Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms.

Denise S Fernandez-Twinn,Ana Piekarz,Maria Z Alfaradhi,Daniella E Duque-Guimaraes,Susan E Ozanne,Malgorzata S Martin-Gronert,Martin Bushell,David Ferland-Mccollough

doi:10.1016/j.molmet.2014.01.007

Abstract

We determined the effects of maternal diet-induced obesity on offspring adipose tissue insulin signalling and miRNA expression in the aetiology of insulin resistance in later life. Although body composition and glucose tolerance of 8-week-old male offspring of obese dams were not dysregulated, serum insulin was significantly (p<0.05) elevated. Key insulin signalling proteins in adipose tissue were down-regulated, including the insulin receptor, catalytic (p110β) and regulatory (p85α) subunits of PI3K as well as AKT1 and 2 (all p<0.05). The largest reduction observed was in IRS-1 protein (p<0.001), which was regulated post-transcriptionally. Concurrently, miR-126, which targets IRS-1, was up-regulated (p<0.05). These two features were maintained in isolated primary pre-adipocytes and differentiated adipocytes in-vitro. We have therefore established that maternal diet-induced obesity programs adipose tissue insulin resistance. We hypothesise that maintenance of the phenotype in-vitro strongly suggests that this mechanism is cell autonomous and may drive insulin resistance in later life.

Highlights

The prevalence of obesity has been increasing at alarming rates in both the developed and the developing world [1]
The current study demonstrates that maternal diet-induced obesity leads to impaired adipose tissue insulin signalling in young mice of obese mothers through reduced IRβ, insulin receptor substrate-1 (IRS-1) and the p110β catalytic and p85α regulatory subunits of phosphatidylinositol 3-kinase (PI3K)
Insulin resistance in the adipose tissue, leading to increased demands on pancreatic β-cells to produce insulin could contribute to the eventual hypoinsulinaemia and impaired glucose tolerance observed in the offspring of obese dams at 6 months of age

Summary

Introduction

The prevalence of obesity has been increasing at alarming rates in both the developed and the developing world [1]. Animal models strongly support the concept that maternal obesity during pregnancy can transmit to the offspring, through non-genetic mechanisms, an increased risk of obesity, insulin resistance and glucose intolerance (reviewed in [5]). These include models in non-human primates [8,9], sheep [10], maternal high fat fed rodents [11,12,13], and rodent models employing a cafeteria diet [14,15]. Offspring of dams fed this diet throughout pregnancy and lactation gain excess weight, become obese, insulin resistant and develop impaired glucose tolerance in adulthood [16] In addition they develop non-alcoholic fatty liver disease and demonstrate muscle mitochondrial dysfunction [17]. We further aimed to investigate the potential mechanisms underlying the programming of insulin signalling protein expression with a focus on post-transcriptional gene regulation

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Conclusion