Efficacy of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 toward synthesis of labeled-20:4n-6 was studied in ... more Efficacy of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t ½ ) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2-21%) of plasma 13 C-U-18:2n-6 was used for synthesis of 13 C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of 13 C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13 C-20:4n-6. The percentage of 2 H 5 -20:3n-6 converted to 2 H 5 -20:4n-6 was lower (mean: 26%, p Ͻ 0.02) than the 13 C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (Ϯ1.7) and 2.8 mg/kg/d (Ϯ 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.
The need to improve the nutritional status of extremely low birth weight infants has resulted in ... more The need to improve the nutritional status of extremely low birth weight infants has resulted in a higher incidence of problems related to glucose intolerance. The inability of the newborn to inhibit gluconeogenesis in response to a glucose infusion has been postulated as an important determinant of the hyperglycemia observed in extremely low birth weight infants. The 2 proposed mechanisms to explain this finding include inappropriate secretion of insulin by the pancreas and decrease sensitivity of the liver to the gluco-regulatory effect of insulin. The capacity of extremely low birth weight infants to oxidize glucose at higher rates, and the positive effect that insulin may have in glucose utilization and tolerance, support the use of insulin in the prevention and treatment of hyperglycemia. Continuous infusion of insulin appears to be safe for the treatment of hyperglycemia, based on the available studies. However, the effectiveness of insulin treatment needs to be critically tested further before it can be implemented in routine clinical practice.
The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but fu... more The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but functional measures associated with n-3 deficiency in human and nonhuman primates. Functional development of the retina and the occipital cortex are affected by α-linolenic acid deficiency and by a lack of docosahexaenoic acid (DHA) in preterm infant formulas and, as reported more recently, in term diets. Functional effects of n-3 supply on sleep-wake cycles and heart rate rhythms support the need for dietary n-3 fatty acids during early development. Our results indicate that n-3 long-chain polyunsaturated fatty acids should be considered provisionally essential for infant nutrition. DHA may also be required by individuals with inherited metabolic defects in elongation and desaturation activity, such as patients with peroxisomal disorders and some forms of retinitis pigmentosa.
Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPU... more Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPUFA) in their feeding, based on the changes in plasma and tissue fatty composition. However, consistent functional effects across different studies conducted over the past two decades has been more difficult to document. The interpretation of these data has scientific and public interest with the introduction of LCPUFA supplemented formula. There are 14 controlled trials in term infants that have included formula feeding with or without LCPUFA and functional assessment of visual and other measures of neural development; in addition, 7 have evaluated specific measures related to cognitive development. We chose to examine the effect of DHA dose provided daily on the development of visual acuity to explain the differences in visual acuity responses across randomized studies. A ''meta-regression'' was performed with the use of a DHA effective dose as the independent variable and visual acuity at 4 months as the dependent variable. Since the two main dietary determinants of DHA status are the LNA provided and the preformed DHA consumed, we defined DHA equivalent dose across studies by assuming a 1%, 5%, and 10% conversion of LNA to DHA. Results indicate a strong and significant effect of DHA equivalent dose on magnitude of the visual acuity response at all conversions tested; greatest significance was found when using a 10% bioequivalency (r 2 = 0.68, and P = .001). We conclude that there is a significant relation between the total DHA equivalents provided and effectiveness as defined by visual acuity measurements at 4 months of age. (J Pediatr 2003;143:S17-S25) From the Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile; and the Retina Foundation of the Southwest, Dallas, Texas.
