M. J. De Blasio

Review: Placental Programming of Postnatal Diabetes and Impaired Insulin Action after IUGR

Being born small due to poor growth before birth increases the risk of developing metabolic disease, including type 2 diabetes, in later life. Inadequate insulin secretion and decreasing insulin sensitivity contribute to this increased diabetes risk. Impaired placental growth, development and function are major causes of impaired fetal growth and development and therefore of IUGR. Restricted placental growth (PR) and function in non-human animals induces similar changes in insulin secretion and sensitivity as in human IUGR, making these valuable tools to investigate the underlying mechanisms and to test interventions to prevent or ameliorate the risk of disease after IUGR. Epigenetic changes induced by an adverse fetal environment are strongly implicated as causes of later impaired insulin action. These have been well-characterised in the PR rat, where impaired insulin secretion is linked to epigenetic changes at the Pdx-1 promotor and reduced expression of this transcription factor. Present research is particularly focussed on developing intervention strategies to prevent or reverse epigenetic changes, and normalise gene expression and insulin action after PR, in order to translate this to treatments to improve outcomes in human IUGR.

Placental Restriction Increases Adipose Leptin Gene Expression and Plasma Leptin and Alters Their Relationship to Feeding Activity in the Young Lamb

Low birth weight and catch-up growth predict increased adiposity in children and adults. This may be due in part to leptin resistance, as adults who were born small exhibit increased plasma leptin concentration relative to adiposity. Placental restriction (PR), a major cause of intrauterine growth restriction, reduces size at birth and increases feeding activity and adiposity by 6 wk in sheep. We hypothesized that PR would increase plasma leptin concentration and alter its relationship with feeding activity and adiposity in young lambs. Body size, plasma leptin, feeding activity, adiposity, leptin, and leptin receptor gene expression in adipose tissue were measured (12 control, 12 PR). PR reduced size at birth and increased adiposity. Plasma leptin concentration decreased with age, but to a lesser extent after PR and correlated positively with adiposity similarly in control and PR. PR increased plasma leptin concentration and perirenal adipose tissue leptin expression. Feeding activity correlated negatively with plasma leptin concentration in controls, but positively after PR. PR increases adipose tissue leptin expression and plasma leptin concentration, however, this increased abundance of peripheral leptin does not inhibit feeding activity (suckling event frequency), suggesting PR programs resistance to appetite and energy balance regulation by leptin, leading to early onset obesity.

Maternal responses to daily maternal porcine somatotropin injections during early-mid pregnancy or early-late pregnancy in sows and gilts

Piglet neonatal survival and postnatal growth and efficiency are positively related to birth weight. In gilts, daily maternal porcine ST (pST) injections from d 25 to 100 (term approximately 115 d), but not d 25 to 50, of pregnancy increase progeny birth weight. Daily maternal pST injections from d 25 to 50 increase fetal weight at d 50 in gilts and sows. We therefore hypothesized that daily pST injections from d 25 to 100, but not d 25 to 50, of pregnancy would increase birth weight similarly in both parities. Landrace x Large White gilts and sows were uninjected (controls) or were injected daily with pST (gilts: 2.5 mg/d; sows: 4.0 mg/d, each approximately 15 microg of pST/kg per day) from d 25 to 50 or 100 of pregnancy. Litter size and BW were recorded at birth, midlactation, and weaning. Dams were followed through the subsequent mating and pregnancy. Maternal pST injections from d 25 to 100, but not d 25 to 50, increased mean piglet birth weight by 11.6% in sows (P <or= 0.001) and by 5.6% in gilts (P = 0.008). Both pST treatments decreased litter size by approximately 0.6 live-born piglets (each P <or= 0.025). In sows, maternal pST treatment from d 25 to 100 increased culls at weaning (P = 0.037). In remated dams, prior treatments did not affect (P > 0.1) the weaning-remating interval, conception rate, or subsequent litter size. Greater pST-induced birth weight increases in sows than in gilts may mean that underlying metabolic or placental mechanisms for pST action are constrained by maternal competition for nutrients in rapidly growing gilts.

