Maternal protein restriction induces alterations in insulin signaling and ATP sensitive potassium channel protein in hypothalami of intrauterine growth restriction fetal rats

Abstract

It is well recognized that intrauterine growth restriction leads to the development of insulin resistance and type 2 diabetes mellitus in adulthood. To investigate the mechanisms behind this ”metabolic imprinting” phenomenon, we examined the impact of maternal undernutrition on insulin signaling pathway and the ATP sensitive potassium channel expression in the hypothalamus of intrauterine growth restriction fetus. Intrauterine growth restriction rat model was developed through maternal low protein diet. The expression and activated levels of insulin signaling molecules and KATP protein in the hypothalami which were dissected at 20 days of gestation, were analyzed by western blot and real time PCR. The tyrosine phosphorylation levels of the insulin receptor substrate 2 and phosphatidylinositol 3'-kinase p85α in the hypothalami of intrauterine growth restriction fetus were markedly reduced. There was also a downregulation of the hypothalamic ATP sensitive potassium channel subunit, sulfonylurea receptor 1, which conveys the insulin signaling. Moreover, the abundances of gluconeogenesis enzymes were increased in the intrauterine growth restriction livers, though no correlation was observed between sulfonylurea receptor 1 and gluconeogenesis enzymes. Our data suggested that aberrant intrauterine milieu impaired insulin signaling in the hypothalamus, and these alterations early in life might contribute to the predisposition of the intrauterine growth restriction fetus toward the adult metabolic disorders.

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation

“…However, insulin did not increase phosphorylated GSK3, indicating hormone resistance. The same results have been reported for undernourished fetuses (30). The insulin and leptin central resistances together with their low plasma levels, discussed later, help explain the increased energy intake of the undernourished animals.…”

Insulin: Its role in the central control of reproduction

“…We speculate that hypothalamus, where information about nutritional status is “read”, and which plays a key role in governing reproduction, could be one such region. In support of this, recent studies using an intrauterine growth restriction rat model (maternal low protein restriction) found impaired insulin signaling in the hypothalamus in 20 days old pups [64]. Specifically, tyrosine phosphorylation levels of IRS2 and PIK3 p85α were impaired, changes which could potentially block insulin signal transduction.…”

Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

“…is study demonstrated that major UPR pathways in pancreas were dysregulated by protein deficiency in utero, but most International Journal of Endocrinology UPR factors restore to normal in adulthood. Using the same model, we previously reported that blood glucose and plasma insulin level were lower in FGR fetus [27], but higher in adulthood [8]. We speculate that lower insulin levels in FGR fetus was due to fetal pancreatic dysplasia.…”