Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates

Abstract

Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 ± 0.22%wt DHA and 0.62 ± 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]α-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was ∼3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group.These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels. Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 ± 0.22%wt DHA and 0.62 ± 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]α-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was ∼3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels. It is well established that the long-chain polyunsaturated fatty acids (LCPs) docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are required for proper neural development. Mammals can synthesize DHA from linolenic acid (LNA) and ARA from linoleic acid (LA) by a series of elongation and desaturation reactions (1Lauritzen L. Hansen H.S. Jorgensen M.H. Michaelsen K.F. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina.Prog. Lipid Res. 2001; 40: 1-94Crossref PubMed Scopus (830) Google Scholar). LNA and LA are considered to be dietary essential fatty acids (FAs) because mammals are incapable of synthesizing these FAs. The n-3 and n-6 FAs are not interconvertible, and it has long been assumed that they compete for the same elongation and desaturation enzymes; it was shown only recently that the Δ6-desaturase, the first step in DHA and ARA biosynthesis from LNA and LA, respectively, operates on both LNA and LA (2Cho H.P. Nakamura M. Clarke S.D. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Tracer studies show that preterm and term human infants (3Demmelmair H. von Schenck U. Behrendt E. Sauerwald T. Koletzko B. Estimation of arachidonic acid synthesis in full term neonates using natural variation of 13C content.J. Pediatr. Gastroenterol. Nutr. 1995; 21: 31-36Crossref PubMed Scopus (154) Google Scholar, 4Salem Jr., N. Wegher B. Mena P. 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PubMed Scopus Google Scholar). the of to these same to the of and on ARA and DHA biosynthesis. biosynthesis and brain and ARA and DHA accretion to ARA and DHA accretion to in the of human The of was in in a E. A. Nathanielsz P.W. Brenna J.T. The of and long chain in adjusted baboon brain and Res. PubMed Scopus Google Scholar). be The was by the and the is by the for the and of baboons were in the first of gestation from the for in to were in of at one other and were a which as of n-3 were assigned to one of four term, breast-fed term, preterm, and preterm, supplemented with at 182 days of these four neonates were assigned to the group and for of breast milk were on the of The the group, were to the of birth and a formula available preterm infant formula for were on at ± days of age, as by of fetal and of the baboon PubMed Google Scholar). The group of premature the to the group. The preterm the group, were a formula of with of DHA and of ARA of formula formulas and were by were The that were weeks of at and were in E. A. Nathanielsz P.W. Brenna J.T. The of and long chain in adjusted baboon brain and Res. PubMed Scopus Google Scholar) on were from all in were weeks adjusted at the time of received a combined oral dose of ± of (LNA*) and ± of and were and were in The dose was to of the neonates at 14 days to 14 days for term neonates and 14 days adjusted for preterm neonates ± days The dose was as and were and a of The was and was and for The were a The was with of which was a The of both were of to the a were by were and in was in and and were by The were and and were in and in were in and to a they were were from tissue using the and E. A of and J. Sci. Scholar) to that the for tissue was a R.C. H.M. Brenna J.T. of to docosahexaenoate is not by dietary of in tracer using Lipid Res. 1995; Full Text PDF PubMed Google Scholar). FAs were to fatty acid with in and the were in as was as to tissue was to the formula and breast milk as concentrations were by with a using a and factors for were using and data were with as Tracer for 13C was using a isotope in Brenna J.T. tracer using isotope and Chem. PubMed Scopus Google Scholar). data are as the from in is the of the to isotope for the from of the isotope in the can be as excess is by the from the were from of of a at as (6Su H.M. Bernardo L. Mirmiran M. Ma X.H. Corso T.N. Nathanielsz P.W. Brenna J.T. Bioequivalence of dietary alpha-linolenic and docosahexaenoic acids as sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons.Pediatr. Res. 1999; 45: 87-93Crossref PubMed Scopus (123) Google Scholar). The of tracer that in a tissue can be by the by the in the dose is from sources LNA to DHA and LA to must be by the of of in the by the of of in the dose to be in of the of that have the is the dose J.T. Corso T.N. H.J. isotope 1997; PubMed Scopus Google Scholar) and is as from oral the are by the of by the The the of and organs in of of the and for DHA and ARA The FAs are for the in the The that must be are the which in are LNA and LA in the the data to the to be about the of dietary FAs in the to in as by are of the and not be considered the LNA and LA concentrations were for the and groups but for the group. The breast milk were adjusted by by the LA breast and the the can be as the that have been found the concentrations of breast milk LA and LNA were to of the other and with H.M. Huang M.C. Saad N.M. Nathanielsz P.W. Brenna J.T. Fetal baboons convert 18:3n-3 to 22:6n-3 in vivo. A stable isotope tracer study.J. Lipid Res. 2001; 42: 581-586Abstract Full Text Full Text PDF PubMed Google Scholar, H.M. Corso T.N. Nathanielsz P.W. Brenna J.T. acid and to arachidonic acid in the and fetal Lipid Res. 1999; 40: Full Text Full Text PDF PubMed Google to as among tracer concentrations in and tissue were from data from to group to the to which in human infants with