Annual Review of Nutrition - Volume 25, 2005

Dietary fiber has been a topic of considerable interest among nutritionists and clinicians for the past 50 years. Many studies on fiber have concentrated on fiber isolates, resulting in findings that have ignored fiber as a component of fruits, vegetables, nuts, cereals, and legumes in the general diet. The principle actions of fiber are to alter the nature of the contents of the gastrointestinal tract and to modify the absorption of other nutrients and chemicals. Fiber is but one component of plant food, and to neglect the other components—be they proteins, lipids, vitamins, minerals, antioxidants, or the secondary metabolites—is to seriously limit our understanding. Much of the effort expended in defining fiber and studying the fiber isolate would have been better focused using this whole-plant-food approach. Greater progress in our understanding of the relevance of fiber in the etiology of disease would have been achieved if a more holistic approach had been followed.

Infection leads to profound alterations in whole-body metabolism, which is characterized by marked acceleration of glucose, fat and protein, and amino acid flux. One of the complications of infection, especially in the nutritionally supported setting, is hyperglycemia. The hyperglycemia is caused by peripheral insulin resistance and alterations in hepatic glucose metabolism. The defects in hepatic glucose metabolism include overproduction of glucose and a failure of the liver to appropriately adapt when nutritional support is administered. Investigators have suggested that multiple factors contribute to the observed defects. In this review, I focus primarily on alterations in carbohydrate metabolism, examining both the metabolic response to infection and inflammatory stress, the role of the accompanying neuroendocrine and inflammatory responses in the metabolic response, and the interaction between the endocrine response to infection and nutritional support.

Breastfed infants have lower morbidity and mortality due to diarrhea than those fed artificially. This had been attributed primarily to the secretory antibodies and prebiotic factors in human milk. Oligosaccharides are the third largest component of human milk. They were initially considered to be functionless by-products of glycoprotein and glycolipid synthesis during milk production. However, in the past few decades it has become apparent that the human milk oligosaccharides are composed of thousands of components, at least some of which protect against pathogens. Oligosaccharide protection against infectious agents may result in part from their prebiotic characteristics, but is thought to be primarily due to their inhibition of pathogen binding to host cell ligands. Most human milk oligosaccharides are fucosylated, and their production depends on enzymes encoded by the genes associated with expression of the Lewis blood group system. The expression of specific fucosylated oligosaccharides in milk thus varies in relation to maternal Lewis blood group type, and is significantly associated with the risk of infectious disease in breastfed infants. Specific fucosylated moieties of oligosaccharides and related glycoconjugates (glycans) are able to inhibit binding and disease by specific pathogens. This review presents the argument that specific glycans, especially the oligosaccharides, are the major constituent of an innate immune system of human milk whereby the mother protects her infant from enteric and other pathogens through breastfeeding. The large input of energy expended by the mother in the synthesis of milk oligosaccharides is consistent with the human reproductive strategy of large parental input into rearing relatively few offspring through a prolonged period of maturation. These protective glycans may prove useful as a basis for the development of novel prophylactic and therapeutic agents that inhibit diseases caused by mucosal pathogens.

The amino acid response (AAR) pathway in mammalian cells is designed to detect and respond to amino acid deficiency. Limiting any essential amino acid initiates this signaling cascade, which leads to increased translation of a “master regulator,” activating transcription factor (ATF) 4, and ultimately, to regulation of many steps along the pathway of DNA to RNA to protein. These regulated events include chromatin remodeling, RNA splicing, nuclear RNA export, mRNA stabilization, and translational control. Proteins that are increased in their expression as targets of the AAR pathway include membrane transporters, transcription factors from the basic region/leucine zipper (bZIP) superfamily, growth factors, and metabolic enzymes. Significant progress has been achieved in understanding the molecular mechanisms by which amino acids control the synthesis and turnover of mRNA and protein. Beyond gaining additional knowledge of these important regulatory pathways, further characterization of how these processes contribute to the pathology of various disease states represents an interesting aspect of future research in molecular nutrition.

