Metabolic alterations associated with maternal undernutrition during the first half of gestation lead to a diabetogenic state in the rat.

BACKGROUND: Although recent studies have investigated the effect of maternal nutrition on metabolic programming of the offspring, the question whether a nutritional insult during early gestation favours an altered metabolic state of the mother that persists during the remainder period of pregnancy, when foetal growth is maximal, remains to be answered. METHODS: To address this issue, we analysed the effect of 40% food restriction during the first 12 days of gestation on glucose tolerance, as well as on liver and adipose tissue metabolism, in Sprague-Dawley pregnant rats. RESULTS: We found that undernutrition at early gestation blocks pregnancy-associated accumulation of fat, leading to a net breakdown of lipids that may account for an increased delivery of fatty acids and glycerol to the liver. Together with altered expression of hepatic enzymes, this creates a catabolic state, characterized by decreased lipogenesis and increased ß-oxidation, which contributes to the ketonemia of underfed mothers. Furthermore, we observed that undernutrition during early pregnancy impairs insulin sensitivity at this stage and, importantly, exacerbates insulin resistance at late gestation, contributing to a diabetogenic state. CONCLUSION: Undernutrition during the first half of pregnancy not only alters liver and adipose tissue metabolism, but also exacerbates the maternal insulin resistance at late gestation, which may increase their risk of gestational diabetes. GENERAL SIGNIFICANCE: Together, these findings highlight the persistent impact of maternal nutrition during early gestation on the metabolism of the mother during late pregnancy.

Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol.

Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up-regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN(-/-) ) mice and in mice with cortex- and hippocampus-specific transgenic PTN over-expression (PTN-Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN(-/-) compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN-Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN-Tg mice, suggesting that up-regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.