Role of High Maternal Linoleic Acid on Offspring Health

Abstract

Maternal nutrition during pregnancy plays a critical role in the adult-onset of disease in a mother’s children. The first 1000 days, spanning from conception to two years of life, are an important period when appropriate nutritional needs must be ensured for long-term health. Studies have shown that inadequate nutritional condition in utero and early life increases the risk of developing chronic conditions later in life. In recent years, the intake of linoleic acid (LA) has increased gradually in human populations, due to changes in a dietary pattern that have resulted in increased consumption of vegetable oils and foods processed in vegetable oils. LA is an omega-6 polyunsaturated fatty acid (n-6 PUFA), which is an essential fatty acid required in the human diet. LA plays a vital role in fetal growth and development. Even though LA is essential in our diet, studies have raised concern over its beneficial effect, as excess LA is shown to have pro-inflammatory characteristics. In addition, the n-6/n-3 PUFA ratio should be balanced in the diet however, increased consumption of n-6 PUFA and limited consumption of n-3 PUFA perturb the optimal balance of n-6 and n-3 PUFA in the Westernized diet. There are conflicting findings on the effect of increased LA in human health. Further, as women of reproductive age have increased their consumption of LA, the effect of increased maternal LA on offspring risk of developing metabolic diseases is yet to be determined. This thesis aimed to investigate the effect of a maternal diet high in LA on maternal physiology, fetal growth, placental function, and offspring metabolic outcomes. Wistar Kyoto female rats were fed with either low LA diet (LLA; 1.44% of energy from LA) or a high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy. The total fat and n-3 PUFA content were matched in the experimental diet. Respective diets were fed during pregnancy and pregnant females were sacrificed at gestation day 20 (E20). For the animal model to study the effect on offspring, they were weaned at postnatal day (PN) 25 and exposed to either LLA or HLA postnatal diet until sacrifice. Offspring were sacrificed at PN40 to study the effect of maternal HLA during adolescence, and at PN180 to study its effect during adulthood. To investigate the effect of LA in a human placental cell line, LA was treated in the Swan71 cells for 24 hours. The major finding of the thesis was that maternal HLA diet decreased total n-3 PUFA and alpha-linolenic acid (ALA) in the plasma of dams and her offspring, during embryonic development, adolescence and adulthood. Postnatal HLA diet had a greater impact on fatty acid composition rather than maternal diet in adult offspring. Maternal HLA diet decreased the circulating concentration of leptin in the dams and had a sex-specific effect on the plasma leptin in the offspring. The decreased concentration of plasma leptin in the dams was accompanied by downregulation of mRNA expression of the leptin gene in the maternal white adipose tissue. Furthermore, maternal HLA diet increased prostaglandin E metabolite in the maternal circulation and altered the inflammatory mediators in the maternal liver. Interestingly, maternal HLA diet decreased the proportion of male fetuses. Furthermore, maternal HLA diet decreased blood total cholesterol and high-density lipoprotein (HDL)-cholesterol in the dams and adolescent female offspring. Postnatal HLA diet decreased blood total cholesterol and HDLcholesterol in male offspring. Also, maternal and postnatal HLA diet altered the cardiac function in the adolescent offspring and expression of genes related to hepatic lipid metabolism in adult offspring in a sex-specific manner. In conclusion, the findings presented in this thesis suggested that the maternal diet high in LA during pregnancy alters the parameters related to metabolic function in the offspring. These findings further support the previous research about the controversial role of LA in inflammatory responses and lipids. The data obtained from this thesis expanded our knowledge on the role of a maternal and postnatal diet high in LA on offspring lipid metabolism. The change in the circulating leptin concentrations in both the mother and offspring without a change in body weight and fat mass suggests the role of leptin in developmental programming is independent of adiposity. Future studies are needed to identify the molecular mechanism underlying the relation between LA and leptin in developmental programming.