Small size at birth predicts decreased cardiomyocyte number in the adult ovine heart

Low birth weight is associated with increased risk of cardiovascular disease in adulthood. Intrauterine growth restriction (IUGR) hearts have fewer CMs in early postnatal life, which may impair postnatal cardiovascular function and hence, explain increased disease risk, but whether the cardiomyocyte deficit persists to adult life is unknown. We therefore studied the effects of experimentally induced placental restriction (PR) on cardiac outcomes in young adult sheep. Heart size, cardiomyocyte number, nuclearity and size were measured in control (n=5) and PR (n=5) male sheep at 1 year of age. PR lambs were 36% lighter at birth (P=0.007), had 38% faster neonatal relative growth rates (P=0.001) and had 21% lighter heart weights relative to body weight as adults (P=0.024) than control lambs. Cardiomyocyte number, nuclearity and size in the left ventricle did not differ between control and PR adults; hearts of both groups contained cardiomyocytes (CM) with between one and four nuclei. Overall, cardiomyocyte number in the adult left ventricle correlated positively with birth weight but not with adult weight. This study is the first to demonstrate that intrauterine growth directly influences the complement of CM in the adult heart. Cardiomyocyte size was not correlated with cardiomyocyte number or birth weight. Our results suggest that body weight at birth affects lifelong cardiac functional reserve. We hypothesise that decreased cardiomyocyte number of low birth weight individuals may impair their capacity to adapt to additional challenges such as obesity and ageing.

Maternal low-dose porcine somatotropin treatment in late gestation increases progeny weight at birth and weaning in sows, but not in gilts

Birth weight positively predicts postnatal growth and performance in pigs and can be increased by sustained maternal porcine ST (pST) treatment from d 25 to 100 of pregnancy (term ∼115 d). The objective of this study was to test whether a shorter period of maternal pST treatment in late pregnancy (d 75 to 100) could also increase birth and weaning weights of progeny under commercial conditions. Gilts (parity 0) and sows (parities 2 and 3) were not injected (controls) or injected daily with pST (gilts: 2.5 mg•d(-1), sows: 4.0 mg•d(-1), both ∼13 to 14 μg•kg(-1)•d(-1)) from d 75 to 100 of pregnancy. Litter size and BW were recorded at birth and weaning, and dams were followed through the subsequent mating and pregnancy. Maternal pST injections from d 75 to 100 increased litter average progeny weight at birth (+96 g, P = 0.034) and weaning (+430 g, P = 0.038) in sows, but had no effect on progeny weight in gilts (each P > 0.5). Maternal pST treatment did not affect numbers of live-born piglets and increased numbers of stillborn piglets in sows only (+0.4 pigs/litter, P = 0.034). Maternal pST treatment did not affect subsequent reproduction of dams. Together with our previous data, these results suggest that sustained increases in maternal pST are required to increase fetal and postnatal growth in gilt progeny, but that increasing maternal pST in late pregnancy may only be an effective strategy to increase fetal and possibly postnatal growth in sow progeny.

285. Increased perinatal mortality following restriction of placental and fetal growth

Intrauterine growth restriction and subsequent low birth weight in humans are associated with increased perinatal mortality and morbidity. Impaired placental function is a major cause of IUGR in humans, but its impact on perinatal survival has not been clearly defined. We have therefore investigated the effect of restriction of placental and fetal growth on perinatal survival and behaviour in the neonatal lamb. Placental growth was surgically restricted (PR) by removal of the majority of endometrial implantation sites prior to pregnancy, leaving either 6 to 7 (moderate PR) or 3 to 4 (severe PR) visible caruncles in each uterine horn, and ewes were mated following at least 10 weeks recovery. Perinatal outcomes (stillbirths and neonatal death before 3 days of age) were recorded in a cohort of 48 control (30 singleton, 18 twin) and 28 moderate PR (14 singleton, 14 twin), and 21 severe PR (11 singleton, 10 twin) lambs, and effects of PR or twinning were evaluated by Chi-square analysis. Rates of stillbirth (P = 0.006) and total perinatal deaths (P < 0.001) were higher in severe PR pregnancies than in control or moderate PR lambs, overall (see Table in PDF file). Similarly, severe PR increased stillbirths and perinatal deaths in twins alone (P = 0.003 and P = 0.015 respectively), but the effects of PR were not significant in singletons (P = 0.10, P = 0.26 respectively). Twinning increased stillbirths and perinatal deaths overall (P = 0.002, P = 0.001) and in control lambs alone (P = 0.038, P = 0.017). Restricted fetal growth due to twinning or severe surgical restriction of placental growth thus decreases perinatal survival, due to increased stillbirths. We will further investigate the characteristics of neonatal morbidity following PR by recording neonatal behaviour, including time taken to stand and suckle, in a subsequent cohort of control and PR lambs.