Abstract
Exposure to maternal obesity before and/or throughout pregnancy may increase the risk of obesity and insulin resistance in the offspring in childhood and adult life, therefore, resulting in its transmission into subsequent generations. We have previously shown that exposure to maternal obesity around the time of conception alone resulted in increased adiposity in female lambs. Changes in the abundance of insulin signalling molecules in skeletal muscle and adipose tissue precede the development of insulin resistance and type 2 diabetes. It is not clear, however, whether exposure to maternal obesity results in insulin resistance in her offspring as a consequence of the impact of increased adiposity on skeletal muscle or as a consequence of the programming of specific changes in the abundance of insulin signalling molecules in this tissue. We have used an embryo transfer model in the sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for one week after conception on the expression and abundance of insulin signalling molecules in muscle in the offspring. We found that exposure to maternal obesity resulted in lower muscle GLUT-4 and Ser 9 phospho-GSK3α and higher muscle GSK3α abundance in lambs when compared to lambs conceived in normally nourished ewes. Exposure to maternal weight loss in normal or obese mothers, however, resulted in lower muscle IRS1, PI3K, p110β, aPKCζ, Thr 642 phospho-AS160 and GLUT-4 abundance in the offspring. In conclusion, maternal obesity or weight loss around conception have each programmed specific changes on subsets of molecules in the insulin signalling, glucose transport and glycogen synthesis pathways in offspring. There is a need for a stronger evidence base to ensure that weight loss regimes in obese women seeking to become pregnant minimize the metabolic costs for the next generation.
Highlights
More women in the developed world are entering pregnancy with a high body mass index (BMI) in the overweight or obese range [1,2,3,4,5]
There was no difference in the mRNA expression (CC, 0.16 ± 0.01; CR, 0.13 ± 0.02; HH, 0.19 ± 0.03; HR, 0.17 ± 0.01) and protein abundance of insulin receptor (IR) and protein abundance of Tyr 1162/1163 phospho-IR, IRS1 (Figures 1a - c), the p85α and p110β subunits of phosphatidylinositol 3-kinase (PI3K), phosphatase and tensin homologue (PTEN), PDK1, Ser 241 phosphoPDK1, aPKCζ (Figures 2a - f), Akt1, Akt2, Thr 308 and Ser 473 phospho-Akt (Figures 3a - d) in skeletal muscle between the HH and CC lambs
We have shown that exposure to maternal obesity during the periconceptional period does not appear to impact directly on the early components of the insulin receptor signalling pathway in skeletal muscle of the offspring but rather results in specific changes to molecules downstream of Akt, namely glucose transporters (GLUTs)-4 and GSK3α (Figure 6)
Summary
More women in the developed world are entering pregnancy with a high body mass index (BMI) in the overweight or obese range [1,2,3,4,5]. A study by Long and colleagues found that exposure of ewes to a period of maternal overnutrition from before conception and throughout pregnancy resulted in an increase in offspring adiposity as well as a decrease in glucose tolerance and insulin sensitivity in adult offspring [18]. These offspring had decreased abundance of a specific subset of insulin signalling molecules in skeletal muscle [19]. These findings and other experimental studies suggest that exposure to maternal obesity may result in an ‘intergenerational cycle’ of obesity and insulin resistance [2,20,21]
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