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Maternal nutrient restriction during early-mid gestation increases adipocyte stress in obese juvenile offspring

Presented at the Neonatal Society 2007 Summer Meeting (programme).

Sharkey D, Gardner DS, Symonds ME, Budge H

Centre for Reproduction and Early Life, University of Nottingham, NG7 2UH, UK

Introduction: Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular disease. Adipocytes secrete many of the important adipokines implicated in the development of the metabolic syndrome. Endoplasmic reticulum (ER) stress, within adipocytes, mediates dysregulation of adipokines culminating in the metabolic syndrome in obesity (Chevillotte et al 2007 Diabetes; 56:1042-50). Markers of ER stress in obesity include glucose related protein 78 (GRP78), C/EBP homologous protein (CHOP) and uncoupling protein 2 (UCP-2). Growing evidence suggests that maternal nutrient restriction (NR) during critical periods of fetal development can increase the risk of disease in later life. We have previously shown that early-mid gestation NR adversely affects the expression of key genes in adipose tissue (Gnanalingham et al, 2005; Am J Physiol 289:1407-15). The extent to which the expression of ER stress related genes is altered by maternal NR is unknown. The present study examined the combined effects of maternal nutritional manipulation during pregnancy and earlyonset obesity on ER stress within adipose tissue.

Methods: Sixteen pregnant sheep were randomly assigned to a normal (C, 7 MJ/day, n=7) or NR diet (NR, 3.5 MJ/day, n=9) from days 30 to 80 gestation (term = 147 days) and fed to requirements at all other times. Following weaning at 10 weeks postnatal age, offspring were reared in an environment of restricted activity and increased energy dense food to promote fat deposition and, thus, obesity. All sheep were humanely euthanased at 1 year and tissues sampled. GRP78, CHOP and UCP-2 mRNA expression in adipose tissue were measured by real-time PCR, normalised to 18s rRNA and expressed as ratio of control (arbitrary units). Statistical analyses were performed using Mann Whitney test and Spearmanís correlation coefficient. All animal procedures had local Animal Ethics Committee Approval and were performed in accordance with U.K. legislation.

Results: Maternal NR had no effect on perirenal fat mass but did cause a pronounced up regulation of GRP78 expression. In addition, irrespective of maternal diet both GRP78 and UCP-2 correlated well with important adipokines including TNFα (r=0.6 p<0.01, r=0.66 p<0.001), IL-6 (r=0.6 p<0.001, r=0.56 p<0.01) and MCP-1 (r=0.54 p<0.01, r=0.61 p<0.01) respectively but most strikingly with each other (r=0.77 p<0.0001).


Conclusions: This is the first study to demonstrate maternal nutrient restriction during early fetal adipose deposition increases the susceptibility of adipocytes to cellular stress coupled with markers of inflammation in juvenile obesity. In the offspring, this may accelerate the onset of the metabolic syndrome.

Acknowledgements: This study was supported by the British Heart Foundation

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