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.
Highlights
Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring
We have shown previously that reduction in adipose tissue of insulin signaling protein expression is one mechanism by which maternal diet-induced obesity leads to increased risk of type 2 diabetes mellitus (T2DM) in the offspring[14]
This was associated with reduced protein levels of adipose tissue insulin receptor substrate-1 (IRS-1) and a parallel increase in miR-126 expression, a miRNA that directly regulates translation of Irs[1] mRNA through binding to its 3′un-translated region
Summary
Previous studies have shown that maternal diet-induced obesity leads to increased risk of type 2 diabetes in offspring. Our results suggest that whilst programmed reductions in IRS-1 are associated with increased levels of miR-126 and reduced translation of Irs[1] 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. Mouse offspring of dams fed a high fat-high sugar diet during pregnancy developed insulin resistance by 8 weeks of age when weaned onto a low fat chow diet and were lean This was associated with reduced protein levels of adipose tissue IRS-1 and a parallel increase in miR-126 expression, a miRNA that directly regulates translation of Irs[1] mRNA through binding to its 3′un-translated region. These programmed effects on IRS-1 and miR-126 were cell autonomous and were retained in pre-adipocytes from programmed animals that were differentiated in vitro[14]
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