Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Abstract

Maternal caloric restriction during late gestation reduces birth weight, butwhether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment afterweaning is not established. We induced IUGR in twin-pregnant sheep using a 40%maternal caloric restriction commencing from 110 days of gestation until term (~147 days), compared with mothers fed to 100% of requirements. Offspringwere reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environmentwiththe exceptionof a subgroupof IUGRoffspring, rearedastwins,maintainedin a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reducedmaternal plasmaglucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy andglucocorticoidsensitivity. These long-termadaptationswere reducedbutnotnormalizedin IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.