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Maternal nutrient restriction affects neonatal brown adipose tissue development

Presented at the Neonatal Society 2012 Summer Meeting (programme).

Ojha S, Elvidge L, Symonds ME, Budge H

Early Life Nutrition Research Unit, Academic Child Health, University Hospital, Nottingham, NG7 2UH

Background: Newborn infants have relatively large depots of brown adipose tissue (BAT) which enable nonshivering thermogenesis for maintenance of body temperature. Animal models of in utero nutrition restriction have demonstrated that growth restricted newborns have poorly developed BAT and impaired ability to withstand cold stress (1). Pericardial adipose tissue (PcAT) is a depot of intra-thoracic fat which contains brown adipocytes in newborns and adults. PcAT has several paracrine influences on the heart and is associated with development of cardiovascular diseases in adults (2). In this study, we aimed to study the early neonatal development of PcAT to determine how key markers of BAT are affected by maternal nutrient restriction in late gestation.

Methods: Pregnant sheep were randomised to be fed 100% of total metabolisable energy requirements throughout pregnancy (C) or nutrient restriction (NR) to be fed 60% of this amount in late gestation. Both groups had equal access to mineral licks to provide adequate micronutrients. They gave birth to twins at term gestation. PcAT was sampled immediately after humane euthanasia at 6 hours of age. All procedures were conducted with Home Office Approval under UK legislation. Gene expression for key markers of brown adipose tissue was determined using qPCR and protein analysis was performed by Western blotting and densitometry. Statistical analysis was performed using SPSS (Version 17).

Results: Uncoupling protein 1 (UCP1) gene expression was not affected by maternal NR but protein abundance was significantly reduced in offspring of NR mothers at day 0 compared to C mothers (C, 0 days: 0.91 0.10; NR, 0 days: 0.52 0.11 a.u. (p<0.05)). Gene expression of type 2 iodothyronine deiodinase (DIO2) was significantly downregulated in offspring of NR mothers (C, 0 days: 1.00 0.66; NR 0 days: 0.54 0.30 a.u. (p<0.005)) as was the expression of insulin receptor (IR) (C, 0 days: 1.00 0.16; NR, 0 days: 0.50 0.11 a.u. (p<0.05)) and the cell proliferation marker Ki67 (C, 0 days: 1.00 0.21; NR, 0 days: 0.45 0.07 a.u. (p<0.05)). Expression of other genes associated with BAT such as beta adrenergic receptors types 1 and 2, PGC1α and PPARγ was unchanged.

Conclusion: Reduced abundance of UCP1 protein in PcAT of offspring of NR mothers at birth provides evidence of the effect of in utero nutrition on BAT development in the newborn. Reduced expression of Ki67 further suggests poor turnover of BAT in these animals (3). DIO2 is essential for adaptive thermogenesis in BAT (4) and its downregulation with maternal NR may be the mechanism for reduced nonshivering thermogenesis in growth restricted newborns. BAT is one of the most-insulin responsive/ glucose sensitive tissues (5) and transgenic mice lacking IR have less BAT (6). Downregulation of IR in BAT due maternal nutrient restriction can reduce glucose uptake into brown adipocytes diminishing BAT depots in the offspring. These latest results illustrate that maternal nutrient restriction can affect the course of BAT development in visceral adipose tissue depots such as pericardial adipose and suggest mechanisms for the susceptibility of IUGR infants to cold stress.

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1.Cogneville, A.M et al. (1975), J Nutr, 105:982-8.
2.Clement, K et al. (2009), Arterioscler Thromb Vasc Biol 29:615-6.
3.Scholzen, T et al. (2000) J Cell Physiol 182:311-22. Jesus, L.A et al. (2001) J Clin Invest, 108:1379-85.
5.Storlien, L.H et al (1986) Am J Physiol 251:E576-83.
6.Guerra, C., et al (2001) J Clin Invest 108:1205-13.

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