1. Investigación

The amount of peroxisome proliferator-activated receptor-ex (PPARcx) protein was markedly augmented in the liver of suckling rats compared to adult rats. This different PPARcx abundance was used to study the sensitivity to nutritional changes in the expression and activity of this receptor. Thus, 10-day-old and adult rats were orally given either glucose, Intralipid or a combination of both diets, and liver mRNA levels of PPARcx and the PPAR related genes, acyl-CoA oxidase (ACO) and phosphoenolpyruvate carboxykinase (PEPCK), and plasma metabolites were measured. In neonates, the expression of PPARcx and ACO was seen to increase when the level of FF A in plasma was also high, unless an elevated level of insulin was also present. However, this fatty acid-induced effect was not detected in adult rats. On the contrary, the hepatic expression of PEPCK was modulated by the nutritional changes similarly in both neonates and adult rats. Thus, it may be concluded that the expression of the PPARcx gene in adult rats seems to be less sensitive to nutritional changes than in neonates.

It was previously found that the expression of peroxisome proliferator-activated receptor-a (PP ARa) was markedly augmented in the liver of suckling rats, in comparison to the fetuses and most notably to adult rats and it paralleled similar changes in hepatic lipid concentration. To determine whether these changes could be related to the high lipid content of the maternal milk and/or to hormonal status, the role of changes in nutrient availability and in plasma insulin concentration on liver expression during the perinatal stage in vivo in the rat was studied. When suckling rats were weaned on day 17, instead of on day 20, the level of hepatic PPARa mRNA decreased earlier than in rats weaned later. When 10-day-old rats were force-fed with either glucose or Intralipid or a combination of both diets, it was found that, at similar low levels of plasma insulin, a high level of FFA stimulated PPARa expression, whereas, at similar high plasma FF A concentrations, an elevated insulin level attenuated the increase in PPARa expression. It is proposed that both the high lipid intake and decreased plasma insulin level are responsible for the high PP ARa expression detected in rat neonates.

The present study was addressed to determine whether the high expression of peroxisome proliferator-activated receptor-a (PPAR-a) in rat liver during the perinatal stage plays a role in the induction of liver lipoprotein lipase (LPL) expression and activity. Parallel increases in liver mRNA PPAR-a and LPL activity were found in newborn rats, and after a slight decline, values remained elevated until weaning. Anticipated weaning for 3 days caused a decline in those two variables as well as in the mRNA LPL level, and a similar change was also found in liver triacylglycerol concentration. Force-feeding with Intralipid in 10-day-old rats or animals kept fasted for 5 h showed high mRNA-PPARa and -LPL levels as well as LPL activity with low plasma insulin and high FFA levels, whereas glucose and a combination of glucose and Intralipid produced low mRNA-PPARa and -LPL levels as well as LPL activity. Under these latter conditions, plasma insulin and FFA levels were high in those rats receiving the combination of glucose and Intralipid, whereas plasma FF A levels were low in those force-fed with glucose. It is proposed that the hormonal and nutritional induction of liver PPAR-a expression around birth and its maintained elevated level throughout suckling is responsible for the induction of liver LPLexpression and activity during suckling.

The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARγ (peroxisome-proliferator-activated receptor γ ) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARγ ligands and by hyperinsulinaemia as being responsible for a major insulinresistant condition.