A post-weaning obesogenic diet exacerbates the detrimental effects of maternal obesity on offspring insulin signaling in adipose tissue

Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. The current study investigated if weaning onto an obesogenic diet exaggerated the detrimental effects of maternal diet-induced obesity in adipose tissue. Maternal obesity and offspring obesity led to reduced expression of key insulin signalling proteins, including insulin receptor substrate-1 (IRS-1). The effects of maternal obesity and offspring obesity were, generally, independent and additive. Irs1 mRNA levels were similar between all four groups of offspring, suggesting that in both cases post-transcriptional regulation was involved. Maternal diet-induced obesity increased miR-126 expression however levels of this miR were not influenced by a post-weaning obesogenic diet. In contrast, a post-weaning obesogenic diet was associated with increased levels of suppressor of cytokine signaling-1, implicating increased degradation of IRS-1 as an underlying mechanism. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and consequently reduced translation of Irs1 mRNA, the effects of a post-weaning obesogenic diet on IRS-1 are mediated by miR-126 independent mechanisms, including increased IRS-1 protein degradation. These divergent mechanisms explain why the combination of maternal obesity and offspring obesity leads to the most pronounced effects on offspring metabolism.The. Medical Research Council (MC_UU_12012/4), Biotechnology and Biological Sciences Research Council (BB/M001636/1), British Heart Foundation (PG/14/20/30769) and São Paulo Research Foundation (2014/17012-4 and 2014/20380-5) supported this research

Effects of maternal diet-induced obesity on metabolic disorders and age-associated miRNA expression in the liver of male mouse offspring

Objective: This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. Methods: A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. Results: Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfβ1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (−3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and −5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05). Conclusion: Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny

Maternal overnutrition programs cardiac dysfunction independently of post-natal diet in mice

PURPOSE Gestational exposure to maternal obesity increases the risk of cardiovascular disease in the offspring. Exposure to overnutrition during fetal life is likely to be followed by continued exposure to the same calorie-rich environment post-natally. The aim of this project was to characterize the consequences of combined exposure to a maternal and post-natal obesogenic diet on offspring cardiac structure and function. METHODS A well-established mouse model of maternal diet-induced obesity where C57bl/6 dams are fed a high fat/high simple carbohydrate diet during pre-gestation, gestation and lactation was used. Male offspring from control (C-) and obese (O-) were assigned at weaning to either a control (-C) or obesogenic diet (-O), generating 4 experimental groups (CC, CO, OC and OO). Metabolic profile, cardiac structure and function, gene expression, and blood pressure were assessed in male offspring at 8 weeks of age. RESULTS Dams fed the obesogenic diet were significantly heavier on the day of mating (p<0.0001), and remained heavier throughout pregnancy and at weaning compared to controls. Young adult (8 weeks) offspring exposed to maternal overnutrition had heavier hearts (17%) than control mice (effect of maternal diet p=0.005). A post-weaning obesogenic diet also increased heart weight (effect of offspring diet p=0.019). Circulating levels of insulin and leptin were increased by feeding the obesogenic diet, and further elevated by the maternal exposure. Mice born to overnourished mothers developed pathological ventricular remodelling associated with re-expression of cardiac fetal genes (Nppa, Myh7, Myh7:Myh6 ratio), interventricular septum thickening (p=0.0004), increased left ventricular area (p=0.02), cardiac systolic dysfunction with reduced ejection fraction and fractional shortening. Most importantly, up-regulation of genes involved in cardiac contraction was observed in fetuses from obese dams as early as in utero. CONCLUSIONS Maternal overnutrition programs adverse cardiac remodelling and dysfunction in adult male offspring. These findings suggest that a maternal caloric-rich uterine environment is a critical determinant of cardiovascular disease risk in the next generation, and is as detrimental as current obesity