Aims/hypothesis: With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period, in mothers with high-fat diet (HFD)-induced obesity, could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS. Methods: First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/gestation/lactation period. At weaning, both male and female second generation (F2) were fed a HFD. Weight, caloric intake, lipid parameters, glucose and insulin sensitivity were assessed. Results: Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant (p<0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic, remained lean, with normal insulin sensitivity and glycemia, but mild hypercholesterolemia and glucose intolerance, thus displaying a satiety phenotype. Conclusion/interpretation: This suggests that an appropriate dietary fatty-acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions.