Downregulation of insulin receptor isoform A in the forebrain of fetal growth-restricted rats.

Abstract

Children with asymmetrical fetal growth restriction (FGR), whose head size is relatively preserved, often have a poor neurodevelopmental prognosis. Insulin receptor isoform A (IR-A) is predominantly expressed in neurons and is important in neurodevelopment. This study investigated changes in brain IR-A expression in neonatal FGR model rats. FGR model rats were generated by maternal caloric restriction (CR). Glucose uptake and the expression of glucose transporter (GLUT) genes in the brain and liver, and of the IR-A gene in the brain were compared between CR and control group neonates. Gene expression in the brain was examined by RNA sequencing. Brain IR-A localization was analyzed using immunohistochemistry. The brain-to-liver ratios for organ weight and glucose uptake were significantly higher in CR rats. GLUT gene expression was maintained in the CR brain. Whole brain IR-A expression was reduced in CR rats. Furthermore, IR-A expression was decreased in the forebrain of CR rats, but not changed in the hindbrain. The regional differences in IR-A in the FGR rat brain indicate that an endocrinological mechanism regulates brain IR-A to maintain brain function under nutrient deficiency. However, a decrease in IR-A in the fetal period may cause postnatal brain impairment. Insulin receptor isoform A (IR-A) expression is reduced in the neonatal brain of asymmetrical fetal growth restriction (FGR) model rats generated by maternal caloric restriction. IR-A expression is decreased in the forebrain, which is important for cognitive brain functions, whereas IR-A expression is maintained in the hindbrain, which is important for basic vital activities. The expression of genes related to forebrain development is significantly decreased, while the expression of genes related to hindbrain development is increased in neonatal FGR model rats. These results can explain why FGR infants have a poor neurodevelopmental prognosis despite their brain size being relatively protected.