Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

Abstract

Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious “metabolic programming.” In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.

Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism

“…Postnatally, DEX-IUGR pups remained lighter than control animals until weaning (PND21), as previously reported (7). Maternal supplementation with bLf during lactation resulted in different effects compared to the gestational period.…”

“…By enhancing fetal lung maturation, this antenatal treatment presents an immediate benefit for preterm neonate survival but long-term consequences of repeated doses of antenatal glucocorticoid include alterations in growth and brain development (6). Rodent studies also showed that antenatal glucocorticoid exposure predisposes the offspring to early glucose intolerance (7) and disturbed cerebral development (8).…”

Role of maternal nutrition in programming adiposity in the offspring: potential implications of glucocorticoids

“…Consistent with these observations, the prenatally undernourished newborns [22] and weanling pups [24] showed an enhanced adipogenesis (i.e., increased PPARγ and C/EBP isoforms) in the different fat pads before the onset of obesity. In adulthood, the rat offspring from the food-restricted dams also showed an increased expression of the several genes associated with lipogenesis (i.e., FAS and leptin) in a depot-specific manner [22,23].…”

Nutritional manipulations in the perinatal period program adipose tissue in offspring

“…Numerous studies using maternal nutrition manipulations have revealed a close relationship between altered postnatal leptin surge observed in undernourished rodent (25,26,91,93) or overnourished sheep offspring (74) and fat accumulation in adulthood. Thus, early postnatal leptin blockage leads to longterm leptin resistance and increased susceptibility to diet induced obesity in rats (5), whereas administration of leptin during the postnatal period reverses obesity in prenatally undernourished adult rats (104). Finally, leptin directly activates adipogenesis by promoting differentiation of preadipocytes (13), whereas it shows antilipogenic effects on mature adipocytes (58).…”

“…Numerous studies have described programming effects on the long-term hypothalamus-adipose axis in offspring after maternal excess GC exposure (54). Indeed, prenatal dexamethasone-exposed animals displayed persistent adipogenic gene profiles in a depot-dependent manner (23,33,86,104). Chronic GC exposure activates adipogenesis via both GR and MR primarily by regulating key adipogenic transcription factors (i.e., C/EBP␣, PPAR␥) (22,77).…”