Intrauterine growth restriction (IUGR) modifies the hypothalamic response to a systemic glucose load in adult male rats, as assessed by proteomic analysis

Abstract

We have previously demonstrated that 4-month-old IUGR male rats had obesity, hyperglycemia, and increased hypothalamic glucose levels, indicative of disruption of hypothalamic glucose metabolism. To evaluate, by proteomic analysis, the hypothalamic response to a systemic glucose load before the development of IUGR-induced obesity. Wistar rats were fed either ad libitum (Control group, C) or received 50% of C intake throughout pregnancy (Restricted group, R), and fed ad libitum during lactation. The male C and R offspring were fed ad libitum from weaning to 3-months-old. They were injected intraperitoneally with either saline (CS and RS) or 2 g/kg glucose (CG and RG) (n = 4 each), euthanized after 45 min., and had their hypothalami harvested. Pathway search was conducted with significantly modulated proteins (Student's t-test, p < 0.05). When comparing CS and RS, the tricarboxylic acids cycle and the respiratory chain pathways had multiple down-regulated proteins. Comparing CG and RG, while these pathways were also affected, only pyruvate dehydrogenase complex (PDH) (Fold change (FC) 0.63) was down-regulated while citrate synthase (FC 1.43) and respiratory chain complex I (FC 1.63) were up-regulated. This could represent a compensatory response aimed at overcoming the down-regulation of the respiratory chain induced by IUGR. These seemingly beneficial responses may, however, induce increased reactive oxidative species, insulin resistance and obesity. The results suggest that, even before the establishment of obesity and hyperglycemia, IUGR may have impacted metabolic pathways and the hypothalamic response to a systemic glucose load, that in the long term, could have a negative impact on energy homeostasis.

Keywords: Energy homeostasis; Fetal programming; Hypothalamus; Metabolism; Obesity.