Effects of maternal high fat diet and pharmacological intervention on the developmental origins of metabolic & cardiovascular disease

Abstract

A high fat (HF) diet leads to hypercholesterolemia and predisposes the individual to developing cardiovascular disease (CVD). We hypothesised that mother‘s HF diet before and during pregnancy and lactation can also influence predisposition to CVD in offspring fed a similar diet. The thesis sets out to investigate whether (1) the effects of long-term consumption of a HF diet by the mother predisposes her offspring to developing a CVD/ metabolic syndrome in adult life and (2) pharmacological intervention using statin alleviates the detrimental effects of maternal HF diet on the health of the dams and their offspring. Female C57BL/6 mice were fed either a HF diet (45% kcal fat) or standard chow (C; 21% kcal fat) from weaning through pregnancy and lactation. Pregnant C57/BL6 mice on HF diet were further given pravastatin in the drinking water (5 mg/kg of body weight per day) either short-term (2nd half of pregnancy and during lactation) or long-term (from weaning through to pregnancy and lactation) to lower cholesterol and improve post-weaning maternal blood pressure. Weaned female offspring from each group were then fed either a HF or C diets to adulthood. Body weight, blood pressure, plasma cholesterol, C-reactive protein (CRP) and bone marrow derived endothelial progenitor cells (EPC) were measured at 24, 28 and 36 weeks post-weaning in different experiments. Histology of the liver and kidneys were performed. Offspring from hypercholesterolemic mothers on HF diet were significantly obese (bodyweight in grams; 17.2+4.2 vs. 13.8+4.7; P&lt;0.05), hypertensive (SBP mmHg; 134+4.2 vs. 117+3.4; P&lt;0.001), less active (distance in cm; 312 + 31 vs. 563 + 45; P&lt;0.001), demonstrated increased lipid laden vacuoles in liver and kidneys; and showed reduced expression of EPC (P&lt;0.05) than offspring from C dams independent of their postnatal nutrition respectively. Pravastatin therapy in HF mothers resulted in abrogation of these variables in offspring independent of post weaning nutrition (P&lt;0.05). The effects were more permanent when the dams were given long-term statin treatment. The study demonstrates that long-term maternal HF feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids, fatty liver, kidney disorders, raised CRP and inhibition of EPC numbers and expression in offspring. Pravastatin treatment of these dams inhibits these effects on the offspring and may reduce their risk of later cardiovascular pathophysiology. The findings may have implications for understanding the effects of the ?nutritional transition‘ to higher dietary intake of fat which could lead to increased cardiovascular disease in many societies.<br/