RESEARCH LINES
1. Involvement of estradiol on feeding neurohormonal circuit modulation and programming in the rat.
Modulatory activity of estradiol during development
Through preclinical studies in rats, our work has focused on investigating, first, the role of estradiol during development on the alterations that malnutrition produces, either by high-fat diet or low-protein diet. This hormone modulates during the second week of life the alterations produced by malnutrition in female rats, since a low-protein diet decreases the expression of the proopiomelanocortin peptide (POMC), but the treatment with estradiol from the postnatal day (P) 6 until P13 increases POMC levels at the same levels to those of the control group (Carrillo et al., 2016). Likewise, estradiol also modulates differentially the alterations produced by a high-fat diet in male and female rats. In the case of males, the high-fat diet produced a significant increase in body weight but estradiol promoted a decrease in this parameter to match that of the control males. In females we did not find any effect of estradiol on body weight, but we did in hypothalamic mRNA levels, since the increase in the mRNA levels of this peptide produced by a high-fat diet was reverted to that of the control group when estradiol was administered during the second week of life (Carrillo et al., 2019). Therefore, the modulating function of estradiol during development on some of the alterations produced by the intake of a low-protein or a high-fat diet was demonstrated.
Programming activity of estradiol during development
The programming function of estradiol on the hypothalamic circuit that regulates food intake was showed blocking the activity of the main receptors of estradiol, ERα, ERβ and GPER, from P5 to P13. We could verify that the lack of action of estradiol on its receptors produced a decrease in the body weight of male rats and a decrease in hypothalamic POMC mRNA levels in females when animals are analysed in adulthood. In addition, it was also shown that these effects did not appear if the receptors were blocked from P1 to P5, since no effect was found in these parameters in males or females. Therefore, we demonstrated the participation of the estradiol through its receptors during the development in the programming of the energy metabolism, and we could also determine that the period of maximum susceptibility in the regulation of POMC did not begin in the female before day 5 of postnatal life, coinciding with the onset of estrogen secretion by the ovary.
CM = Control male; CF = Control female;
ERB-M = ER-blocked males; ERB-F = ER-blocked females.
2. Neurohormonal mechanisms involved in the programming of the neurohormonal circuitry controlling ingestion
We are currently developing this project in which we are studying the possible mechanism through which estradiol exerts its modulatory role during development on the alterations observed in the long term due to dietary restriction or high fat diet intake. Specifically, we studied whether neurogenesis, apoptosis and glial cells are involved in the modulatory and programming actions of estradiol on energy metabolism and the establishment of neurohumoral circuits that regulate them.
3. Effects of genistein during development on energy metabolism and neurohormonal network that regulates feeding.
Genistein is a phytoestrogen that belongs to the group of isoflavones. It is present in a wide variety of legumes, mainly soybeans and their derivatives, which makes it one of the most consumed phytoestrogens by humans. Soy is a very usual ingredient in the traditional Asian diet, and nowadays, it is also a widely consumed food in Western countries, being one of the most common milk substitutes, mostly in lactating children. We have demonstrated that the exposure to genistein in the early stages of development modifies hypothalamic POMC neurons’ long-term expression in the arcuate nucleus of female but not male Wistar rats. Moreover, high doses of genistein produced a delay in the emergence of sex differences in body weight. In contrast, caloric intake or orexin expression were not altered in either sex.
B, C) Photomicrographs showing the distribution of immunostaining of POMC-ir positive cells in Arc nucleus. D, E) orexin-ir positive cells in the PF and LH. Arrows show orexin-ir and POMC-ir positive cells counted.
4. Alterations produced by Activity-Based Anorexia (ABA)
In collaboration with the group led by Professor Ricardo Pellón we have studied behavioural and neurophysiological aspects of anorexia nervosa, through the based-activity anorexia model in the rat. Our objective is to study the alterations that occur in the brain in two systems involved in anorexia nervosa: the homeostatic system of food intake and the reinforcement system. In the first system we have already obtained some results that follow the line of the studies described in the previous projects, since the expression of POMC anorexigenic neuropeptide in the arcuate nucleus, but not the orexigenic peptide orexin, significantly decreases in male rats subjected to ABA compared to the control groups ad libitum without activity, or those who have only been subjected to a restriction of the diet.
5. Psychobiological foundations of the interaction between development and lifestyle: implications for health. NEURODEVSTYLE.
In this project, coordinated by the University of Oviedo, we participate in a network of excellence with psychobiology groups from seven other Spanish universities. U. Oviedo, U. Almería, U. Rovira I Virgili, U. Granada, U. Valencia, U. Sevilla, U. Barcelona. The works we carry out are related to the effects that exposure to potential harmful factors during development have on health. In our case, we study the effects that high-fat or low-protein diets have on adult organisms. The focus of the project is to transfer the results obtained in the preclinical studies that we are carrying out to humans, to determine possible markers that indicate the risk factors to which people are exposed and what ultimately determines the exposome, term proposed by Wild (2005). Considering the psychological aspects within exposome concept, our network has proposed to extent this term to Psychoexposome, in order to include psychological factors in two aspects, as risk factors for certain disorders, and as disorders to be studied (Colomina et al, 2018).