Programación metabólica asociada al exceso de grasa corporal. Efectos de la reversión de la dieta de cafetería (modelo de postcafetería) antes de la gestación sobre la descendencia y efectos directos de la dieta en ratas jóvenes

Abstract

Overweight and obesity in childhood and adolescence have been associated with increased mortality rate in adulthood. This is more alarming if consider that the prevalence of obesity and overweight in children has risen dramatically in recent years. Moreover, obesity in childhood is not a benign disorder, despite the popular belief that overweight children leave this problem when they grow. In addition, it has also increased the incidence of obesity in women of childbearing age, which can lead not only to certain complications during pregnancy but also health disorders in their offspring, both in short and long term. There are a lot of nutritional recommendations to reduce the incidence of risk during pregnancy in order to reduce body weight before pregnancy. However, appears that there is no unanimous consensus on the recommendation on how and when lose the excess of weight before pregnancy. In any cases, it is desirable to avoid calorie restriction during pregnancy because it is known that this can produce negative effects on the offspring. In this doctoral thesis, the objective has been to study the metabolic programming associated with excess body fat in perinatal stages. On the one hand, we analyzed in rats the short term effects of the intake of an obesogenic diet at early stages. On the other hand, we wanted to determine the effects on the offspring of dams that has been exposed to cafeteria diet and obesity, although this followed a period of reversion to normal diet before pregnancy. In this thesis we studied the effect of the exposure to a short period of an obesogenic diet (cafeteria diet) in young male rats. We have observed that this short cafeteria diet feeding, despite did not produce any apparent changes in body weight, induced an accumulation of body fat, compared to control animals. In addition, the animals fed with cafeteria diet had greater energy intake, hyperletinemia and altered expression of Npy in hypothalamus, reflecting a dysfunction in the control of food intake; they also showed an impaired metabolic response to fasting and feeding conditions in key tissues involved in energy homeostasis (white adipose tissue retroperitoneal and liver). It is known that maternal obesity during pregnancy and lactation predispose to obesity and other metabolic disorders in offspring in adulthood. In this thesis we aimed to study whether the adverse effects expected in the offspring associated with maternal dietary obesity can be reversed with the removal of the obesogenic diet in mothers before pregnancy. The cafeteria diet has been mainly used as fattening diet, because induces in rats persistent hyperphagia and increased energy intake as a result of the variety, palatability and the novelty of the food available, similarly to unhealthy eating habits observed in humans. This cafeteria diet was administered to female rats from day 10 to day 100 of age. At the end of the period of cafeteria diet intake, the rats had higher body weight and body fat content than the controls. One month before pregnancy, the cafeteria diet was replaced with a standard diet (postcafeteria model). When cafeteria diet was removed, rats presented a decrease in body weight and body fat content, although remained an 8% and 13% respectively higher at mating compared with the control group. During lactation, no differences were found in body weight between groups; however, postcafetería dams had higher body fat content and higher serum and milk leptin levels during lactation. From week 9 of life, the offspring of postcafetería dams had lower body weight than controls. At 15 weeks of age the offspring of postcafetería dams did not presented alterations in any of biochemical parameters analyzed. In addition, we study the metabolic response to changes in feeding/fasting conditions in postcafetería young pups at early age (26-day-old). We observed that male offspring of postcafetería dams had a lower expression of lipogenic (Pparg, Srebf1 and Fasn) and lipolytic genes (Pnpla2) in the retroperitoneal adipose tissue compared to the offspring of control dams. Female offspring of postcafeteria dams had a lower hepatic expression of genes involved in lipogenesis compared to control females, although the response to the in fasting condition was not impaired. Therefore, if the cafeteria diet is removed one month before pregnancy in mothers with a dietary induced obesity, apparently can prevent the harmful effects of the maternal obesity on metabolism lipid in their offsprings, although a complete reversion of the excess body weight is reached. In the adult age, the offspring of the postcafetería dams both males and females, presented a lower food intake, lower weight gain and lower percentage of body fat when exposed to an obesogenic diet, compared to the offspring of control dams. After 2 months of exposure to western diet, male offspring of postcafetería dams showed in white retroperitoneal adipose tissue a decrease in the expression of lipogenic genes (Ppara, Srebf1, Fasn), Pnpla2, Cpt1b, Insr, Lep and Mest, which it was not observed in the offspring of control dams. In addition, they also had a lower hypothalamic expression of the orexigenic neuropeptide Npy, which may explain the lower intake observed in these animals and lover activation of gene expression associated with hepatic lipogenesis (Srebf1, Fasn, Scd1) that can explain the lower hepatic lipid accumulation observed in these animals compared to the offspring of control dams. Therefore, there is a phenomenon of metabolic programming, especially in male offspring, which could be attributed to the elimination one month before pregnancy of obesogenic diet to dietary induced obesity rats, which has generated a protective effect in the offspring in adulthood against weight gain, fat accumulation, hyperphagia and hepatic lipid accumulation even after exposure to an obesogenic environment. If we could apply this to obese people who plan to become pregnant, it would be important to recommend a balanced diet and the loss of at least part of the excess of body weight few months before pregnancy in order to assure that the offspring can have a healthy metabolic programming.