Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation

Compelling epidemiological and experimental evidence indicates that a suboptimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of several chronic diseases including obesity and diabetes in which altered carbohydrate metabolism plays a central role. One of the most interesting and significant features of developmental programming is the evidence from several studies that the adverse consequences of altered intrauterine environments can be passed transgenerationally from mother (F-0) to daughter (F-1) to second generation offspring (F-2). We determined whether when F-0 female rats are exposed to protein restriction during pregnancy and/or lactation their F-1 female pups deliver F-2 offspring with in vivo evidence of altered glucose and insulin metabolism. We fed F0 virgin Wistar rats a normal control 20% casein diet (C) or a protein restricted isocaloric diet (R) containing 10% casein during pregnancy. F-1 female R pups weighed less than C at birth. After delivery, mothers received C or R diet during lactation to provide four F, offspring groups CC (first letter pregnancy diet and second lactation diet), RR, CR and RC. All F-1 female offspring were fed ad libitum with C diet after weaning and during their first pregnancy and lactation. As they grew female offspring (F-1) of RR and CR mothers exhibited low bodyweight and food intake with increased sensitivity to insulin during a glucose tolerance test at 110 days of postnatal life. Male F-2 CR offspring showed evidence of insulin resistance. In contrast RC F-2 females showed evidence of insulin resistance. Sex differences were also observed in F-2 offspring in resting glucose and insulin and insulin: glucose ratios. These sex differences also showed differences specific to stage of development time window. We conclude that maternal protein restriction adversely affects glucose and insulin metabolism of male and female F-2 offspring in a manner specific to sex and developmental time window during their mother's (the F-1) fetal and neonatal development.