was by a data for and for are as ± were compared with the for using the by for the of group and and of FAs and was at were in for and weight data are Premature baboons at of the birth weight of term neonates At the time of weeks adjusted age, in weight were no at weeks adjusted age, were no significant in the of the at birth ± ± at breast-fed and term, group are from birth The of preterm, and preterm, supplemented groups are adjusted The period for baboons is 182 28 ± 28 ± weight that not the same are significantly at ± ± ± ± weight at ± ± ± ± weight at ± ± ± ± weight ± ± ± ± weight ± ± ± ± are as ± The breast-fed and term, group are from birth The of preterm, and preterm, supplemented groups are adjusted The period for baboons is 182 that not the same are significantly at in a are as ± The of breast unsupplemented formula and supplemented formula and the are shown in The of is to that of the human and a breast milk of were to one at and for the unsupplemented and supplemented The unsupplemented formula was of the supplemented formula contained as ARA and a of DHA as breast milk contained significant of 22:6n-3 and the step of 22:6n-3 synthesis to be the of 18:3n-3 Jr., N. of alpha-linolenic acid in Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google and n-3 are assumed to as precursors for 22:6n-3 than for is no to in breast milk and in the supplemented formula was acid the elongation of acid n-6 that is not in the of synthesis H. The of a in the biosynthesis of polyunsaturated fatty PubMed Scopus Google was in all of in in their supplemented formulas of of and the ARA and DHA concentrations in supplemented formula were than found in however, the of ARA to DHA was to that in the DHA in the supplemented formula was to that in the breast-fed of breast a and of as ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± fatty long-chain polyunsaturated fatty fatty not fatty in a fatty long-chain polyunsaturated fatty fatty not fatty of concentrations for are E. A. Nathanielsz P.W. Brenna J.T. The of and long chain in adjusted baboon brain and Res. PubMed Scopus Google Scholar). DHA was in most tissues of the unsupplemented with of of the breast-fed and supplemented DHA DHA concentrations in and but and DHA concentrations were than of the breast-fed group. ARA concentrations in the unsupplemented groups were in no than in the breast-fed group and were significantly in the brain and of the unsupplemented preterm group. with ARA not significantly but and ARA compared with polyunsaturated tissue at weeks adjusted ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± in a significantly are ± of by weight of FAs. for and not in a in a significantly are ± of by weight of FAs. for and not tracer for and in brain a and was significantly for the group than for the formula groups and group were significantly than group in all that the partially attenuated DHA synthesis to be in with synthesis in the breast-fed was ± in the group and to greater in the formula groups ± ± ± and were to greater in the formula groups than in the group. of was that of the group compared with the formula the only in and not in brain were no among formula Tracer data for and are in for these were to in and and were significant for all The the and formula groups was most for for which the group had in all was significantly in and for the compared with the group, with in was in the group and in the formula and a for the and formula group and formula group were These that the accretion of and in brain and their in are in formula compared with The synthesis of and was significantly in most of neonates compared with breast-fed these a as the in in formula group that in the group. for the on the of the brain in group in the all than in the formula the of the and as data in DHA to formula from to and ARA from for brain to for at these 14 time of to the in arachidonic acid (ARA) docosahexaenoic acid (DHA) in formula groups and compared with the group. The is the of DHA ARA. These data show that acid-derived DHA brain accretion on than linoleic acid-derived ARA accretion to formula with other shown are of all formula groups in excess of the not in a to the in arachidonic acid (ARA) docosahexaenoic acid (DHA) in formula groups and compared with the group. The is the of DHA ARA. These data show that acid-derived DHA brain accretion on than linoleic acid-derived ARA accretion to formula with other shown are of all formula groups in excess of the not A in these data is that is greater than for a by the of the from shown in the of These show that brain accretion in formula compared with in and in the and from of and and and and were significant at and the for the most and are in the of the from all of are and one in organs was with than was for to is the of to because to be the same for both the of be a of the than that of The greater of accretion compared with accretion shown in The in show that were a of brain and and than was was a of levels. The of the the of the to in tracer for from to greater than the for brain and and are in are significant at in a are in are significant at is as the of infant and as a for dietary for weight have at only in the is little to that breast milk to the of the very preterm infant J. Koletzko B. Fatty acid of human milk during the after term and preterm J. Pediatr. 1997; PubMed Google Scholar). infant formulas were and were at the growth of term the in the of human is the of tissue FAs to It is that tissue and concentrations to in function be and must be A. B. of dietary polyunsaturated on the of fatty acids in PubMed Scopus Google Scholar). the variation in the regulation of concentrations from tissue to tissue from in and dietary FAs by H. R. The of dose of essential fatty acids fatty acid of the Lipid Res. Full Text PDF PubMed Google Scholar) and inclusion of in formula in the of synthesis from precursors (2Cho H.P. Nakamura M. Clarke S.D. Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). tracer data can in the of precursors to a of and to and only that of DHA and ARA that has been from their 18-carbon precursors with a weeks at adjusted of brain of DHA (6Su H.M. Bernardo L. Mirmiran M. Ma X.H. Corso T.N. Nathanielsz P.W. Brenna J.T. Bioequivalence of dietary alpha-linolenic and docosahexaenoic acids as sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons.Pediatr. Res. 1999; 45: 87-93Crossref PubMed Scopus (123) Google Scholar, 7Greiner R.C. Winter J. Nathanielsz P.W. Brenna J.T. Brain docosahexaenoate accretion in fetal baboons: bioequivalence of dietary alpha-linolenic and docosahexaenoic acids.Pediatr. Res. 1997; 42: 826-834Crossref PubMed Scopus (100) Google Scholar) and ARA H.M. Corso T.N. Nathanielsz P.W. Brenna J.T. acid and to arachidonic acid in the and fetal Lipid Res. 1999; 40: Full Text Full Text PDF PubMed Google Scholar) is the tracer concentrations in brain at time and is in other is and be with of and the and groups shown in and that of formula accretion of from their be to synthesis to in the data among these accretion in the preterm groups compared with the and groups that not DHA as shown in and the and that DHA inclusion in formula partially At at these dietary DHA not accretion to the lower, breast-fed levels. ARA inclusion in formula not ARA It is well known that tissue are by dietary concentrations A. B. of dietary polyunsaturated on the of fatty acids in PubMed Scopus Google Scholar). not to in as excess tissue as be that preterm neonates DHA/ARA formula of DHA to of breast-fed neonates E. A. Nathanielsz P.W. Brenna J.T. The of and long chain in adjusted baboon brain and Res. PubMed Scopus Google Scholar). The data shown in that DHA concentrations are in by formulas ARA concentrations are not These that tissue of DHA and ARA is to very the low of and DHA that combined and brain synthesis is inadequate to breast-fed DHA levels. ARA concentrations are ARA synthesis in the groups ARA in neonates were of breast-fed and show that is to greater in the formula groups than in the group for and for brain and the are and only the and is The in of the formula groups the group is as shown in A for the of is that neonates on than breast-fed was milk not be in however, that among groups were not at and the group the weight significantly and that was not a is the of precursors in breast milk that were not in milk contained a of n-6 the of ARA and compared with supplemented with 1.21%wt ARA and These breast milk are for milk at it is that concentrations were in is in at and by in the first weeks in human 1999; PubMed Scopus Google Scholar, M. P.R. of human milk in the of the and during the J. Nutr. PubMed Scopus Google Scholar). these to baboons as that the group of ARA and compared with the group. DHA in the supplemented formula was to that in breast milk the of and both DHA was in the breast milk but only in the supplemented that and breast milk is in n-3 that breast milk DHA and n-3 precursors have been greater in breast milk than in the A greater in DHA synthesis by in for to greater in synthesis in the and groups with is A in DHA synthesis to in ARA synthesis other for the regulation of n-3 and n-6 levels. the that inadequate DHA in the ARA biosynthesis as studies with DHA be required to The of DHA in the supplemented formula was that of the in as The greater for DHA than for shown in the of supplemented preterm neonates to brain DHA of breast-fed and the significant concentrations of DHA precursors in breast milk that formula DHA at of FAs not be to brain DHA These data to of DHA in as as of as was recently shown to function in M. Jr., N. Fatty acid formula and development in Res. PubMed Scopus Google Scholar). not be because human breast milk DHA to in excess of in human 1999; PubMed Scopus Google Scholar). for the of be the concentrations of the in the formulas and the breast milk were and is not to in but of the group LA and LNA concentrations in human breast milk not in the first weeks of in human 1999; PubMed Scopus Google Scholar). in are to neonates are not to and other in breast that on on as ARA and the DHA acid are the precursors to their on are not it is that greater of in greater The of in the group is with tissue in the preterm the DHA in the and adipose tissue that can be as a during the in DHA the preterm and term human infant to be as as (1Lauritzen L. Hansen H.S. Jorgensen M.H. Michaelsen K.F. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina.Prog. Lipid Res. 2001; 40: 1-94Crossref PubMed Scopus (830) Google and stores for term human infants are in Brenna J.T. infants a of brain and docosahexaenoate than infants not dietary PubMed Scopus Google Scholar). It is that stores in the preterm compared with that in the term breast-fed The shown in be for synthesis in tracer studies of human infants that have only to The in show that of in and and of that in is by levels. Brain and are with than is and is with in with the as a of FAs. The for that synthesis in and is to in synthesis in and of ARA synthesis compared with the that in DHA and ARA not in is that these are from a time at 14 days after dose. Brain and are to be at a at however, the and in other tissues at 14 days after dose at which is to the these data that formula to term preterm neonates potentiates the synthesis of DHA and ARA to and that for preterm is only partially by the inclusion of of from DHA and of from ARA in in ARA synthesis were in and among formula these dietary DHA in tissue than ARA to brain DHA in supplemented preterm neonates not that of breast-fed well with brain and was a of These that to the of formula in excess of the is and were the of was by of arachidonic acid docosahexaenoic acid fatty acid fatty acid linoleic acid [U-13C]linoleic acid long-chain polyunsaturated fatty acid acid [U-13C]α-linolenic acid