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The influence of maternal nutrient restriction in late pregnancy and accelerated postnatal growth on plasma insulin and leptin and hypothalamic gene expression following obesity in the sheep

Presented at the Neonatal Society 2010 Spring Meeting.

Dellschaft NS1, Sebert SP1, Keisler D1, Symonds ME2, Budge H1

1 Early Life Nutrition Research Unit, Academic Child Health, School of Clinical Sciences, University of Nottingham, Nottingham, UK
2 Department of Animal Sciences, University of Missouri, Columbia, Missouri 65201, USA

Background: Prenatal caloric restriction, followed by accelerated postnatal growth, influences later risk for metabolic diseases associated with obesity. This may be associated with a resetting of hypothalamic appetite control and insulin sensitivity.

Aim: The aim of this study was to differentiate between the long term effects of nutrient restriction in late pregnancy and those of accelerated early postnatal growth followed by obesity. Outcomes measured were plasma leptin, insulin sensitivity and hypothalamic regulation of energy balance and blood pressure regulation.

Methods: Pregnant twin-bearing sheep were either fed to requirements (R; n=8) or nutrient restricted to 60% of this amount (N; n=15) from 110 days up to term (~147 days). Twin offspring were either reared by their mother as singletons to promote accelerated early postnatal growth (A) (RA, n=8; NA n=9) or both offspring were reared together by their mother to promote standard early postnatal growth (S) (NS, n=7). After weaning, offspring were then kept in a low activity environment until 17 months of age when insulin response to a glucose challenge was assessed and entire hypothalami dissected for gene expression analysis by quantitative real-time PCR. Appropriate institutional Animal Ethics Committee approval was obtained.

Results: Although birth weight was reduced in N offspring, adult offspring body weight and composition were similar between groups. Plasma leptin and insulin responsiveness were higher in N compared to R offspring. Whilst gene expression of hormone receptors i.e. insulin, leptin and ghrelin were unaffected, genes involved in insulin and leptin signalling (protein tyrosine phosphatase, non-receptor type 1), energy sensing (mammalian target of rapamycin, adenosin monophosphate kinase, fat mass and obesity associated), blood pressure regulation (arginine vasopressin) and the glucocorticoid system (glucocorticoid receptor) were overexpressed in N compared to R offspring. None of these effects were significantly influenced by changes in postnatal growth.

Conclusion: Although maternal diet did not alter adult body weight or composition, long term systemic changes in leptin and insulin regulation were induced by fetal growth restriction. These adaptations were further associated with differential responses in the gene expression profiles within the hypothalamus, suggesting programmed alterations in energy sensing pathways.

Acknowledgements:

References
Symonds ME et al. Nat Rev Endocrinol 2009; 5(11): 604-610
Sebert SP et al. Reproduction 2010; 139(1): 265-274

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