Nuevos mecanismos y biomarcadores de la interacción de la vitamina A con el metabolismo lipídico y energético y su papel en la programación metabólica

Abstract

New mechanisms and biomarkers of the interaction of vitamin A with lipid and energy metabolism and their role in metabolic programming Nutritional factors in adulthood and in early stages of life can condition the development of obesity and metabolic diseases. Our group has been a pioneer in the study of the biological activity of the active forms of vitamin A (retinoids) and provitamin A carotenoids in relation to body adiposity control and metabolic health, pointing to an antiadiposity action. The main objective of this thesis has been to further understand the interaction of vitamin A with energy metabolism and the development of adipose tissue and its mechanisms, including epigenetic mechanisms possibly related to metabolic programming, and to identify new biomarkers of this interaction. To achieve this we have used different experimental designs: a) adult mice treated subcutaneously with all-trans retinoic acid (ATRA) or vehicle; b) primary cultures of adipocytes exposed to ATRA and other stimuli; and c) rat pups supplemented with moderate excess of vitamin A in the form of retinyl palmitate or -carotene during the lactation stage. Our results show that ATRA treatment increased the functional capacity of the mitochondria in mouse white adipose tissue (WAT) and favored the acquisition of markers of beige/BRITE adipocytes, including the gene expression of Ucp1 and Cd137. Other markers showed limited utility and there were intrinsic variations between the different fat depots (visceral and subcutaneous). These effects of ATRA may result in indirect mechanisms of action, through the induction of IRISINE of hepatic origin and of the adipose tissue itself. In accordance to the results of studies in primary culture and adult animals, we identified the ratio between Rarb and Rxrg expression as a new transcriptional marker in the browning process and metabolic activation WAT. Moreover, treatment with ATRA affected the levels of a whole series of circulating metabolites: some changes may reflect the activation of tissue mobilization and oxidation of lipids (eg acylcarnitines), while others may play a more active or causal role. The metabolomic analysis allowed us to identify several plasma markers of brown adipose tissue activation and metabolic activation of visceral WAT. Vitamin A supplementation during lactation induced changes in the state of DNA methylation in inguinal adipose tissue in regulatory regions of genes related to cell proliferation, differentiation and adipogenic determination and thermogenesis, and differently when administered as retinyl palmitate or -carotene. The observed effects underlie the differences in the programming phenomena of the characteristics and responses of WAT in the later stages of life. Knowledge of active compounds in metabolic programming and in the optimization of the mitochondrial function of adipose tissue, as well as the availability of new biomarkers, is of great interest and may contribute to new strategies for obesity control and its comorbidities.