Mechanisms involved in the digestion and absorption of dietary vitamin A require the participation of several proteins. Dietary retinyl esters are hydrolyzed in the intestine by the pancreatic enzyme, pancreatic triglyceride lipase, and intestinal brush border enzyme, phospholipase B. Unesterified retinol taken up by the enterocyte is complexed with cellular retinol-binding protein type 2 and the complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (LRAT). The retinyl esters are then incorporated into chylomicrons, intestinal lipoproteins containing other dietary lipids, such as triglycerides, phospholipids, and free and esterified cholesterol, and apolipoprotein B. Chylomicrons containing newly absorbed retinyl esters are then secreted into the lymph. Although under normal dietary conditions much of the dietary vitamin A is absorbed via the chylomicron/lymphatic route, it is also clear that under some circumstances there is substantial absorption of unesterified retinol via the portal route. Evidence supports the idea that the cellular uptake and efflux of unesterified retinol by enterocytes is mediated by lipid transporters, but the exact number, identity, and role of these proteins is not known and is an active area of research.

Ascorbic acid and dehydroascorbic acid (DHAA, oxidized vitamin C) are dietary sources of vitamin C in humans. Both nutrients are absorbed from the lumen of the intestine and renal tubules by, respectively, enterocytes and renal epithelial cells. Subsequently vitamin C circulates in the blood and enters all of the other cells of the body. Concerning flux across the plasma membrane, simple diffusion of ascorbic acid plays only a small or negligible role. More important are specific mechanisms of transport and metabolism that concentrate vitamin C intracellularly to enhance its function as an enzyme cofactor and antioxidant. The known transport mechanisms are facilitated diffusion of DHAA through glucose-sensitive and -insensitive transporters, facilitated diffusion of ascorbate through channels, exocytosis of ascorbate in secretory vesicles, and secondary active transport of ascorbate through the sodium-dependent vitamin C transporters SVCT1 and SVCT2 proteins that are encoded by the genes Slc23a1 and Slc23a2, respectively. Evidence is reviewed indicating that these transport pathways are regulated under physiological conditions and altered by aging and disease.

The vitamin K–dependent (VKD) carboxylase uses the oxygenation of vitamin K to convert glutamyl residues (Glus) to carboxylated Glus (Glas) in VKD proteins, rendering them active in a broad range of physiologies that include hemostasis, apoptosis, bone development, arterial calcification, signal transduction, and growth control. The carboxylase has a high-affinity site that selectively binds VKD proteins, usually through their propeptide, and also has a second low-affinity site of VKD protein interaction. Propeptide binding increases carboxylase affinity for the Glu substrate, and the coordinated binding of the VKD propeptide and Glu substrate increases carboxylase affinity for vitamin K and activity, possibly through a mechanism of substrate-assisted catalysis. Tethering of VKD proteins to the carboxylase allows clusters of Glus to be modified to Glas by a processive mechanism that becomes disrupted during warfarin therapy. Warfarin inhibits a vitamin K oxidoreductase that generates the reduced vitamin K cofactor required for continuous carboxylation and causes decreased carboxylase catalysis and increased dissociation of partially carboxylated, inactive VKD proteins. The availability of reduced vitamin K may also control carboxylation in r-VKD protein-expressing cells, where the amounts of reduced vitamin K are sufficient for full carboxylation of low, but not high, expression levels of VKD proteins, and where carboxylation is not improved by overexpression of r-carboxylase. This review discusses these recent advances in understanding the mechanism of carboxylation. Also covered is the identification of functional carboxylase residues, a brief description of the role of VKD proteins in mammalian and lower organisms, and the potential impact of quality control components on carboxylation, which occurs in the endoplasmic reticulum during the secretion of VKD proteins.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the Western world. Its incidence has also been increasing lately in developing countries. Several lines of evidence support a role for oxidative stress and inflammation in atherogenesis. Oxidation of lipoproteins is a hallmark in atherosclerosis. Oxidized low-density lipoprotein induces inflammation as it induces adhesion and influx of monocytes and influences cytokine release by monocytes. A number of proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) modulate monocyte adhesion to endothelium. C-reactive protein (CRP), a prototypic marker of inflammation, is a risk marker for CVD and it could contribute to atherosclerosis. Hence, dietary micronutrients having anti-inflammatory and antioxidant properties may have a potential beneficial effect with regard to cardiovascular disease. Vitamin E is a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, α-tocopherol (AT) has potential beneficial effects with regard to cardiovascular disease. AT supplementation in human subjects and animal models has been shown to decrease lipid peroxidation, superoxide (O2^-) production by impairing the assembly of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase as well as by decreasing the expression of scavenger receptors (SR-A and CD36), particularly important in the formation of foam cells. AT therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, the chemokine IL-8 and plasminogen activator inhibitor-1 (PAI-1) levels as well as decrease adhesion of monocytes to endothelium. In addition, AT has been shown to decrease CRP levels, in patients with CVD and in those with risk factors for CVD. The mechanisms that account for nonantioxidant effects of AT include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine–kinase as well as cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.

