Differential effects of prenatal stress and glucocorticoid administration on postnatal growth and glucose metabolism in rats K L Franko, A J Forhead and A L Fowden Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK (Correspondence should be addressed to A L Fowden; Email: alf1000@cam.ac.uk) Abstract Glucocorticoid administration during pregnancy pro- grammes cardiovascular and metabolic functions in the adult offspring. Often, the control procedures are stressful per se and raise maternal glucocorticoid concentrations. This study compared the effects of maternal injection with dexametha- sone (dex, 200 mg/kg) or saline with no treatment from 15 to 20 days of rat pregnancy on offspring growth and glucose metabolism. Near term, maternal corticosterone concen- trations were higher in the saline-treated dams and lower in the dex-treated dams relative to untreated animals. In both male and female offspring, growth rate was measured for 14 weeks, and glucose tolerance was assessed between 12 and 13 weeks together with body fat content and plasma concen- trations of insulin, leptin, and corticosterone between 14 and 15 weeks. Offspring liver was collected at different ages and was analyzed for glycogen content and gluconeogenic enzyme activity. Compared with untreated animals, both dex and saline treatments altered postnatal growth although adult body weight was unaffected. The two treatments had different effects on adult insulin concentrations and on hepatic glycogen content and gluconeogenic enzyme activities both pre- and postnatally. Relative to untreated animals, adult glucose tolerance was improved by maternal saline injection in males but not in females, while it was impaired in female offspring but not in male offspring of the dex-treated dams. Adult glucose tolerance was related to male body fat content but not to female body fat content. Dex and saline treatments of pregnant rats have differential sex-linked effects on the growth and glucose metabolism of their offspring, which indicates that the programming actions of natural and synthetic glucocorticoids may differ. Journal of Endocrinology (2010) 204, 319–329 Introduction Human epidemiological studies have shown that impaired intrauterine growth is associated with an increased risk of cardiovascular, metabolic, and other diseases in later life (Barker 1994). These associations have led to the concept that adult disease can originate in utero as a result of developmental programming of key tissues and organ systems during suboptimal intrauterine conditions associated with poor fetal growth (Gluckman et al. 2008). Experimentally, prenatal programming of postnatal metabolism has been demonstrated in a number of species using a range of different techniques to induce intrauterine growth restriction (IUGR) including maternal stress and glucocorticoid administration (see McMillen & Robinson 2005, Fowden et al. 2006, Seckl 2008). Similarly, in naturally occurring IUGR in polytocous species, low birth weight is associated with adult glucose intolerance and altered fat deposition (Poore & Fowden 2002, 2004). In both naturally occurring and experimentally induced IUGR, the programmed alterations in postnatal glucose handling are associated with functional changes in a range of tissues involved in growth and glucoregulation, including several endocrine systems (see McMillen & Robinson 2005, Fowden et al. 2006). In pregnant rats, maternal treatment with the synthetic glucocorticoid, dexamethasone (dex), via a number of different routes leads to IUGR and glucose intolerance of the adult offspring, accompanied by changes in the liver, fat, and skeletal muscle, and in circulating concentrations of insulin, leptin, and corticosterone in the adults (Muneoka et al. 1997, Nyirenda et al. 1998, 2006, Smith & Waddell 2000, Sugden et al. 2001, Cleasby et al. 2003, O’Regan et al. 2004, Wyrwoll et al. 2006, 2008). Similarly, stresses during rat pregnancy that raise maternal glucocorticoid concentrations, such as restraint, noise, and isolation, induce IUGR and alter glucose handling and hypothalamic–pituitary–adrenal (HPA) axis function in the adult offspring (Barbazanges et al. 1996, Valle ´e et al. 1996, Maccari et al. 2003, Lesage et al. 2004, D’mello & Lin 2006). Indeed, in pregnant rats, procedures such as saline injection, often used as a control in studying prenatal origins of adult disease, lead to elevated maternal and fetal corticosterone concentrations, which may programme tissue development per se (Ward & Weisz 1984, Barbazanges et al. 1996). Consequently, the stress of injection may mimic, 319 Journal of Endocrinology (2010) 204, 319–329 DOI: 10.1677/JOE-09-0390 0022–0795/10/0204–319 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 05/31/2020 01:02:50PM via free access