Abstract
Individuals with intrauterine growth retardation (IUGR) are prone to insulin resistance, whereas the underlying molecular mechanisms remain unclear. In this study, we investigated if the PI3K/Akt signaling pathway in skeletal muscle tissues involves insulin resistance in IUGR offsprings, particularly ones with catch-up growth. An IUGR rat model was established by feeding rats an isocaloric (30.50 Kcal/g) diet containing 8% protein (low-protein diet) from day 1 of pregnancy until the birth of their pups. Glucometabolic parameters were measured and compared. Quantitative PCR and western blot were performed to assess mRNA and protein expression changes of the PI3K/Akt related signals in skeletal muscle tissues. Pearson analysis was used to assess the correlation of the PI3K/Akt signaling level and catch-up growth with the insulin resistance index (IRI). The values of fasting plasma glucose, fasting insulin and IRI were significantly higher, whereas insulin sensitivity index was significantly lower in IUGR offsprings than those in the controls. The PI3K mRNA and protein levels as well as the phospho-AktSer473 levels were significantly lower in IUGR offsprings compared to the controls. Reductions of GLUT4 as well as increases of PTEN and nuclear fractional PPARγ were detected in IUGR offsprings. Catch-up growth IUGR rats were positively correlated with insulin resistance and underwent more remarkable alterations of the PI3K, PTEN and GLUT4 expressions. Our results demonstrated that rats born IUGR developed insulin resistance later in life, which was likely mediated by reductions of the PI3K/Akt related signaling activities, particularly in those with excess catch-up growth.
Highlights
We investigated the dynamic changes of insulin sensitivity and the phosphoinositide 3-kinase (PI3K)/Akt related signaling activities in skeletal muscle tissues as well as the correlation of catch-up growth with insulin resistance in rat Intrauterine growth retardation (IUGR) offsprings
We analyzed the abundance of PPARγ in nuclear fractions extracted from skeletal muscle tissues, showing that the level of nuclear PPARγ increased dramatically in the IUGR offsprings. These results suggested that PPARγ-mediated increase of Phosphatase and tensin homology (PTEN) expressions may inhibit the PI3K/Akt activity, leading to reduction of Glucose transporter type 4 (GLUT4) expressions and the development of insulin resistance in IUGR offsprings
Increased PTEN level was detected only in the OCG-IUGR rats. These findings suggested that reduction of GLUT4 potentially mediated by the PTEN/PI3K/Akt signaling may involve the regulation of insulin sensitivity in the IUGR offsprings with catch-up growth
Summary
Sprague-Dawley rats, 8 weeks old, with body weights (BWs) 220– 240 g, were purchased from Laboratory Animal Science Department of Peking University Health and Science Center (Beijing, China). Pregnant rats were ad libitum fed an isocaloric (30.50 Kcal/g) diet containing 8% protein (low-protein diet) or 20% protein diet (normal diet) from day 1 of pregnancy until the birth of their pups. Both diets were obtained from Beijing Huakangkang Biotechnology Co., Ltd. Male pups were studied in order to avoid gender and hormonal influence Both control and IUGR group had same litter size, 5 pups per litter. Diet assignment was performed by an animal technician who was not involved in the outcome assessments
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