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Programming of adiponectin and leptin mRNA expression in juvenile offspring after maternal nutrient restriction in late gestation

Presented at the Neonatal Society 2006 Summer Meeting (programme).

Sharkey D, Hyatt M, Gardner D, Symonds ME, Budge H

Centre for Reproduction and Early Life, School of Human Development, University Hospital, Nottingham NG7 2UH, UK

Introduction: There has been a significant increase in the incidence of type 2 diabetes and obesity worldwide in children and adults. Circulating levels of leptin and adiponectin, both produced by adipocytes, increase and decrease respectively with increasing adiposity in adults1. Whilst leptin suppresses appetite and stimulates energy expenditure, adiponectin down regulates the inflammatory response seen in the metabolic syndrome and reduces insulin resistance (1). Fetal undernutrition is an important factor in the development of insulin resistance and obesity and maternal nutrient restriction (NR) during late gestation in sheep impairs glucose-insulin homeostasis and enhances fat deposition in juvenile offspring (2). The current study set out to establish whether maternal NR during this period of rapid fetal growth is accompanied by alteration in the expression of key adipokines in the juvenile offspring.

Methods: Singleton bearing sheep were randomised to receive either 100% metabolizable energy (ME) (Controls, n=7) throughout pregnancy or 50% ME from day 110-term (NR Late, n=4). Offspring were reared by their mother until 3 months, weaned and fed at pasture until 1 year when they were humanely euthanased. Total RNA was extracted from perirenal adipose tissue (PAT), reverse transcribed and leptin and adiponectin mRNA quantification performed by real time PCR using ovine specific primers. Expression was normalised to 18s rRNA using the 2-Δct method and expressed as a ratio to the controls. Statistical differences between groups were determined by Mann Whitney test and Spearmanís correlation coefficients. All animal procedures were performed in accordance with U.K. legislation.

Results: There was a 9 fold increase in leptin mRNA abundance compared to controls which accompanied the greater fat mass in NR late offspring. Interestingly, not only was adiponectin expression positively associated with glucose area under the curve (R2 0.57; P<0.01) in NR late offspring but adiponectin mRNA abundance increased 8 fold.

Conclusions: Maternal NR during late gestation promotes adipose tissue deposition and leads to insulin resistance in the offspring2 which exhibit raised adipokine mRNA abundance. Whilst the latter is the opposite of the effect reported in adult humans with established insulin resistance1, whether it reflects an adiponectin resistant state or an early compensatory response prior to the development of the phenotype of obesity and type 2 diabetes as part of the metabolic syndrome remains to be elucidated.

Acknowledgements: D Sharkey is funded by a BHF Clinical Research Training Fellowship.

1. Fasshauer M, Pashke R Diabetologia 2003; 46: 1594-1603
2. Gardner DS et al Am J Physio 2005; 289: R947 -954

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