Maternal obesity has sex‐dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring

Abstract

Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control-fed mothers. We hypothesized that MO-F1 are predisposed to sex-dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning, all male and female F1 ate a control diet. At PND 110, F1 serum, liver and fat were collected to analyse metabolites, histology and liver differentially expressed genes. Male and female MO-F1 showed increased adiposity index, triglycerides, insulin and homeostatic model assessment vs. C-F1 with similar body weight and glucose serum concentrations. MO-F1 males presented greater physiological and histological NAFLD characteristics than MO-F1 females. RNA-seq revealed 1365 genes significantly changed in male MO-F1 liver and only 70 genes in female MO-F1 compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic processes. Male MO-F1 liver showed the following altered pathways: insulin signalling (22 genes), phospholipase D signalling (14 genes), NAFLD (13 genes) and glycolysis/gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MO-F1 females. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signalling pathways, leading to liver dysfunction and insulin resistance.

Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta‐analysis of animal studies

“…Third, although we accounted for heterogeneity by using a random rather than a fixed effect model for meta‐analysis, variation between the studies was high. A recent study has suggested evidence of sex‐dependent differences in pathways related to CVD development . Our subgroup analyses based on offspring sex showed no differences in effects; however, not all studies could be included because of missing data on males and females separately.…”

Maternal obesity accelerates rat offspring metabolic ageing in a sex‐dependent manner

“…We have previously reported that MO prior to and throughout pregnancy and lactation programme the offspring to the development of non‐alcoholic fatty liver disease in a sex‐dependent manner (Lomas‐Soria et al . ).…”

“…PND 110 represents the young adult and was chosen to enable comparisons with our paper on RNASeq in programming, addressing mechanisms of MO programming of the liver at 110 days (Lomas‐Soria et al . ). PND 450 represents a mature adult and we have also published programming outcomes at this age (Rodriguez‐Gonzalez et al .…”

Nutritional programming by maternal obesity: insights into the development of non‐alcoholic fatty liver disease

“…In a recent article by Lomas‐Soria et al . () in The Journal of Physiology , a cross‐sectional study was conducted to investigate the effects of MO on the development of NAFLD in young adult rat offspring. This study in particular was designed in part to address previous results showing programming by MO displays a bias between sexes whereby disease severity is often more pronounced in male than female offspring.…”

“…To elucidate the underlying cause of these observed differences, Lomas‐Soria et al . () examined the effects of MO on female and male F1 rat livers independently by analysing liver metabolites, structure and transcriptome changes. This study was performed on F1 progeny from mothers who were fed with either a high‐fat or a control diet.…”