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SJ Bernard
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I Yuen
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C McMillen
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ME Symonds
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PC Owens
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Leptin mRNA was measured in adipose tissue of fetal sheep by reverse transcription polymerase chain reaction (RTPCR). Abundance of leptin mRNA relative to b-actin mRNA in fetal perirenal adipose tissue increased (P<0.02) with gestation, being higher at 144 d (0.73 +/- 0. 10, n=5) than at 90-91 d (0.40 +/- 0.08, n=6) or 125 d (0.40 +/- 0. 04, n=5) gestation (term approximately 147- 150 d). There was a positive relationship between relative abundance of leptin mRNA (y) and fetal body weight (x)between 90 and 144 d gestation (r 2 =0.27, P<0.01). The slope of the linear dependence of leptin mRNA on fetal weight was 15-fold greater (P<0.001) at 90-91d (y = 2.81x - 1.1, n=6, r 2 =0.71, P<0.025) than between 125-144 d gestation (y = 0.195x - 0.15, n=16, r 2 =0.39, P<0.01). Thus the leptin synthetic capacity of fetal adipose tissue appears to increase in late gestation but this is accompanied by constraint of its sensitivity to fetal body weight. We hypothesise that leptin synthesis in fetal adipose tissue is related to fetal nutrient supply and growth rate.

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Kimberley C W Wang Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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Kimberley J Botting Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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Song Zhang Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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I Caroline McMillen Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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Doug A Brooks Mechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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Janna L Morrison Early Origins of Adult Health Research Group, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia

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Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT1R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT1 receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.

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M A Hyatt Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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G S Gopalakrishnan Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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J Bispham Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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S Gentili Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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I C McMillen Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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S M Rhind Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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M T Rae Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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C E Kyle Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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A N Brooks Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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C Jones Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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H Budge Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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D Walker Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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T Stephenson Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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M E Symonds Institute of Clinical Research, Centre for Reproduction and Early Life,
Children’s Brain Tumour Research Centre,
School of Nursing, The University of Nottingham, Nottingham NG7 2UH, UK
Macaulay Institute, Craigiebuckler, Aberdeen AB15 8QH, UK
Astra Zeneca, Alderley Park, Cheshire, UK
Discipline of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia

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The liver is a major metabolic and endocrine organ of critical importance in the regulation of growth and metabolism. Its function is determined by a complex interaction of nutritionally regulated counter-regulatory hormones. The extent to which hepatic endocrine sensitivity can be programed in utero and whether the resultant adaptations persist into adulthood is unknown and was therefore the subject of this study. Young adult male sheep born to mothers that were fed either a control diet (i.e.100% of total live weight-maintenance requirements) throughout gestation or 50% of that intake (i.e. nutrient restricted (NR)) from 0 to 95 days gestation and thereafter 100% of requirements (taking into account increasing fetal mass) were entered into the study. All mothers gave birth normally at term, the singleton offspring were weaned at 16 weeks, and then reared at pasture until 3 years of age when their livers were sampled. NR offspring were of similar birth and body weights at 3 years of age when they had disproportionately smaller livers than controls. The abundance of mRNA for GH, prolactin, and IGF-II receptors, plus hepatocyte growth factor and suppressor of cytokine signaling-3 were all lower in livers of NR offspring. In contrast, the abundance of the mitochondrial protein voltage-dependent anion channel and the pro-apoptotic factor Bax were up regulated relative to controls. In conclusion, maternal nutrient restriction in early gestation results in adult offspring with smaller livers. This may be mediated by alterations in both hepatic mitogenic and apoptotic factors.

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