Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep

Abstract

The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2-to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 μg kg −1 ) plus arginine vasopressin (AVP) (0.1 μg kg −1 ). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex-and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.

Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring

“…Intriguingly, despite the decreased maternal weight gain during pregnancy, pups from calorie-restricted dams were not underweight at birth. These findings are consistent with other studies showing that the weight at birth could be unaffected when caloric restriction is implemented in the early stages of pregnancy (Sebert et al, 2009; Palou et al, 2010; Poore et al, 2010). The absence of differences in pups’ body weight may be associated to the significant increase in body weight and caloric intake of diet-restricted rat dams when the food restriction ended, which may have determined an accelerated weight gain in the fetus, as reported previously (Baik et al, 2014).…”

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

“…This finding is in agreement with previous studies in humans, which demonstrated that offspring exposed to famine or hyperemesis gravidarum in the first part of pregnancy did not show lower birth weight (Roseboom et al, 2006; Grooten et al, 2015). Similarly, animal studies documented normoweight at birth when the early pregnancy was conducted under caloric restriction (Cleal et al, 2007; Palou et al, 2010; Poore et al, 2010). In contrast, a lower weight at birth has been described in several studies when the calorie-restricted diet was prolonged to birth (Desai et al, 2005; Lukaszewski et al, 2011).…”

Genetic Basis, Nutritional Challenges and Adaptive Responses in the Prenatal Origin of Obesity and Type-2 Diabetes

“…The sheep is especially interesting for pregnancy studies, due to singleton pregnancy and similar developmental trajectory to human beings [16]. Furthermore, the undernutrition during pregnancy in sheep has long-term effects on homeostasis and endocrine and cardiovascular systems [10,11,[17][18][19][20].…”