The present study was designed to evaluate the effect of gestational age and intrauterine growth ... more The present study was designed to evaluate the effect of gestational age and intrauterine growth on the long chain polyunsaturated fatty acid (LCP) synthesis from dietary precursors in neonates as reflected by plasma pools. These have been considered conditionally essential nutrients for normal growth, sensory maturation, and neurodevelopment. In vivo elongation/desaturation of deuterated d5-linoleic acid (d5-LA) to form arachidonic acid (AA), and d5-alpha-linolenic acid (d5-LNA) to form docosahexaenoic acid (DHA), was studied in 19 preterm appropriate-for-gestational-age (AGA) infants, 11 AGA term, and 11 intrauterine growth-retarded (IUGR) infants. They received a dose of 50 mg/kg body weight of d5-LA and d5-LNA enterally during the first days of life; d5-labeled derivatized fatty acids were determined in blood samples obtained at 24, 48, and 96 h after dosing. Lipids were extracted and fatty acids analyzed by gas chromatography and negative ion mass spectrometry. Mean concentrations, microg/mL, and d5/d0 for n-3 and n-6 precursor and products were computed at various times and were also integrated over the complete study period. Significantly higher time-integrated concentration of d5-AA and d5-DHA were observed in preterm infants relative to the other two groups. Time-integrated enrichment of DHA relative to LNA was 100-fold lower in preterms, 410-fold lower in term, and 27-fold lower in IUGR infants. Similar significant declines in product to precursor enrichments were noted for the n-6 series. A significant negative correlation of AA and DHA formation based on time-integrated d5/d0 ratios with gestational age was noted; product/ precursor enrichment versus gas chromatography for the n-6 series had an r of -0.5, p = 0.001, and for the n-3 series had an r of -0.6, p = 0.0001. Birth weight or weight adequacy did not add further strength to the relationship. We conclude that LCP formation from deuterated precursors occurs as early as 26 wk gestation, and in fact is more active at earlier gestational ages; growth retardation appears to slow down or diminish LCP formation. No quantitative estimates of LCP synthesis or nutritional sufficiency can be derived from these data.
Proceedings of The National Academy of Sciences, 1996
It is becoming clear that an adequate level of long-chain highly unsaturated fatty acids in the n... more It is becoming clear that an adequate level of long-chain highly unsaturated fatty acids in the nervous system is required for optimal function and development; however, the ability of infants to biosynthesize long-chain fatty acids is unknown. This study explores the capacity of human infants to convert 18-carbon essential fatty acids to their elongated and desaturated forms, in vivo. A newly developed gas chromatography/negative chemical ionization/mass spectrometry method employing 2H-labeled essential fatty acids allowed assessment of this in vivo conversion with very high sensitivity and selectivity. Our results demonstrate that human infants have the capacity to convert dietary essential fatty acids administered enterally as 2H-labeled ethyl esters to their longer-chain derivatives, transport them to plasma, and incorporate them into membrane lipids. The in vivo conversion of linoleic acid (18:2n6) to arachidonic acid (20:4n6) is demonstrated in human beings. All elongases/desaturases necessary for the conversion of linolenic acid (18:3n3) to docosahexaenoic acid (22:6n3) are also active in the first week after birth. Although the absolute amounts of n-3 fatty acid metabolites accumulated in plasma are greater than those of the n-6 family, estimates of the endogenous pools of 18:2n6 and 18:3n3 indicate that n-6 fatty acid conversion rates are greater than those of the n-3 family. While these data clearly demonstrate the capability of infants to biosynthesize 22:6n3, a lipid that is required for optimal neural development, the amounts produced in vivo from 18:3n3 may be inadequate to support the 22:6n3 level observed in breast-fed infants.
Lipids are structural components of all tissues and are indispensable for cell membrane synthesis... more Lipids are structural components of all tissues and are indispensable for cell membrane synthesis. The brain, retina, and other neural tissues are particularly rich in LCPUFAs, affecting neural structural development and function. LCPUFAs serve also as specific precursors for eicosanoid production (prostaglandins, prostacyclins, thromboxanes, and leukotrienes). These autocrine and paracrine mediators are powerful regulators of numerous cell and tissue functions (e.g., thrombocyte aggregation, inflammatory reactions, and leukocyte functions, vasoconstriction and vasodilatation, blood pressure, bronchial constriction, uterine contraction). Dietary lipid intake affects cholesterol metabolism at an early age and is associated with cardiovascular morbidity and mortality in later life. Over recent years, the role of fatty acids in modulating signal transduction and regulating gene expression have been described, emphasizing the complex of fatty acid effects. Dietary fatty acids, especially LCPUFA, can have significant effects in the modulation of developmental processes affecting the clinical outcomes of extremely premature infants.
