Developmental programming phenotypes can be recapitulated in subsequent generations not directly exposed to the initial suboptimal intrauterine environment. A maternal low-protein diet during pregnancy and postnatal catch-up growth ('recuperated') alters insulin signaling and inflammation in rat offspring (F1-generation). We aimed to establish if this phenotype is also present in F2-generation females. Insulin-receptor-substrate-1 protein expression was decreased in para-ovarian adipose tissue at 3 months in offspring exposed to a grand-maternal low-protein diet (F2-recuperated), vs. F2-control animals (p < 0.05). There was no effect of grand-maternal diet upon Insulin-receptor-substrate-1 mRNA. Protein-kinase C-zeta protein levels were increased at 3 and 6 months in F2-recuperated animals (p < 0.01 at both ages). Phosphorylated-Aktser473 levels were decreased in F2-recuperated animals (p < 0.001). Interleukin-1β protein levels were increased at 3 (p < 0.01) and (p < 0.001) 6 months in F2-recuperated animals. Vastus-lateralis insulin-receptor-β protein expression (p < 0.001) and pAktser473 (p < 0.01) were increased at 3 months in F2-recuperated animals compared to controls. At 6 months, PAktser473 was lower in F2-recuperated animals (p < 0.001). Aspects of insulin signalling dysregulation and inflammation present in offspring of low-protein fed dams can be transmitted to subsequent generations without further exposure to a suboptimal maternal diet. These findings contribute to our understanding of insulin-resistance in grandchildren of sub-optimally nourished individuals during pregnancy