Evidence is emerging that biotin participates in processes other than classical carboxylation reactions. Specifically, novel roles for biotin in cell signaling, gene expression, and chromatin structure have been identified in recent years. Human cells accumulate biotin by using both the sodium-dependent multivitamin transporter and monocarboxylate transporter 1. These transporters and other biotin-binding proteins partition biotin to compartments involved in biotin signaling: cytoplasm, mitochondria, and nuclei. The activity of cell signals such as biotinyl-AMP, Sp1 and Sp3, nuclear factor (NF)-κB, and receptor tyrosine kinases depends on biotin supply. Consistent with a role for biotin and its catabolites in modulating these cell signals, greater than 2000 biotin-dependent genes have been identified in various human tissues. Many biotin-dependent gene products play roles in signal transduction and localize to the cell nucleus, consistent with a role for biotin in cell signaling. Posttranscriptional events related to ribosomal activity and protein folding may further contribute to effects of biotin on gene expression. Finally, research has shown that biotinidase and holocarboxylase synthetase mediate covalent binding of biotin to histones (DNA-binding proteins), affecting chromatin structure; at least seven biotinylation sites have been identified in human histones. Biotinylation of histones appears to play a role in cell proliferation, gene silencing, and the cellular response to DNA repair. Roles for biotin in cell signaling and chromatin structure are consistent with the notion that biotin has a unique significance in cell biology.

The type IIa Na/phosphate (Pi) cotransporter (Npt2a) is expressed in the brush border membrane (BBM) of renal proximal tubular cells where the bulk of filtered Pi is reabsorbed. Disruption of the Npt2a gene in mice elicits hypophosphatemia, renal Pi wasting, and an 80% decrease in renal BBM Na/Pi cotransport, and led to the demonstration that Npt2a is the target for hormonal and dietary regulation of renal Pi reabsorption. Regulation is achieved by changes in BBM abundance of Npt2a protein and requires the interaction of Npt2a with various scaffolding and regulatory proteins. Molecular studies in patients with renal Pi wasting resulted in the identification of novel regulators of Pi homeostasis: fibroblast growth factor-23 (FGF-23) and a phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). In mouse models, increased FGF-23 production or loss of Phex function causes hypophosphatemia and decreased renal Pi reabsorption, secondary to decreased BBM Npt2a protein abundance. Thus, Npt2a plays a major role in the maintenance of Pi homeostasis in both health and disease.

Selenoprotein P is an abundant extracellular glycoprotein that is rich in selenocysteine. It has two domains with respect to selenium content. The N-terminal domain of the rat protein contains one selenocysteine residue in a UxxC redox motif. This domain also has a pH-sensitive heparin-binding site and two histidine-rich amino acid stretches. The smaller C-terminal domain contains nine selenocysteine and ten cysteine residues. Four isoforms of selenoprotein P are present in rat plasma. They share the same N terminus and amino acid sequence. One isoform is full length and the three others terminate at the positions of the second, third, and seventh selenocysteine residues. Selenoprotein P turns over rapidly in rat plasma with the consequence that approximately 25% of the amount of whole-body selenium passes through it each day. Evidence supports functions of the protein in selenium homeostasis and oxidant defense. Selenoprotein P knockout mice have very low selenium concentrations in the brain, the testis, and the fetus, with severe pathophysiological consequences in each tissue. In addition, those mice waste moderate amounts of selenium in the urine. Selenoprotein P binds to endothelial cells in the rat, and plasma levels of the protein correlate with prevention of diquat-induced lipid peroxidation and hepatic endothelial cell injury. The mechanisms of these apparent functions remain speculative and much work on the mechanism of selenoprotein P function lies ahead. Measurement of selenoprotein P in human plasma has shown that it is depressed by selenium deficiency and by cirrhosis. Selenium supplementation of selenium-deficient human subjects showed that glutathione peroxidase activity was optimized before selenoprotein P concentration was optimized, indicating that plasma selenoprotein P is the better index of human selenium nutritional status.

