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

Abstract

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.

Exposure to maternal obesity during suckling outweighs in utero exposure in programming for post-weaning adiposity and insulin resistance in rats

“…Male offspring exposed to maternal obesity during suckling also displayed a minor effect of lower gonadal mRNA expression of AKT2 at 4 weeks, and IRS2 at 12 weeks, an upstream activator of PI3K. Whilst white adipose tissue only accounts for a small amount of glucose uptake, it is susceptible to insulin resistance due to adverse maternal nutrition in offspring 16,49 . One limitation of the current study was that we only considered mRNA and not protein expression.…”

Intrauterine programming of obesity and type 2 diabetes

“…Adipose tissue has been shown to be an important target of developmental programming in animal models of both maternal undernutrition and overnutrition. In studies carried out only in male offspring and, specifically, in the epididymal white adipose tissue (eWAT), both maternal undernutrition [102] and maternal obesity [103] program an adipose tissue-insulin resistant phenotype accompanied by increased adiposity [102, 104, 105]. These programmed changes have both been attributed to epigenetic changes in adipose tissue.…”

“…Importantly, an increase in adipose tissue miR-483 and parallel reduction in growth differentiation factor 3 (GDF-3) was also observed in adipose tissue from humans with low birthweight, showing conservation of this programmed mechanism. Programmed changes in miRNAs were also observed in a mouse model of maternal diet-induced obesity [103, 105]. Maternal feeding of a high-fat and high-simple-carbohydrate diet led to a programmed increase in miR-126, which led to a reduction in its direct target, insulin receptor substrate-1 (IRS-1), in eWAT of male offspring [103].…”

Maternal diet-induced obesity programmes cardiac dysfunction in male mice independently of post-weaning diet

“…Children born to obese women are more likely to be exposed to the same obesogenic environment growing up, 23 which implies that CVD risk may be further modified by the quality of postnatal life. In rodents, a post-weaning obesogenic diet has been reported to exacerbate the detrimental effects of maternal diet-induced obesity on offspring body weight gain, 24 , 25 lipid metabolism, 26 insulin sensitivity, 16 , 27 and endothelial dysfunction. 28 However, whether an additional exposure to a calorie-rich postnatal environment worsens the programmed cardiac effects on the adult offspring of a maternal obesogenic diet is relatively unexplored in any species.…”