1. Investigación

Pleiotrophin is a pleiotropic cytokine that has been demonstrated to have a critical role in regulating energy metabolism, lipid turnover and plasticity of adipose tissue. Here, we hypothesize that this cytokine can be involved in regulatory processes of glucose and lipid homeostasis in the liver during pregnancy. Using 18-days pregnant Ptn-deficient mice, we evaluated the biochemical profile (circulating variables), tissue mRNA expression (qPCR) and protein levels of key enzymes and transcription factors involved in main metabolic pathways. Ptn deletion was associated with a reduction in body weight gain, hyperglycemia and glucose intolerance. Moreover, we observed an impairment in glucose synthesis and degradation during late pregnancy in Ptn−/− mice. Hepatic lipid content was significantly lower (73.6%) in Ptn−/− mice and was associated with a clear reduction in fatty acid, triacylglycerides and cholesterol synthesis. Ptn deletion was accompanying with a diabetogenic state in the mother and a decreased expression of key proteins involved in glucose and lipid uptake and metabolism. Moreover, Ptn−/− pregnant mice have a decreased expression of transcription factors,such as PPAR-α, regulating lipid uptake and glucose and lipid utilization. Furthermore, the augmented expression and nuclear translocation of glycerol kinase, and the decrease in NUR77 protein levels in the knock-out animals can further explain the alterations observed in hepatic glucose metabolism. Our results point out for the first time that pleiotrophin is an important player in maintaining hepatic metabolic homeostasis during late gestation, and further highlighted the moonlighting role of glycerol kinase in the regulation of maternal glucose homeostasis during pregnancy.

By using different experimental designs in the rat we have been able to answer several unanswered questions on the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first was to demonstrate the importance of maternal body fat accumulation during the first half of pregnancy, since undernutrition in this critical period when fetal growth is slow, impedes fat depot accumulation and not only restrains intrauterine development but has long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect of decreasing body weight, even though food intake is kept normal from the weaning period. Our findings also show that a diet rich in n-3 fatty acids during pregnancy and lactation has adverse effects on offspring development, but cross fostered experiments showed that this effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a n-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake or altered dietary fatty acid composition, or both, were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a n-3 fatty acidrich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition, have major effects on postnatal development and affect glucose/insulin relationships in adult rats.

During pregnancy, lipid metabolism plays a major role to warrant the availability of substrates to the foetus. By using different experimental designs in the rat we have been able to answer several questions that were open about the short- and long-term effects of alterations of lipid metabolism during the perinatal stage. The first one was to demonstrate the importance of maternal body fat depot accumulation during the first half of pregnancy. We found that conditions like undernutrition circumscribed to this specific period when foetal growth is still small, that impede such fat accumulation not only restrain intrauterine development but also have long-term consequences, as shown by an impaired glucose tolerance when adults. Secondly, undernutrition during suckling has major long-term effect decreasing body weight, even though food intake was kept normal from the weaning period. Present findings also show that a diet rich in co-3 fatty acids during pregnancy and lactation has negative effects on offspring development, but cross fostered experiments showed that the effect was a consequence of the intake of these fatty acids during the lactation period rather than during pregnancy. Pups from dams that were fed a fish oil-rich diet during pregnancy and lactation were found to have altered glucose/insulin relationship at the age of 10 weeks. Since a ro-3 fatty acid-rich diet decreases milk yield during lactation, additional experiments were carried out to determine whether decreased food intake, altered dietary fatty acid composition, or both were responsible for the long-term effects on the glucose/insulin axis. Results show that the decreased food intake caused by a ro-3 fatty acid-rich diet rather than the change in milk composition during suckling was responsible for the reduced pancreatic glucose responsiveness to insulin release at 16 weeks of age. In conclusion, present findings indicate that impaired maternal fat accumulation during early pregnancy and food intake during lactation, rather than a difference in dietary fatty acid composition have a greater influence on postnatal development and affect glucose/insulin relationships in adult rats.