The size and frequency of meals are fundamental aspects of nutrition that can have profound effects on the health and longevity of laboratory animals. In humans, excessive energy intake is associated with increased incidence of cardiovascular disease, diabetes, and certain cancers and is a major cause of disability and death in industrialized countries. On the other hand, the influence of meal frequency on human health and longevity is unclear. Both caloric (energy) restriction (CR) and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by mechanisms involving reduced oxidative damage and increased stress resistance. Many of the beneficial effects of CR and fasting appear to be mediated by the nervous system. For example, intermittent fasting results in increased production of brain-derived neurotrophic factor (BDNF), which increases the resistance of neurons in the brain to dysfunction and degeneration in animal models of neurodegenerative disorders; BDNF signaling may also mediate beneficial effects of intermittent fasting on glucose regulation and cardiovascular function. A better understanding of the neurobiological mechanisms by which meal size and frequency affect human health may lead to novel approaches for disease prevention and treatment.

Cells in multicellular organisms are exposed to both endogenous oxidative stresses generated metabolically and to oxidative stresses that originate from neighboring cells and from other tissues. To protect themselves from oxidative stress, cells are equipped with reducing buffer systems (glutathione/GSH and thioredoxin/thioredoxin reductase) and have developed several enzymatic mechanisms against oxidants that include catalase, superoxide dismutase, and glutathione peroxidase. Other major extrinsic defenses (from the diet) include ascorbic acid, β-carotene and other carotenoids, and selenium. Recent evidence indicates that in addition to their antioxidant function, several of these redox species and systems are involved in regulation of biological processes, including cellular signaling, transcription factor activity, and apoptosis in normal and cancer cells. The survival and overall well-being of the cell is dependent upon the balance between the activity and the intracellular levels of these antioxidants as well as their interaction with various regulatory factors, including Ref-1, nuclear factor-κB, and activating protein-1.

Early investigations of gene regulation revealed that nutrients could modulate gene expression, an example being the discovery of metal-regulated gene transcription (11, 19, 44). Only more recently have we focused on the ability of non-nutritional botanicals or functional food components to affect gene expression at the transcriptional level. Significant findings include the discovery that hyperforin is an active ingredient of the herbal remedy St. John's wort, and activates gene transcription of cytochrome p450-3A4, causing significant botanical-drug interactions. Recently, the lipid-regulating peroxisome proliferator-activated receptors have been studied as receptors activated by soy isoflavones, perhaps explaining the lipid-lowering effect of soy intake. Epigallocatechin gallate has been shown to be an inhibitor of the protealytic activity of the proteasome; this inhibition has a significant implication for cell proliferation and the stability of transcription factors in the nucleus. Very recently, the effects of botanicals have been studied as activators of sirtuins, important deacetylation enzymes that have been shown to enhance lifespan in a variety of organisms. Sirtuins have been implicated in the lifespan-enhancing effect of caloric restriction. Originally presumed to act mainly on compaction or accessibility of DNA, recent evidence shows important activity of sirtuins as controllers of transcriptional coactivator availability. This review focuses on novel mechanisms by which botanical products regulate cell function via gene transcription. Investigating these newly appreciated mechanisms will assist with the characterization and clarification of specific effects of botanicals on gene expression.

Apart from being an important macronutrient, dietary fat has recently gained much prominence for its role in regulating gene expression. Polyunsaturated fatty acids (PUFAs) affect gene expression through various mechanisms including, but not limited to, changes in membrane composition, intracellular calcium levels, and eicosanoid production. Furthermore, PUFAs and their various metabolites can act at the level of the nucleus, in conjunction with nuclear receptors and transcription factors, to affect the transcription of a variety of genes. Several of these transcription mediators have been identified and include the nuclear receptors peroxisome proliferator-activated receptor (PPAR), hepatocyte nuclear factor (HNF)-4α, and liver X receptor (LXR) and the transcription factors sterol-regulatory element binding protein (SREBP) and nuclear factor-κB (NFκB). Their interaction with PUFAs has been shown to be critical to the regulation of several key genes of lipid metabolism. Working out the mechanisms by which these interactions and consequent effects occur is proving to be complicated but is invaluable to our understanding of the role that dietary fat can play in disease management and prevention.

