Graham C. Burdge

The principal biological role of alpha-linolenic acid (alphaLNA; 18:3n-3) appears to be as a precursor for the synthesis of longer chain n-3 polyunsaturated fatty acids (PUFA). Increasing alphaLNA intake for a period of weeks to months results in an increase in the proportion of eicosapentaenoic acid (EPA; 20:5n-3) in plasma lipids, in erythrocytes, leukocytes, platelets and in breast milk but there is no increase in docosahexaenoic acid (DHA; 22:6n-3), which may even decline in some pools at high alphaLNA intakes. Stable isotope tracer studies indicate that conversion of alphaLNA to EPA occurs but is limited in men and that further transformation to DHA is very low. The fractional conversion of alphaLNA to the longer chain n-3 PUFA is greater in women which may be due to a regulatory effect of oestrogen. A lower proportion of alphaLNA is used for beta-oxidation in women compared with men. Overall, alphaLNA appears to be a limited source of longer chain n-3 PUFA in humans. Thus, adequate intakes of preformed long chain n-3 PUFA, in particular DHA, may be important for maintaining optimal tissue function. Capacity to up-regulate alphaLNA conversion in women may be important for meeting the demands of the fetus and neonate for DHA.

The extent to which women of reproductive age are able to convert the n-3 fatty acid alpha-linolenic acid (ALNA) to eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) was investigated in vivo by measuring the concentrations of labelled fatty acids in plasma for 21 d following the ingestion of [U-13C]ALNA (700 mg). [13C]ALNA excursion was greatest in cholesteryl ester (CE) (224 (sem 70) micromol/l over 21 d) compared with triacylglycerol (9-fold), non-esterified fatty acids (37-fold) and phosphatidylcholine (PC, 7-fold). EPA excursion was similar in both PC (42 (sem 8) micromol/l) and CE (42 (sem 9) micromol/l) over 21 d. In contrast both [13C]DPA and [13C]DHA were detected predominately in PC (18 (sem 4) and 27 (sem 7) micromol/l over 21 d, respectively). Estimated net fractional ALNA inter-conversion was EPA 21 %, DPA 6 % and DHA 9 %. Approximately 22 % of administered [13C]ALNA was recovered as 13CO2 on breath over the first 24 h of the study. These results suggest differential partitioning of ALNA, EPA and DHA between plasma lipid classes, which may facilitate targeting of individual n-3 fatty acids to specific tissues. Comparison with previous studies suggests that women may possess a greater capacity for ALNA conversion than men. Such metabolic capacity may be important for meeting the demands of the fetus and neonate for DHA during pregnancy and lactation. Differences in DHA status between women both in the non-pregnant state and in pregnancy may reflect variations in metabolic capacity for DHA synthesis.

OBJECTIVE: Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS: Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10%, we related methylation status to maternal pregnancy diet and to child's adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS: In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4-31], P = 0.009, n = 64, and β = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1-19], P = 0.023, n = 64 and β =12% [4-20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2-10] and β = 4% [1-7], respectively, both P = 0.002, n = 239). CONCLUSIONS: Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

The capacity for conversion of alpha-linolenic acid (ALNA) to n-3 long-chain polyunsaturated fatty acids was investigated in young men. Emulsified [U-13C]ALNA was administered orally with a mixed meal to six subjects consuming their habitual diet. Approximately 33 % of administered [13C]ALNA was recovered as 13CO2 on breath over the first 24 h. [13C]ALNA was mobilised from enterocytes primarily as chylomicron triacylglycerol (TAG), while [13C]ALNA incorporation into plasma phosphatidylcholine (PC) occurred later, probably by the liver. The time scale of conversion of [13C]ALNA to eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) suggested that the liver was the principal site of ALNA desaturation and elongation, although there was some indication of EPA and DPA synthesis by enterocytes. [13C]EPA and [13C]DPA concentrations were greater in plasma PC than TAG, and were present in the circulation for up to 7 and 14 d, respectively. There was no apparent 13C enrichment of docosahexaenoic acid (DHA) in plasma PC, TAG or non-esterified fatty acids at any time point measured up to 21 d. This pattern of 13C n-3 fatty acid labelling suggests inhibition or restriction of DHA synthesis downstream of DPA. [13C]ALNA, [13C]EPA and [13C]DPA were incorporated into erythrocyte PC, but not phosphatidylethanolamine, suggesting uptake of intact plasma PC molecules from lipoproteins into erythrocyte membranes. Since the capacity of adult males to convert ALNA to DHA was either very low or absent, uptake of pre-formed DHA from the diet may be critical for maintaining adequate membrane DHA concentrations in these individuals.