This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-l... more This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-labeled linoleic acid (d5-LA) and ␣-linolenic acid (d5-LNA) precursors in infants with intrauterine growth restriction (IUGR) compared with control groups matched by gestational age (GA) or birth weight. We compared DHA and AA formation from deuterated precursors d5-LA and d5-LNA in 11 infants with IUGR with 13 and 25 control subjects who were appropriate for GA and matched by GA and by birth weight, respectively. After an enteral administration of d5-LA and d5-LNA, we determined unlabeled and d5-labeled fatty acids at 24, 48, and 96 h in plasma. Absolute concentrations and area under the curve (AUC) over the 96-h study were used for analysis. Absolute concentration of d5-DHA and the product/precursor ratio of the d5-labeled AUCs indicated a less active DHA formation from LNA in infants with IUGR compared with their GAmatched (2-fold) and birth weight-matched (3-fold) control subjects. The ratios of eicosapentaenoic and n-3 docosapentaenoic acid to DHA were also affected. Similar evaluation for the n-6 series was not significant. DHA metabolism is affected in infants with IUGR; the restricted DPA to DHA conversion step seems to be principally responsible for this finding. Abbreviations AA, arachidonic acid AGA, appropriate for gestational age AUC, area under the curve DHA, docosahexaenoic acid d5-LA, deuterated linoleic acid d5-LNA, deuterated ␣-linolenic acid DPA, docosapentaenoic acid EFA, essential fatty acids EPA, eicosapentaenoic acid GA, gestational age IUGR, intrauterine growth restriction LA, linoleic acid LCP, long-chain polyunsaturated fatty acids LNA, ␣-linolenic acid PGC-1, peroxisome proliferator-activated receptor-␥ coactivator-1 PPAR, peroxisome proliferator-activated receptor SGA, small for gestational age
Efficacy of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 toward synthesis of labeled-20:4n-6 was studied in ... more Efficacy of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of 13 C-U-18:2n-6 and 2 H 5 -20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t ½ ) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2-21%) of plasma 13 C-U-18:2n-6 was used for synthesis of 13 C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of 13 C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13 C-20:4n-6. The percentage of 2 H 5 -20:3n-6 converted to 2 H 5 -20:4n-6 was lower (mean: 26%, p Ͻ 0.02) than the 13 C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (Ϯ1.7) and 2.8 mg/kg/d (Ϯ 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.
The need to improve the nutritional status of extremely low birth weight infants has resulted in ... more The need to improve the nutritional status of extremely low birth weight infants has resulted in a higher incidence of problems related to glucose intolerance. The inability of the newborn to inhibit gluconeogenesis in response to a glucose infusion has been postulated as an important determinant of the hyperglycemia observed in extremely low birth weight infants. The 2 proposed mechanisms to explain this finding include inappropriate secretion of insulin by the pancreas and decrease sensitivity of the liver to the gluco-regulatory effect of insulin. The capacity of extremely low birth weight infants to oxidize glucose at higher rates, and the positive effect that insulin may have in glucose utilization and tolerance, support the use of insulin in the prevention and treatment of hyperglycemia. Continuous infusion of insulin appears to be safe for the treatment of hyperglycemia, based on the available studies. However, the effectiveness of insulin treatment needs to be critically tested further before it can be implemented in routine clinical practice.
The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but fu... more The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but functional measures associated with n-3 deficiency in human and nonhuman primates. Functional development of the retina and the occipital cortex are affected by α-linolenic acid deficiency and by a lack of docosahexaenoic acid (DHA) in preterm infant formulas and, as reported more recently, in term diets. Functional effects of n-3 supply on sleep-wake cycles and heart rate rhythms support the need for dietary n-3 fatty acids during early development. Our results indicate that n-3 long-chain polyunsaturated fatty acids should be considered provisionally essential for infant nutrition. DHA may also be required by individuals with inherited metabolic defects in elongation and desaturation activity, such as patients with peroxisomal disorders and some forms of retinitis pigmentosa.
Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPU... more Healthy term infants who are not breast-fed may need long-chain polyunsaturated fatty acids (LCPUFA) in their feeding, based on the changes in plasma and tissue fatty composition. However, consistent functional effects across different studies conducted over the past two decades has been more difficult to document. The interpretation of these data has scientific and public interest with the introduction of LCPUFA supplemented formula. There are 14 controlled trials in term infants that have included formula feeding with or without LCPUFA and functional assessment of visual and other measures of neural development; in addition, 7 have evaluated specific measures related to cognitive development. We chose to examine the effect of DHA dose provided daily on the development of visual acuity to explain the differences in visual acuity responses across randomized studies. A ''meta-regression'' was performed with the use of a DHA effective dose as the independent variable and visual acuity at 4 months as the dependent variable. Since the two main dietary determinants of DHA status are the LNA provided and the preformed DHA consumed, we defined DHA equivalent dose across studies by assuming a 1%, 5%, and 10% conversion of LNA to DHA. Results indicate a strong and significant effect of DHA equivalent dose on magnitude of the visual acuity response at all conversions tested; greatest significance was found when using a 10% bioequivalency (r 2 = 0.68, and P = .001). We conclude that there is a significant relation between the total DHA equivalents provided and effectiveness as defined by visual acuity measurements at 4 months of age. (J Pediatr 2003;143:S17-S25) From the Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile; and the Retina Foundation of the Southwest, Dallas, Texas.
The present study was designed to evaluate the effect of gestational age and intrauterine growth ... more The present study was designed to evaluate the effect of gestational age and intrauterine growth on the long chain polyunsaturated fatty acid (LCP) synthesis from dietary precursors in neonates as reflected by plasma pools. These have been considered conditionally essential nutrients for normal growth, sensory maturation, and neurodevelopment. In vivo elongation/desaturation of deuterated d5-linoleic acid (d5-LA) to form arachidonic acid (AA), and d5-alpha-linolenic acid (d5-LNA) to form docosahexaenoic acid (DHA), was studied in 19 preterm appropriate-for-gestational-age (AGA) infants, 11 AGA term, and 11 intrauterine growth-retarded (IUGR) infants. They received a dose of 50 mg/kg body weight of d5-LA and d5-LNA enterally during the first days of life; d5-labeled derivatized fatty acids were determined in blood samples obtained at 24, 48, and 96 h after dosing. Lipids were extracted and fatty acids analyzed by gas chromatography and negative ion mass spectrometry. Mean concentrations, microg/mL, and d5/d0 for n-3 and n-6 precursor and products were computed at various times and were also integrated over the complete study period. Significantly higher time-integrated concentration of d5-AA and d5-DHA were observed in preterm infants relative to the other two groups. Time-integrated enrichment of DHA relative to LNA was 100-fold lower in preterms, 410-fold lower in term, and 27-fold lower in IUGR infants. Similar significant declines in product to precursor enrichments were noted for the n-6 series. A significant negative correlation of AA and DHA formation based on time-integrated d5/d0 ratios with gestational age was noted; product/ precursor enrichment versus gas chromatography for the n-6 series had an r of -0.5, p = 0.001, and for the n-3 series had an r of -0.6, p = 0.0001. Birth weight or weight adequacy did not add further strength to the relationship. We conclude that LCP formation from deuterated precursors occurs as early as 26 wk gestation, and in fact is more active at earlier gestational ages; growth retardation appears to slow down or diminish LCP formation. No quantitative estimates of LCP synthesis or nutritional sufficiency can be derived from these data.