Cardiovascular disease (CVD) risk is the result of complex interactions between genetic and environmental factors. During the past few decades, much attention has focused on plasma lipoproteins as CVD risk factors. The current evidence supports the concept that gene-environment interactions modulate plasma lipid concentrations and potentially CVD risk. The findings from studies examining gene-diet interactions and lipid metabolism have been highly promising. Several loci (i.e., APOA1, APOA4, APOE, and LIPC) are providing proof-of-concept for the potential application of genetics in the context of personalized nutritional recommendations for CVD prevention. However, the incorporation of these findings to the clinical environment is not ready for prime time. There is a compelling need for replication using a higher level of scientific evidence. Moreover, we need to evolve from the simple scenarios examined nowadays (i.e., one single dietary component, single nucleotide polymorphism, and risk factor) to more realistic situations involving interactions between multiple genes, dietary components, and risk factors. In summary, there is need for both large population studies and well-standardized intervention studies.

The ability of insulin to stimulate glucose disposal varies at least sixfold in apparently healthy individuals, and approximately one-third of the population that is most resistant to this action of insulin is at greatly increased risk to develop a number of adverse clinical outcomes. Type 2 diabetes occurs when insulin resistant individuals are unable to secrete enough insulin to compensate for the defect in insulin action, and this was the first clinical syndrome identified as being related to insulin resistance. Although the majority of insulin-resistant individuals are able to maintain the level of compensatory hyperinsulinemia needed to prevent the development of a significant degree of hyperglycemia, the combination of insulin resistance and hyperinsulinemia greatly increases the likelihood of developing a cluster of closely related abnormalities and the resultant clinical diagnoses that can be considered to make up the insulin resistance syndrome (IRS). Since being overweight/obese and sedentary decreases insulin sensitivity, it is not surprising that the prevalence of the manifestations of the IRS is increasing at a rapid rate. From a dietary standpoint, there are two approaches to attenuating the manifestations of the IRS: (a) weight loss to enhance insulin sensitivity in those overweight/obese individuals who are insulin resistant/hyperinsulinemic; and (b) changes in macronutrient content of diets to avoid the adverse effects of the compensatory hyperinsulinemia. This chapter will focus on defining the abnormalities and clinical syndromes that compose the IRS and evaluating the dietary changes that can ameliorate its adverse consequences.

Over the past 20 years a large and varied body of research has attempted to make the case for the developmental origins of elevated adult blood pressure (BP). Experimental animal research has identified plausible biological mechanisms through which fetal nutritional insufficiency may affect adult BP. The majority of human epidemiologic studies demonstrate an inverse association of birth weight (the most commonly used marker of fetal nutrition) with adult BP and higher risk of hypertension among individuals with lower weight at birth. The most adverse BP outcomes occur among individuals who were small at birth but relatively large as adults, a finding that suggests a role for postnatal growth. We critically review the literature on proposed mechanisms and epidemiologic evidence for developmental origins of adult BP and hypertension, considering associations with birth weight, maternal nutrition during pregnancy, child growth patterns, and infant feeding.

The study of childhood obesity has continued to grow exponentially in the past decade. This has been driven in part by the increasing prevalence of this problem and the widespread potential effects of increased obesity in childhood on lifelong chronic disease risk. The focus of this review is on recent findings regarding the link between obesity and disease risk during childhood and adolescence. We describe recent reports relating to type 2 diabetes in youth (2), prediabetes (69, 166), metabolic syndrome (33, 35), polycystic ovarian syndrome (77), and nonalcoholic fatty liver disease (58, 146), and the mediating role of insulin resistance in these conditions. In addition, we review the implications of this research for the design of more effective treatment and prevention strategies that focus more on the improvement of obesity-related metabolic abnormalities and chronic disease risk reduction than on the conventional energy balance approach that focuses on weight management.

