Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue

Abstract

It is now widely accepted that the early-life nutritional environment is important in determining susceptibility to metabolic diseases. In particular, intra-uterine growth restriction followed by accelerated postnatal growth is associated with an increased risk of obesity, type-2 diabetes and other features of the metabolic syndrome. The mechanisms underlying these observations are not fully understood. Using a well-established maternal protein-restriction rodent model, our aim was to determine if exposure to mismatched nutrition in early-life programmes adipose tissue structure and function, and expression of key components of the insulin-signalling pathway. Offspring of dams fed a low-protein (8%) diet during pregnancy were suckled by control (20%)-fed dams to drive catch-up growth. This ‘recuperated' group was compared with offspring of dams fed a 20% protein diet during pregnancy and lactation (control group). Epididymal adipose tissue from 22-day and 3-month-old control and recuperated male rats was studied using histological analysis. Expression and phosphorylation of insulin-signalling proteins and gene expression were assessed by western blotting and reverse-transcriptase PCR, respectively. Recuperated offspring at both ages had larger adipocytes (P<0.001). Fasting serum glucose, insulin and leptin levels were comparable between groups but increased with age. Recuperated offspring had reduced expression of IRS-1 (P<0.01) and PI3K p110β (P<0.001) in adipose tissue. In adult recuperated rats, Akt phosphorylation (P<0.01) and protein levels of Akt-2 (P<0.01) were also reduced. Messenger RNA expression levels of these proteins were not different, indicating a post-transcriptional effect. Early-life nutrition programmes alterations in adipocyte cell size and impairs the protein expression of several insulin-signalling proteins through post-transcriptional mechanisms. These indices may represent early markers of insulin resistance and metabolic disease risk.