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Suboptimal Maternal Nutrition in Early to Mid Gestation Enhances Adipose Tissue Development in Fetal Sheep

Presented at the Neonatal Society 2013 Summer Meeting (programme).

Ojha S, Symonds ME, Budge H

Life Nutrition Research Unit, Academic Child Health, University of Nottingham, NG7 2UH, UK

Background: Maternal nutrient restriction during pregnancy predisposes the offspring to adult obesity and the metabolic syndrome (1). Stimuli or insults during critical periods of development can “programme” the fetus and the resulting adaptations can be detrimental in later life (2). In both sheep and humans, the majority of fetal adipose tissue is deposited during the final third of gestation and maternal nutritional manipulation induces differential changes in adipose tissue dependent on its timing during fetal development3. In sheep, maternal nutrient restriction between 28-80 days of gestation enhances fetal fat deposition. In this study, we hypothesised that maternal nutrient restriction in early to mid gestation would increase the abundance of uncoupling protein 1 (UCP1) and upregulate the expression of key transcription factors involved in brown adipogenesis in pericardial adipose tissue of fetal lamb.

Methods: Pregnant sheep were randomised to be fed 100% of total metabolisable energy (ME) requirements throughout pregnancy (C) or nutrient restriction (NR) to be fed 60% of this amount between 80-110 days of gestation. Nutrition was restored to 100% of total ME for the remaining gestation. At 140 days gestation (term = 145 days), sheep were humanely euthanased and fetal lambs sampled. All procedures were conducted with Home Office Approval under UK legislation. Gene expression for adipose tissue related genes such as CEBPβ (4) a key transcription factor in brown adipogenesis and BMP4 (5) a promoter of white adipogenesis were determined by qPCR and protein analysis was performed by Western blotting and densitometry. Statistical analysis was performed using SPSS (Version 21).

Results: Maternal nutrient restriction did not affect the body weights of the mothers or the fetus but offspring of NR mothers had significantly more pericardial adipose tissue than the offspring of C mothers (C: 3.86 ± 0.38; NR: 4.95 ± 0.46 g (p<0.05)). Both gene expression and protein abundance of UCP1 was significantly increased in fetal offspring following maternal NR (Gene expression: C: 1.00 ± 0.34; NR: 2.59 ± 0.50 a.u. (p<0.01); Protein abundance: C: 0.93 ± 0.06; NR: 1.36 ± 0.08 a.u. (p<0.05)). Gene expression of transcription factors CCAAT-enhancer binding protein (CEBPβ) (C: 1.00 ± 0.20; NR: 2.02 ± 0.36 a.u. (p<0.05)), bone morphogenetic protein (BMP) 7 (C: 1.00 ± 0.26; NR: 1.87 ± 0.18 a.u. (p<0.05)), Homobox c9 (C: 1.00 ± 0.39; NR: 3.67 ± 0.30 a.u. (p<0.05)) and BMP4 (C: 1.00 ± 0.27; NR: 2.06 ± 0.43 a.u. (p<0.05)) were also significantly upregulated in offspring of NR mothers. There was no difference in either the gene expression of leptin, adiponectin, KCNK3, PPARγ and PGC1α or the abundance of cytochrome c and voltage dependent anion channel (VDAC).

Conclusion: Increase in pericardial adipose tissue deposition with this modest maternal nutrient restriction in is in keeping with previous studies which demonstrated increased fat deposition in other visceral depots6 and the increase in UCP1 signifies that development of fetal brown adipose tissue is enhanced when maternal nutrition is restricted in early to mid gestation. The upregulation of expression of these genes indicates that adipogenesis of both brown and white lineage is enhanced after maternal nutrient restriction. These latest findings further support our hypothesis that maternal nutrient restriction during gestation can programme adipose tissue development in the fetus and are in keeping with human epidemiological data suggesting that maternal malnutrition during gestation may permanently affect adult health without affecting the size of the baby at birth and that adaptations that enable the fetus to continue to grow may have adverse consequences for health in later life.

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1. Barker et al. (1986) Lancet 1:1077-81
2. Lucas (1991). Ciba Found Symp 156:38-50
3. Budge et al.(2004) Biol Reprod. 71:359-65
4.Kajimura et al.(2010) Cell Metab. 11: 257-62
5.Bowers et al.(2007) Cell Cycle
6: 385-9.4.Gopalakrishnan et al. (2001) Early Hum Dev. 63:58-9.

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