Leptin, an adipose tissue hormone, inhibits the brain's central drive to eat, enabling maintenance of normal body weight and composition. In the rodent, a neonatal leptin spike plays a central role in regulating development of the hypothalamic appetite control centers. We have recently reported that obese ewes fed 150% of dietary requirements throughout gestation exhibited markedly greater insulin resistance and elevated baseline blood glucose and insulin during pregnancy than ewes fed to requirements. Female F1 offspring born to obese mothers fed to excess (F1OM) exhibited similar birth weights to female F1 offspring born to mother fed only to requirements (F1RM), but F1OM females exhibited a markedly greater adiposity at birth, as well as a failure to exhibit a leptin spike between 6 and 9 days of postnatal age as observed in F1RM lambs. As adults, F1OM females exhibited an increased appetite when fed ad libitum, leading to increased weight gain, adiposity and insulin resistance when compared to F1RM females. We hypothesized that F2 lambs born to F1OM ewes fed only to requirements would exhibit the same increased adiposity and absence of a postnatal leptin spike as exhibited by their mothers. Mature F1OM (n = 8) and F1RM (n = 7) ewes were fed at 100% NRC recommendations throughout gestation. In late gestation, F1OM ewes exhibited markedly greater (P < 0.01) baseline blood glucose and insulin than F1RM ewes (glucose: 62.2 ± 2.0 vs. 51.9 ± 2.0 mg/dL and insulin: 8.61 ± 1.1 vs. 4.2 ± 1.1 mIU/L, respectively). Further, during a late gestational intravenous glucose tolerance test, blood glucose concentrations remained higher (area under the curve; P < 0.01) in the face of markedly elevated (P < 0.01) insulin in F1OM females when compared to F1RM females, demonstrating markedly greater insulin resistance. Consistent with their maternal environment, newborn presuckled F2 lambs born to F1OB ewes had increased (P < 0.01) blood levels of glucose and insulin when compared to F2 lambs born to F1RM ewes (84.9 ± 6.4 vs. 62.0 ± 6.4 mg/dL and 29.2 ± 4.6 vs. 6.8 ± 4.6 mIU/L, respectively). While birthweights of F2 lambs born to F1OM and F1RM ewes were similar (5.0 ± 0.2 and 5.2 ± 0.2 kg, respectively), F2 lambs born to F1OM ewes had a greater (P < 0.01) percent body fat than F2 lambs born to F1RM ewes (9.7 ± 0.6 vs. 7.1 ± 0.6). Further, as observed in their mothers, F2 lambs born to F1OM ewes failed to exhibit the postnatal leptin spike exhibited by F2 lambs born to F1RM ewes. These data demonstrate the transgenerational impact of maternal obesity and overnutrition on the F2 generation adiposity, and elimination of the postnatal leptin spike, independent of differences in gestational feed intake of F1 ewes. These programmed changes in the F2 generation are consistent with a predisposition for increased appetite, adiposity and metabolic disease in adult life. Supported in part by NIH INBRE #P20RR016474. (poster) Copyright 2011 by The Society for the Study of Reproduction. Copyright 2011 by The Society for the Study of Reproduction.