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Effect of late gestational nutrient restriction on gene expression of markers of white and brown adipocytes in the postnatal sheep

Presented at the Neonatal Society 2009 Summer Meeting (programme).

Pope M, Sebert S, Budge H, Symonds ME

Early Life Nutrition Research Unit, School of Clinical Sciences, University of Nottingham, Nottingham, UK

Introduction: It has recently been shown that brown adipose tissue (BAT) is present in adult humans and that its abundance is reduced with obesity (1). Birth results in the rapid activation of BAT and is normally followed by its loss and replacement with white adipose tissue (2). Recent studies in rodents, however, have suggested that brown and white adipocytes have very different origins with bone morphogenetic protein acting through PR-domain-containing (PRDM)16 (3,4) having a pivotal role in this process. The aim of our study was to establish, in sheep, the primary molecular changes in brown and white fat i.e. uncoupling protein (UCP)1, peroxisome proliferator-activated receptor coactivator (PGC)1α and PRDM16 in the perirenal-abdominal depot which rapidly changes its characteristics over the first month of life. This was combined with an investigation of the impact of late gestational nutrient restriction of the mother, as offspring so exposed deposit more fat in later life (5).

Methods: Eighteen twin-bearing pregnant sheep were randomly assigned to a normal (C, 100% of total metabolisable (ME) requirements, n=9) or nutrient restricted (NR) (60% of total ME, n=9) diet from 110 days gestation until term (i.e. 147 days). The timing of nutrient restriction coincides with the period of maximal fat deposition in the fetal sheep. One twin was humanely euthanased on the first day of life and its sibling sampled at 30 days of age. The mRNA abundance for UCP1, PGC1α and PRDM16 in adipose tissue was measured by real-time PCR. Animal Ethics Committee approval was given.

Results: Over the first month of life, there was the expected decline (~100 fold) in UCP1 mRNA abundance (P<0.0001) in both groups of offspring. However, gene expression for PGC1α and PRDM16 increased by ~10 fold between birth and one month of age (P<0.001). The magnitude of this adaptation was greatest in male offspring born to control fed mothers, a process that was significantly down-regulated in male (e.g. PGC1α: 30 days C 5.10.7; NR 1.50.5 ΔCt (P<0.01)), but not females offspring born to mothers NR through late gestation. Fat mass increased in all offspring with age but this process was much greater in females than males irrespective of prenatal diet (Females: 1.830.18; Males 1.060.13 g/kg body weight P<0.001).

Conclusion: The rapid growth of white fat during postnatal life is accompanied by a pronounced upregulation of molecular markers previously presumed to define BAT. During early postnatal life, the development of white fat also appears to be very different between males and females. This difference may be critical in determining not only the long term effects of maternal diet but also the very different fat distribution with gender.

1. van Marken Lichtenbelt, W. D. et al. N Engl J Med 360, 1500-8 (2009).
2. Symonds, M. E. et al. J Endocrinol 179, 293-9 (2003).
3. Tseng, Y. H. et al. Nature 454, 1000-4 (2008).
4. Seale, P. et al. Nature 454, 961-7 (2008).
5. Gardner, D. S. et al. Am J Physiol Regul Integr Comp Physiol 289, R947-54 (2005).

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