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Effects of intrauterine growth restriction on the profile of O-GlcNAc proteins in the adult rat hypothalamus


The relationship between adverse nutritional conditions during pregnancy and the development of metabolic disorders in adulthood is well established. Several studies have shown that intrauterine growth restriction (IUGR)-induced obesity is related to hypothalamic disorders. In a previous study, we showed that IUGR induced changes in glucose metabolism and increased the flux through the hexosamine biosynthesis pathway (HBP) in the hypothalamus of adult rats. HBP integrates carbohydrates, amino acids, fatty acids and nucleotides metabolism in the synthesis of UDP-GlcNAc, the substrate for protein O-glycosylation (O-GlcNAc). O-GlcNAc is a reversible post-translational modification (PTM), glucose-dependent, that regulates the activity of nuclear and cytoplasmic proteins, and has a key role in several cellular signaling pathways. No previous studies have assessed the IUGR effects on the profile of O-GlcNAc proteins in the hypothalamus. The aim of the present project is to verify the involvement of O-GlcNAcylation of hypothalamic proteins in the late metabolic disorders induced by IUGR. Wistar rats will be fed with half of the food consumed by the control rats on the same day of pregnancy. In control and restricted male offspring, body weight will be evaluated once a week from birth to 120 days-old. After an intraperitoneal injection of saline or glucose, the rats will be euthanized and the hypothalamus will be harvested. The hypothalamic profile of proteins modified by O-GlcNAc will be analyzed by LC-MS/MS; the expression of the enzymes glutamine: fructose-6-phosphate amidotransferase (which controls the HBP flux), O-GlcNAc transferase and O-GlcNAcase (which control O-GlcNAcylation) will be analyzed by western blot; and the location of proteins modified by O-GlcNAc in the different hypothalamic areas will be analyzed by immunofluorescence. A deeper understanding of the molecular changes related to the development of IUGR-induced obesity may guide the identification of new therapeutic targets and the development of drugs for the treatment of this condition, as well as support the development of appropriate public policies for its prevention. (AU)

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