Can neonatal exendin-4 prevent obesity after IUGR? — ASN Events
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Can neonatal exendin-4 prevent obesity after IUGR? (#89)

Hong Liu 1 2 , Christopher G Schultz 3 , Miles De Blasio 1 2 4 , Damien Hunter 1 2 5 , Rebecca Simmons 6 , Karen L Kind 1 5 , Julie A Owens 1 2 , Kathryn L Gatford 1 2
  1. Robinson Institute, University of Adelaide, Adelaide SA 5005, Australia
  2. School of Paediatrics & Reproductive Health , University of Adelaide, Adelaide SA 5005, Australia
  3. Department of Nuclear Medicine & Bone Densitometry, Royal Adelaide Hospital, Australia
  4. Department of Physiology, Development & Neuroscience, University of Cambridge, UK
  5. School of Animal & Veterinary Sciences, University of Adelaide, Adelaide SA 5005, Australia
  6. Medical School, University of Pennsylvania, USA

Background: In humans, low birth weight and accelerated neonatal growth predict later obesity and metabolic disorders. Whilst, central adiposity develops by 4 years of age in intrauterine growth restricted (IUGR) children1, there are limited and conflicting findings regarding obesity and fat distribution in the IUGR adult human2, 3. Similarly, IUGR sheep exhibit catch-up growth and increased visceral fat mass as juveniles4, 5. Neonatal treatment with the GLP-1 analogue, exendin-4, prevented catch-up growth and fat deposition at the end of treatment at d16 of age6 in these IUGR offspring, whilst what happens in the adult remains unknown.  We are therefore investigating the distribution of fat mass and long-term effects of neonatal exendin-4 on growth and fat distribution of IUGR sheep.
Methods: Placental restriction (PR) was induced by surgical removal of most uterine implantation sites of ewes before mating. Weight and size were measured at birth and throughout life in control (CON; n=26F,20M), PR offspring (PR; n=18F, 13M), and PR offspring that were treated with exendin-4 (PR+EX-4; 1 nmol/kg s.c., daily from d1-16 of age; n=13F, 9M). Fat and lean tissue masses were assessed at ~43 weeks age by dual x-ray absorptiometry for total body, total abdominal regions (includes omental, perirenal, and retroperitoneal fat depots), and upper abdominal regions (primarily omental fat depots).

Results: PR reduced birth weight (13%; CON: 5.24±0.15 kg, PR: 4.57±0.20 kg, p=0.002) but not adult weight (p=0.969). Total body fat (% body weight) was not correlated with birth weight (CON: r=0.001, p>0.4; PR: r=-0.063, p>0.3; PR+EX-4: r=0.355, p=0.052). Whilst total abdominal fat (% total body fat) was not correlated with birth weight (CON and PR: r=-0.09, p=0.219; PR+EX-4: r=0.268, p=0.114), fat mass in the upper abdominal region (%total body fat) was negatively correlated with birth weight in animals not treated with EX-4 (CON and PR: r=-0.219, p=0.028) but not in animals treated with EX-4 (PR+EX-4: r=0.261, p=0.120).

Conclusions: IUGR is associated with unchanged overall adiposity in adult sheep, similar to that reported in humans, but with redistribution of fat centrally, possibly contributing to IUGR-associated adverse cardiovascular and metabolic health outcomes. Neonatal exendin-4 treatment of IUGR offspring normalises pattern of fat distribution.

  1. Ibanez, L. et al. (2008) J Clin Endocrinol Metab 93 (3): 925-8
  2. Yajnik, C. S. (2004) Proc Nutr Soc 63 (3): 387-96
  3. Rogers, I. (2003) Int J Obes Relat Metab Disord 27 (7): 755-77
  4. De Blasio, M. J. et al. (2007) Am J Physiol Regul Integr Comp Physiol 292 (2): R875-86
  5. Muhlhausler, B. S. et al. (2008) Domest Anim Endocrinol 35 (1): 46-57
  6. Gatford, K. L. et al. (2013) PLoS One 8 (2): e56553
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