in life.

Molecular programming in utero modulates hepatic lipid metabolism and adult metabolic risk in obese mother offspring in a sex-specific manner

“…We previously demonstrated that MO leads to a sexually dimorphic reprogramming of hepatic lipid composition and gene expression, and that this also occurs when the offspring receive a postweaning control diet. We also showed that other organs are affected in a sex-dependent manner 15 . We now show that MO offspring fed an obesogenic diet have sex-specifically altered liver lipidomes explained by accompanying changes in the transcriptomes.…”

“…Most importantly, we confirm our previous findings that MO modulates hepatic TG molecular species in female but not in male offspring 14 . Somewhat surprising, we demonstrated that MO regulates the gene expression in white adipose in male offspring towards an inflammatory pattern, while instead altering it towards more browning and oxidative phosphorylation patterns in females 15 . The mechanisms by which MO can differently modulate epigenetic marks in utero between sexes and between tissues remain intriguing and require further investigation.…”

“…RNA sequencing of SAT and VAT was performed to explore if MO affected its transcriptional activity, with a special focus on browning process, inflammation and oxidative phosphorylation pathways, which play a major role in adipose tissue homeostasis 15 . Interestingly, females showed very few deregulated genes in response to MO in SAT but a highly enriched oxidative phosphorylation pathway activity, and induced Ucp1 gene expression (marker of browning) in VAT (Suppl.Fig.…”

“…RNA was treated with RNase-free DNase (79254) according to the manufacturer's instructions. cDNA libraries were prepared for bulk-RNA sequencing as previously detailed 15 .…”

“…Our recent studies demonstrated that even when offspring received a control diet after weaning, MO altered the hepatic and adipose lipidome of the offspring in a sex-specific manner, which may contribute to the sexual dimorphism in the metabolic adaptation later in life 14,15 . Furthermore, sex-specific responses to high calorie-diets have also been described 16 , implying that sex hormones might play a major role, although the underlying mechanisms are not well understood.…”