Multigenerational impact of maternal overnutrition/obesity in the sheep on the neonatal leptin surge in granddaughters

Abstract

Background/ObjectivesWe have reported that maternal overnutrition/obesity (OB) in sheep resulting from feeding 150% of National Research Council (NRC) requirements throughout gestation, leads to maternal hyperglycemia and hyperinsulinemia. Further, newborn lambs born to OB vs. control-fed (CON, 100% of NRC) ewes exhibited greater adiposity, increased blood cortisol, insulin and glucose and the elimination of the postnatal leptin spike seen in lambs born to CON ewes. This early postnatal leptin peak is necessary for development of hypothalamic circuits which program appetite in later life. This study evaluated the multigenerational impact of OB on insulin:glucose dynamics of mature female F1 offspring fed only to requirements throughout gestation, and on their lambs (F2 generation).Design and MethodsAdult F1 female offspring born to OB (n=10) or CON (n=7) ewes were utilized. All F1 ewes were subjected to a glucose tolerance test at midgestation and late gestation. Jugular blood was obtained from F2 lambs at birth (day 1) through postnatal day 11, and plasma glucose, insulin, cortisol and leptin concentrations determined. Dual Energy X-ray Absorptiometry (DEXA) was utilized to determine bone mineral density (BMD), bone mineral content (BMC), lean tissue mass, and fat tissue mass.ResultsFasted blood glucose and insulin concentrations were greater (P < 0.05) in OBF1 than CONF1 ewes at mid- and late gestation. Further, after glucose infusion, both glucose and insulin concentrations remained higher in OBF1 ewes (P < 0.05) than CONF1 ewes demonstrating greater insulin resistance. Blood concentrations of glucose, insulin, and cortisol, and adiposity were higher (P < 0.01) in OBF2 lambs than CONF2 lambs at birth. Importantly, OBF2 lambs failed to exhibit the early postnatal leptin peak exhibited by CONF2 lambs.ConclusionsThese data suggest that these OBF2 lambs are predisposed to exhibit the same metabolic alterations as their mothers, suggesting a multi-generational programming effect.

Maternal obesity disrupts the methionine cycle in baboon pregnancy

“…), sheep (Sinclair et al ; Long et al ; Shasa et al. ), nonhuman primates (Aagaard‐Tillery et al ; Grayson et al ; Sullivan et al ; Grant et al. ; Suter et al ; Maloyan et al ), and humans (Gillman et al.…”

“…; Fernandez‐Twinn and Ozanne ; Alfaradhi and Ozanne ; Sullivan et al ; Shasa et al. ). Fetal adaptation to an abnormal nutritional environment is accompanied by changes in gene expression that are mediated (at least in part) by epigenetic modifications such as DNA and histone methylation (Saffery ).…”

“…Nutritional imbalance and obesity during pregnancy predispose adult offspring to a variety of chronic health problems through a process known as developmental (or fetal) programming (Barker 1999;Armitage et al 2004;Fernandez-Twinn and Ozanne 2010;Alfaradhi and Ozanne 2011;Sullivan et al 2011;Shasa et al 2015). Fetal adaptation to an abnormal nutritional environment is accompanied by changes in gene expression that are mediated (at least in part) by epigenetic modifications such as DNA and histone methylation (Saffery 2014).…”

Maternal obesity in pregnancy impacts offspring cardiometabolic health: Systematic review and meta‐analysis of animal studies

“…[80][81][82] For example, the second generation of obese overnourished ewes showed increased adiposity and higher blood glucose and insulin levels compared with controls, independent of their mother's weight. 81 Thus, our findings have a profound public health implication. Our results could be useful in developing strategies to prevent adverse health outcomes among children of mothers with obesity.…”

The Potential Impact of Animal Science Research on Global Maternal and Child Nutrition and Health: A Landscape Review

“…For example, extremes in nutrition (over or under) and environmental temperature can markedly affect conception rates and fetal development, and epigenetic effects that can span multiple generations can manifest in the developing embryo and fetus (7). …”