Maternal nutrient restriction results in IUGR newborns which develop obesity despite normal post-weaning diet. The epidemic of metabolic syndrome is attributed to programmed "thrifty phenotype" and exposure to "Western" diets. We hypothesized that programmed IUGR newborns would demonstrate greater susceptibility to obesity and metabolic abnormalities in response to high-fat diet. From day 10 to term gestation and lactation, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% food-restricted (FR). Cross-fostering techniques resulted in four offspring groups, Control (AdLib/AdLib), FR during pregnancy (FR/AdLib), and FR during lactation (AdLib/FR). At 3 weeks, offspring were weaned to laboratory-chow or high-fat calorie diet (9% versus 17% calorie as fat). Body composition, appetite hormones, and glucose and lipid profiles were determined in 9 month male and female offspring. High-fat diet had no effect on body weight of AdLib/AdLib, but significantly increased weights of FR/AdLib and AdLib/FR offspring. Additionally, high-fat diet significantly increased body fat, reduced lean body mass, and accentuated plasma leptin but not ghrelin levels in both sexes in all groups. In males, high-fat diet caused a significant increase in glucose levels in all three groups with increased insulin levels in AdLib/AdLib and AdLib/FR, but not in the FR/AdLib. In females, high-fat diet had no effect on glucose but significantly increased basal insulin among all three groups. High-fat diet caused hypertriglyceridemia in all three groups though only food-restricted females exhibited hypercholesterolemia. The gender and offspring phenotype associated effects of high-fat diet indicate differing pathophysiologic mechanisms which require specific therapeutic approaches.