Postnatal catch-up growth programs central and peripheral insulin resistance in male mice
Aims: Intra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral insulin sensitivity in mice that underwent IUGR followed by post-natal catch-up growth and investigate potential molecular mechanisms underpinning their physiology. Methods: We used a C57/bl6J mouse model of maternal diet-induced IUGR (maternal diet 8 % protein) followed by cross fostering to a normal nutrition dam (maternal diet 20% protein) and litter size manipulation, to cause accelerated post-natal catch-up growth. We performed intra-cerebroventricular insulin injection and hyperinsulinemic-euglycemic clamps to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real time PCR and western blotting to examine the expression of key insulin signalling components in discrete regions of the hypothalamus. Results: We showed that IUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these “recuperated” animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the P110beta subunit of PI 3-kinase and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Ptpn1 (PTP1B) expression was also increased specifically in this region of the hypothalamus. Conclusions: Mice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin as well as impaired glucose homeostasis seen in these animals.
Medical Research Council (MC_UU_12012/4)
Wellcome Trust (089939/Z/09/A)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (089939/Z/09/Z)
British Heart Foundation (RG/17/12/33167)