Proceedings of The National Academy of Sciences, 1996
It is becoming clear that an adequate level of long-chain highly unsaturated fatty acids in the n... more It is becoming clear that an adequate level of long-chain highly unsaturated fatty acids in the nervous system is required for optimal function and development; however, the ability of infants to biosynthesize long-chain fatty acids is unknown. This study explores the capacity of human infants to convert 18-carbon essential fatty acids to their elongated and desaturated forms, in vivo. A newly developed gas chromatography/negative chemical ionization/mass spectrometry method employing 2H-labeled essential fatty acids allowed assessment of this in vivo conversion with very high sensitivity and selectivity. Our results demonstrate that human infants have the capacity to convert dietary essential fatty acids administered enterally as 2H-labeled ethyl esters to their longer-chain derivatives, transport them to plasma, and incorporate them into membrane lipids. The in vivo conversion of linoleic acid (18:2n6) to arachidonic acid (20:4n6) is demonstrated in human beings. All elongases/desaturases necessary for the conversion of linolenic acid (18:3n3) to docosahexaenoic acid (22:6n3) are also active in the first week after birth. Although the absolute amounts of n-3 fatty acid metabolites accumulated in plasma are greater than those of the n-6 family, estimates of the endogenous pools of 18:2n6 and 18:3n3 indicate that n-6 fatty acid conversion rates are greater than those of the n-3 family. While these data clearly demonstrate the capability of infants to biosynthesize 22:6n3, a lipid that is required for optimal neural development, the amounts produced in vivo from 18:3n3 may be inadequate to support the 22:6n3 level observed in breast-fed infants.
Lipids are structural components of all tissues and are indispensable for cell membrane synthesis... more Lipids are structural components of all tissues and are indispensable for cell membrane synthesis. The brain, retina, and other neural tissues are particularly rich in LCPUFAs, affecting neural structural development and function. LCPUFAs serve also as specific precursors for eicosanoid production (prostaglandins, prostacyclins, thromboxanes, and leukotrienes). These autocrine and paracrine mediators are powerful regulators of numerous cell and tissue functions (e.g., thrombocyte aggregation, inflammatory reactions, and leukocyte functions, vasoconstriction and vasodilatation, blood pressure, bronchial constriction, uterine contraction). Dietary lipid intake affects cholesterol metabolism at an early age and is associated with cardiovascular morbidity and mortality in later life. Over recent years, the role of fatty acids in modulating signal transduction and regulating gene expression have been described, emphasizing the complex of fatty acid effects. Dietary fatty acids, especially LCPUFA, can have significant effects in the modulation of developmental processes affecting the clinical outcomes of extremely premature infants.
This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-l... more This study evaluated the arachidonic acid (AA) and docosahexaenoic acid (DHA) formation from d5-labeled linoleic acid (d5-LA) and ␣-linolenic acid (d5-LNA) precursors in infants with intrauterine growth restriction (IUGR) compared with control groups matched by gestational age (GA) or birth weight. We compared DHA and AA formation from deuterated precursors d5-LA and d5-LNA in 11 infants with IUGR with 13 and 25 control subjects who were appropriate for GA and matched by GA and by birth weight, respectively. After an enteral administration of d5-LA and d5-LNA, we determined unlabeled and d5-labeled fatty acids at 24, 48, and 96 h in plasma. Absolute concentrations and area under the curve (AUC) over the 96-h study were used for analysis. Absolute concentration of d5-DHA and the product/precursor ratio of the d5-labeled AUCs indicated a less active DHA formation from LNA in infants with IUGR compared with their GAmatched (2-fold) and birth weight-matched (3-fold) control subjects. The ratios of eicosapentaenoic and n-3 docosapentaenoic acid to DHA were also affected. Similar evaluation for the n-6 series was not significant. DHA metabolism is affected in infants with IUGR; the restricted DPA to DHA conversion step seems to be principally responsible for this finding. Abbreviations AA, arachidonic acid AGA, appropriate for gestational age AUC, area under the curve DHA, docosahexaenoic acid d5-LA, deuterated linoleic acid d5-LNA, deuterated ␣-linolenic acid DPA, docosapentaenoic acid EFA, essential fatty acids EPA, eicosapentaenoic acid GA, gestational age IUGR, intrauterine growth restriction LA, linoleic acid LCP, long-chain polyunsaturated fatty acids LNA, ␣-linolenic acid PGC-1, peroxisome proliferator-activated receptor-␥ coactivator-1 PPAR, peroxisome proliferator-activated receptor SGA, small for gestational age
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