Adverse effect of high-fat diet on metabolic programming in offspring born to a murine model of maternal hypertension

BACKGROUND We previously reported that offspring heterozygous mice partially lacking endothelial nitric oxide synthase (eNOS) gene, and born to hypertensive eNOS^-/- Knockout mother, are hypertensive. We hypothesized that those offspring when placed on high-fat diet (HFD) will undergo altered metabolic programming increasing their risk for developing metabolic syndrome. METHODS eNOS^-/-KO and wild-type mice (eNOS^+/+WT) were cross-bred to produce heterozygous offspring: maternal heterozygous (Mat, eNOS^-/+), born from hypertensive eNOS^-/-KO mothers; and paternal heterozygous (Pat, eNOS^-/+), born from normotensive WT mothers. Mat, eNOS^-/+ and Pat, eNOS^-/+ female were allocated to HFD or control diet (CD) until 8 weeks of age. Then a metabolic profile was obtained: weight, glucose/insulin tolerance test (GTT, ITT), systolic blood pressure (SBP), serum fasting levels of insulin, adiponectin, leptin, and a lipid panel. RESULTS Weight was not different between all offspring within each diet. GTT curve was higher in Mat, eNOS^-/+ vs. Pat, eNOS^-/+ offspring on both diet (P < 0.001). In ITT, glucose level at 15 minutes was higher in Mat, eNOS^-/+ on HFD. Insulin level was increased in Mat, eNOS^-/+ vs. Pat, eNOS^-/+ on either diet. SBP was elevated in Mat, eNOS^-/+ vs. Pat, eNOS^-/+ on CD and was further raised in Mat, eNOS^-/+ offspring on HFD (P < 0.001). No other differences were seen except for lower high-density lipoprotein levels in Mat, eNOS^-/+ fed HFD (P < 0.003). CONCLUSIONS Mat, eNOS^-/+ offspring exposed in utero to maternal hypertension and fed HFD postnatally have increased susceptibility for metabolic abnormalities. Thus, maternal HTN is a risk factor for altered fetal metabolic programming.