Mammalian hibernation is a temporary suspension of euthermia allowing endotherms to undergo reversible hypothermia and generate a marked savings in energy expenditure. In most fat-storing hibernator species, seasonal changes in food intake, triacylglycerol deposition, metabolism, and reproductive development are controlled by a circannual clock. In ground-dwelling sciurid rodents (ground squirrels and marmots), for example, energy intake increases during a summer body mass gain phase, and toward the end of this phase metabolic rate also begins to decrease, resulting in a profound increase in lipid deposition as fat. Increased activity of lipogenic hormones and enzymes correspond with this increase. The hibernation mass loss phase begins after the body mass peak in the fall and ends in spring. During this phase, stored lipids are slowly utilized in a programmed manner by undergoing deep torpor or hibernation during which the hypothalamic setpoint for body temperature is typically reduced to just above 0°C. Throughout the hibernation season, bouts of deep torpor are punctuated by periodic arousals in which brown adipose tissue thermogenesis plays a critical role. Lipid oxidation nearly exclusively fuels deep torpor and most of the rewarming process. The fatty acid composition of stored lipids can affect the depth and duration of deep torpor, and saturated fatty acids may be preferentially used during hibernation, whereas polyunsaturated fatty acids may be preferentially retained. Female and underweight male hibernators terminate hibernation in spring when aboveground food becomes available; in contrast, heavier males with sufficient lipid reserves spontaneously terminate hibernation several weeks before females and independent of food availability. Mating occurs shortly after emergence from hibernation, and the lipid cycle begins again with the completion of reproduction. Lipid deposition and mobilization, temperature regulation, reproduction, and circannual timing are intimately interdependent. The unique manner in which they are controlled during the annual cycle, especially lipid reserves, makes hibernators valuable and promising models for research into the mechanisms underlying these processes in all mammals.

Nutrigenomics refers to the complex effects of the nutritional environment on the genome, epigenome, and proteome of an organism. The diverse tissue- and organ-specific effects of diet include gene expression patterns, organization of the chromatin, and protein post-translational modifications. Long-term effects of diet range from obesity and associated diseases such as diabetes and cardiovascular disease to increased or decreased longevity. Furthermore, the diet of the mother can potentially have long-term health impacts on the children, possibly through inherited diet-induced chromatin alterations. Drosophila is a unique and ideal model organism for conducting nutrigenomics research for numerous reasons. Drosophila, yeast, and Caenorhabditis elegans all have sophisticated genetics as well as sequenced genomes, and researchers working with all three organisms have made valuable discoveries in nutrigenomics. However, unlike yeast and C. elegans, Drosophila has adipose-like tissues and a lipid transport system, making it a closer model to humans. This review summarizes what has already been learned in Drosophila nutrigenomics (with an emphasis on lipids and sterols), critically evaluates the data, and discusses fruitful areas for future research.

Animal models have been invaluable for studying aspects of food intake regulation that for various reasons cannot be observed in humans. The dairy cow is a unique animal model because of an unrivaled energy requirement; its great drive to eat results in feeding behavior responses to treatments within the physiological range. Cows' docile nature and large size make them ideal for measuring temporal treatment effects because digestion and absorption kinetics and responses in endocrine systems, gene expression, metabolite pools and fluxes, and feeding behavior can be measured simultaneously. Thus, cows are important models to investigate interactions of short-term signals regulating food intake. Furthermore, different physiological states throughout the lactation cycle provide powerful models to study how short- and long-term signals interact to affect long-term energy status. The use of the cow as a model can lead to breakthroughs in understanding the complex interactions of signals regulating food intake.

The presence of docosahexaenoic acid (DHA) and arachidonic acid (ARA) in human milk but not in infant formula, coupled with lower plasma and brain lipid contents of DHA in formula-fed than in breast-fed infants and reports of higher IQ in individuals who were breast-fed versus formula-fed as infants, suggest that exogenous DHA (and ARA) may be essential for optimal development. Thus, since 1990, several studies have examined the impact of formulas containing DHA or DHA plus ARA on visual function and neurodevelopmental outcome. Some of these studies have shown benefits but others have not. These results leave largely unanswered the question of whether these fatty acids are beneficial for either the term or preterm infant. However, evidence that preterm infants might benefit is somewhat more convincing than that for term infants. Despite the limited evidence for efficacy, formulas supplemented with DHA and ARA are now available and appear to be safe.