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, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (w147 days), compared with mothers fed to 100% of requirements. Offspring were 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 environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in 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 reduced maternal plasma glucose, 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 and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in 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.

Neurodevelopment and Health-Related Quality of Life in Infants Born with Gastroschisis: A 6-Year Retrospective French Study

“…19 Accordingly, a higher risk of obesity is well described in young humans and animals born with IUGR and/or with a low birth weight. 20,21 One explanation for this phenomenon is tissue anomalies and hormonal dysfunctions with an origin during its course of its embryonic development and excessive nutritional intake during early childhood. 20 Our study's KIDSCREEN-10 scores seem high, even without comparison to controls, with a mean score of 72.8/100.…”

“…20,21 One explanation for this phenomenon is tissue anomalies and hormonal dysfunctions with an origin during its course of its embryonic development and excessive nutritional intake during early childhood. 20 Our study's KIDSCREEN-10 scores seem high, even without comparison to controls, with a mean score of 72.8/100. Such encouraging QoL scores are consistent with the literature.…”

Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome

“…Growth restriction can also be the result of maternal malnutrition, and the postnatal environment following IUGR can impact the metabolic profile in adulthood. 57 Sheep exposed to maternal caloric restriction to induce IUGR followed by exposure to a low-activity, high calorie postnatal environment to induce rapid catch-up growth demonstrated obesity, insulin and leptin resistance, and elevated cortisol levels. In contrast, IUGR offspring exposed to a normal postnatal environment to induce normal catch-up growth demonstrated significantly less severe outcomes, although their metabolic health was still somewhat impaired when compared to non-growth-restricted controls.…”

The fetal programming of food preferences: current clinical and experimental evidence

“…As cited above, IUGR is associated with higher levels of corticosterone in different ages, leading to chronic hyperactivity of this neuroendocrine axis. 39,40,69 There is also evidence showing that maternal food restriction leads to reduced glucocorticoid and mineralocorticoid receptor expressions in the hippocampus of IUGR newborns. 70 The chronic hyperactivity of the HPA axis may contribute to the programming of chronic diseases, as well as altered response to acute stress, which can influence feeding behavior and food choices.…”