The Role of the Maternal Nutritional Environment on Offspring Growth Factors and Metabolism

Abstract

INTRODUCTION: Rodent models of both maternal caloric restriction and high fat nutrition are characterized by fetal growth restriction followed by postnatal catch-up growth in offspring, with preferential laying down of adipose tissue mass over lean mass in adulthood. Despite a commonality of postnatal phenotypes, it is unknown whether the mechanisms underlying the processes in these disparate nutritional paradigms are due to the same regulating pathways. The growth hormone/insulin−like growth factor (GH−IGF) axis plays a key role in the regulation of both prenatal, postnatal growth and intermediary metabolism. Also the canalisation gene, heat shock protein (Hsp90), is known to stabilise GH−IGF related receptors. HYPOTHESES/AIMS It was hypothesised that, within two disparate models of maternal nutrient adversity that the hepatic Hsp90/GH−IGF signalling pathway utilise similar signalling components, which contribute to altered developmental trajectories and obesity. Using a rodent model, this study set out to determine the effects of a 50% global maternal nutrient restriction during pregnancy (UNP) and maternal high fat nutrition during pregnancy and lactation (PLHF) on hepatic expression of key components of the HSP90−GH/IGF axis during both a period of developmental plasticity (postnatal day 2 (P2) and at a time of established obesogenic phenotype (P160). METHODS: Rat dams were assigned to one of 3 nutritional groups 1) mothers fed a standard diet throughout pregnancy and lactation (CONT group), 2) calorie restricted mothers fed 50% of a standard diet throughout pregnancy (UNP group), and 3) mothers fed a high fat diet throughout pregnancy and lactation (PLHF group). Offspring from these animals were used in quantitative RT-PCR analyses of the hepatic mRNA expression of Hsp90, GHR, IGF-I, IGF-II, IGF-IR, IGF-IIR, IGFBP1 and IGFBP2 at P2 and P160. Adult plasma levels of IGF−I, IGFBP2, and IGFBP3 at P160 offspring were measured by ELISA. RESULTS: Hepatic IGFBP2 was higher in UNP female neonates at P2. In males IGFBP1 was negatively correlated with maternal nutrient availability, and an increase in variation of Hsp90 expression was observed in UNP and PLHF offspring compared to controls. Hepatic GHR levels were reduced in UNP females at P160 and IGFBP2 levels were decreased in both UNP and PLHF offspring. In males at P160, Hsp90 was significantly lower in UNP offspring and both IGFBP1 and IGBP2 were lower in both UNP and PLHF offspring. Circulating levels of IGFBP2 were lower in the plasma of female offspring at P160. Circulating levels of IGF-I were lower in UNP male offspring and plasma IGFBP3 was lower in both UNP and PLHF male offspring compared to controls. CONCLUSIONS: The present study found both supporting and refuting evidence that common signalling mechanisms and changes within the Hsp90/GH-IGF axis are initiated by disparate suboptimal maternal nutrition. Notably, the more severe phenotypes observed in male UNP and PLHF offspring may be due to decreased mRNA levels of hepatic Hsp90. Increases in binding proteins in female and male neonates may limit the severity of an obesogenic phenotype in adult life. In adulthood, reductions in hepatic IGFBP2 appears to reflect suboptimal maternal nutritional history, and further studies identifying the exact role IGFBP2 has in the aetiology of obesity and its correlates are warranted.