INTRODUCTION: Uteroplacental insufficiency is the major cause of intrauterine growth restriction in Western society. Uteroplacental insufficiency is associated with an increased risk of cardiorenal disease, which is exacerbated with second hits such as pregnancy and obesity. We reported that F2 fetuses from growth restricted mothers have nephron deficits, which contributes to the development of F2 high blood pressure. This study examined if the F2 nephron deficits of male fetuses of mothers born small are exacerbated by a maternal high fat diet (HFD) and whether endurance exercise training can prevent these deficits. METHODS: Uteroplacental insufficiency was induced by bilateral uterine artery ligation (Restricted) or sham (Control) surgery on E18 in Wistar-Kyoto rats. Female offspring were fed a chow or high fat (43% kcals from fat) diet from 5 weeks to mating (20 weeks) and throughout pregnancy. Female rats were exercised on treadmills for 4 weeks before pregnancy and throughout pregnancy (Exercise) or during the last two thirds of pregnancy only (PregEx). At E20, F2 fetal body and kidney weights were recorded and fetal sex confirmed by SRY PCR. Male fetal nephron number was quantified using unbiased stereology and fetal kidney mRNA expression determined by qPCR. RESULTS: Exercise in Chow-fed mothers’ increased F2 male fetal weight (+5%) compared to Sedentary, irrespective of maternal birth weight. Absolute and relative kidney weights were not affected by maternal birth weight, exercise or diet. F2 males from Chow-fed Restricted mothers had a nephron deficit (-45%). A HFD reduced nephron number of Control mothers (-32%) compared to Chow. Exercise in mothers who consumed a HFD increased F2 male nephron endowment (+39%) compared to Sedentary, irrespective of maternal birth weight. A nephron deficit was associated with altered expression of genes regulating branching morphogenesis including glial cell line derived neurotrophic factor (Gdnf). Significant mRNA changes were measured in genes regulating apoptosis, with increase in pro-apoptotic Bcl2 and p53 in F2 kidneys of males from Restricted and HFD groups. Increased expression of these factors was reduced significantly by Exercise, but not by PregEx. CONCLUSION: We demonstrated that F2 male fetal nephron deficits from mothers exposed to a HFD were associated with changes in the expression of genes regulating apoptosis, suggesting programmed cell death plays a role in the nephron deficit. These changes were prevented by the lifestyle intervention of endurance exercise when commenced prior to pregnancy, affecting the risk of F2 high blood pressure.