1 Universidade Federal de São Paulo, São Paulo, Brazil; 2 Universidade de São Paulo, São Paulo, Brazil.
Introduction: Intrauterine growth restriction (IUGR) due to poor nutrient supply programs for adulthood diseases, such as obesity, and associates with dysfunctional hypothalamic regulation of energy homeostasis. This study investigated the effects of IUGR on the hypothalamic proteome and metabolome of the adult offspring of rats. Methods: Pregnant dams ate either ad libitum or 50% of ad libitum intake throughout gestation. Control and restricted progenies were fed ad libitum until 4 months-old. Hypothalamic proteins and metabolites were separated by HPLC and analyzed by mass spectrometry. ProteinLynx server was used to search Swiss-Prot protein database. Metabolites were analyzed via multiple reaction monitoring. MetaboAnalyst software was used to perform the joint analysis of pathways affected by IUGR. Results: Restricted progenies had low birth weight but normal food intake and body mass as adults. Restricted females had hyperglycemia while restricted males were hypoglycemic. Restricted females showed altered expression of 15 proteins and altered levels of 13 metabolites, while restricted males showed changes in 26 proteins and 22 metabolites. Restricted females showed enzymatic alterations of glutamate metabolism pointing to glutamate accumulation due to decreased generation of GABA, glutamine and α-ketoglutarate. Signs of TCA cycle impairment appeared in females, with a possible compensation by increased glycolytic activity. Restricted males showed signs of impaired glycolysis and acetyl-CoA generation from pyruvate. Compensation may have occurred, as levels of citrate and α-ketoglutarate dehydrogenase were elevated. However, the males showed signs of impaired ATP production at the respiratory chain level. Conclusions: The study revealed gender-specific alterations in important energetic and biosynthetic pathways in the hypothalamus of adult rats submitted to IUGR. These alterations are likely to disrupt normal tissue metabolism, thus contributing to the disturbances leading to adulthood diseases after IUGR. These results provide important insight for future studies ascertaining the molecular mechanisms programmed by IUGR in the hypothalamus.