Aproximació nutrigenòmica a l'homeòstasi energètica i programació perinatal de l'obesitat

Resumen

The major aim of this thesis is to study the effects of particular nutritional conditions during pregnancy and lactation in the programming of the susceptibility to suffer obesity and other metabolic alterations in later life. In addition, since obesity is characterized by a dysbalance in the regulation of energy balance, we were interested in the description of the normal time-course responses to the feeding/fasting conditions in the main tissues involved in the control of energy homeostasis, and to identify the key genes related with these processes. Analyzing the response to different periods of fasting (0, 4, 8 and 24 h) and to 3 h of refeeding after 8 h fasting, in rats, we observed a temporal sequence of the metabolic adaptations in response to these conditions, at the transcriptional level, which is different for the different genes/tissues depending if their function is anabolic or catabolic. On one hand, the inhibition of lipogenesis is a very rapid event occurring after food deprivation, which occurs first in the liver and afterwards in the white adipose tissue (WAT). On the other hand, the transcriptional enhancing of lipolysis and fatty acid oxidation related genes is somewhat later with respect to changes in the expression of lipogenesis related factors, and also occurs first in the liver. The metabolic activity at the transcripcional level of the lipid metabolism related genes in the WAT changes depending on their anatomical localization, which may be related with their metabolic features. In particular, the retroperitoneal depot shows higher lipogenic and lipolytic activity and lower fatty acid oxidation activity, in comparison with the mesenteric and inguinal depots, and this can contribute to explain the higher pathogenic impact of the excess of fat accumulation in that internal depot. At the hypothalamic level, there is a very rapid increase of gene expression in the orexigenic neurons in the first hours of fasting, without significant changes in the anorexigenic signalling. The negative correlation between AgRP mRNA expression levels and the circulating signals insulin, leptin and glucose, agrees with the fact that orexigenic neurons are highly sensitive to changes in the nutritional status. Nutrigenomic approach to energy homeostasis and perinatal programming of obesity The “thrifty phenotype” theory has already established that fetal malnutrition affects the risk of obesity in adult life. Here, we observed that moderate caloric restriction of 20% during the first part of pregnancy also affects dramatically the metabolic health of the offspring. These animals are programmed for a higher caloric intake, resulting in a higher body weight in adulthood in males, but not in females. This hyperphagia seems to be related with central insulin resistance and with higher blood triglyceride and free fatty acid levels, alterations already present at a juvenile age. These lasting effects of caloric restriction during gestation could be explained, at list in part, by alterations in the hypothalamus development; in fact, at the early age of 25 days, the offspring of caloric restricted dams show an alteration in the hypothalamic structure and function and an impairment of the central response to feeding/fasting conditions. In contrast, a moderate caloric restriction (30%) during lactation has lasting effects in the offspring that are potentially beneficial in the control of energy balance. The offspring is more protected against diet-induced obesity and show an improvement in parameters related to the maintenance of energy homeostasis. In addition, gene expression patterns in the hypothalamus and WAT of these animals provide a better adaptation to the challenge of high fat (HF) diet feeding. Oral supplementation with physiological doses of leptin to neonate rats during lactation confers protection against obesity and the associated metabolic diseases, in later life. In concrete, these animals display lower body weight and food intake, and show increased sensitivity to leptin and insulin. Leptin treatment also affects feeding behavior, improving their food preferences. Changes in the methylation pattern of the POMC gene promoter could be one of the mechanisms by which leptin intake during lactation program for a better resistance to obesity development in adulthood, enhancing the capacity to control food intake in response to HF diet. All in all, these results give us new insight on the effects of particular nutritional conditions and factors during perinatal life in the programming of later metabolic health and homeostatic robustness and also allow us to establish some of the molecular mechanisms responsible.