Exposure to a High-Caloric Diet in utero reduces Fatty Acid Metabolic Flexibility through Hampered Hepatic Capacity for PUFA Metabolism in the Adult Rat when fed a High-Fat Diet.

Lars I Hellgren, Camilla Ingvorsen, DTU Systems Biology, Technical Univervsity of Denmark
Kgs. Lyngby, Denmark
 
Background: Perinatal exposure to energy-dense diets increases the risk for metabolic diseases in the offspring. This might be due to reduced metabolic flexibility, i.e. a reduced capacity to adapt to altered metabolic requirements, as well as to alterations in hepatic fatty acid metabolism.
Methods: Rat dams were given a high fat/high sucrose diet (H) or a chow-diet (C) 6 weeks prior to mating, during gestation and lactation. Pups were cross-fostered the day after birth, creating four groups defined by diets (C or H) during pre- and post-natal life. The offspring were weaned onto chow diet and challenged with a high-fat diet (45 E%) from 20 to 26 weeks of age, when they were sacrificed. Hepatic lipid composition and gene-expression for genes in the related metabolic pathways was analysed. 
Results: Offspring born by H-fed dams had increased FFA levels (effect of prenatal diet p<0.0001), lactation by H-fed dams further increased this effect. Median hepatic FFA level was 4.3 fold higher in these animals compared to rats lactated by H-fed but born by C-fed dams (p<0.0001), despite being exposed to identical diets from birth. Based on FFA composition, we show that this effect is due to hampered metabolism of dietary polyunsaturated fatty acids. This conclusion is supported by a reduced ratio between C18:3 n-6 and C18:2 n-6 in liver phospholipids (PL) in the rats exposed to the H-diet in utero (p<0.01), indicating reduced 6-desaturase activity. This was also manifested as a slight increase in PL C18:2 n-6 in these rats (p<0.05). The observed differences were not explained by altered gene expression. 
Conclusion: Pre-natal exposure to high-caloric diets reduced the hepatic capacity of shunt hepatic FFA into the appropriate pathways and might hence induce lipotoxic effects in the liver after high-fat intake, as well as having detrimental effects on hepatic PUFA-metabolism.