Annual Review of Nutrition - Volume 23, 2003

Selenium is an essential trace element that is incorporated into proteins as selenocysteine (Sec), the twenty-first amino acid. Sec is encoded by a UGA codon in the selenoprotein mRNA. The decoding of UGA as Sec requires the reprogramming of translation because UGA is normally read as a stop codon. The translation of selenoprotein mRNAs requires cis-acting sequences in the mRNA and novel trans-acting factors dedicated to Sec incorporation. Selenoprotein synthesis in vivo is highly selenium-dependent, and there is a hierarchy of selenoprotein expression in mammals when selenium is limiting. This review describes emerging themes from studies on the mechanism, kinetics, and efficiency of Sec insertion in prokaryotes. Recent developments that provide mechanistic insight into how the eukaryotic ribosome distinguishes between UGA/Sec and UGA/stop codons are discussed. The efficiency and regulation of mammalian selenoprotein synthesis are considered in the context of current models for Sec insertion.

Iron deficiency in early life is associated with delayed development as assessed by a number of clinical trials using similar global scales of development; this poor development during infancy persists in most cases after iron therapy has corrected iron status. If iron deficiency occurs in preschool and older children, the consequences appear reversible with treatment. The biologic understanding of this relationship between development, brain iron status, and functioning is sparse though animal studies repeatedly demonstrate alterations in dopamine metabolism and in the myelination process. Dietary iron deficiency can rapidly deplete brain iron concentrations and repletion is able to normalize them. Residual alterations in striatal dopamine metabolism and myelin production persist if neonatal animals are used. Future studies with more specific measures of neurodevelopment in iron-deficient human infants, and animal models, will allow investigators to more clearly define causal roles of brain iron in neural development and functioning.

In humans, the absence of galactose-1-phosphate uridyltransferase (GALT) leads to significant neonatal morbidity and mortality which are dependent on galactose ingestion, as well as long-term complications of primary ovarian failure and cognitive dysfunction, which are diet independent. The creation of a knockout mouse model for GALT deficiency was aimed at providing an organism in which metabolic challenges and gene manipulation could address the enigmatic pathophysiologic questions raised by humans with galactosemia. Instead, the mouse represents a biochemical phenotype without evidence of clinical morbidity. The similarities and differences between mice and humans with galactosemia are explored from metabolite, enzyme, and process points of view. The mouse both produces and oxidizes galactose in a manner similar to humans. It differs in brain accumulation of galactitol. Future directions for exploration of this enigmatic condition are discussed.

Atwater and his colleagues began studying food consumption in the closing years of the nineteenth century and from the very start devoted much effort to collecting data from poor and minority households. This paper reviews some of the fruits of these labors, particularly from the standpoint of what they contribute toward a better historical understanding of American food habits and nutrition. It surveys dietary data from African American, Appalachian white, Mexican American, native-born poor, and immigrant households. These data shed light on several areas of historical concern, including rural versus urban nutrition, seasonal hunger, class disparities, and food-habit change. I suggest the economically and culturally diverse sample of dietary patterns that comes to us as a legacy of the Atwater era sets the stage for a history of American food habits considerably more sophisticated than has been realized to date.

A full review of the strengths and limitations of the various methods used to define amino acid requirements is provided. The focus is on the recent development of carbon oxidation techniques such as indicator amino acid oxidation and 24-h amino acid balance to determine dietary indispensable (essential) amino acid needs in adults. All approaches depend on the change in a metabolic parameter in response to graded intake of the test amino acid. In humans, the within-subject variance is less than the between-subject variance, which has led to an appreciation of the need to study each subject across a range of intakes, above and below the mean requirement level. The data can then be analyzed using two-phase linear regression crossover and a precise population mean requirement can be determined. Several approaches have been used to define the variance of the mean requirement. Finally, a minimally invasive indicator amino acid oxidation model has been developed which allows the determination of dietary essential amino acid requirements in children and other vulnerable populations.

It has been a little more than 20 years since the first appreciation that the biologically active hormonal form of the secosteroid vitamin D—classically categorized as a regulator of calcium/phosphorous metabolism and bone mineralization—can exert effects on cells of the immune system. Since then a substantial literature has accumulated to suggest that these effects are exerted on multiple immune cell types, are predominantly suppressive at pharmacologic levels, and are potent enough to have true therapeutic potential in the management or prevention of immune-mediated diseases. Less clear at present, however, are the physiological roles played by the vitamin D endocrine system in the regulation of normal and abnormal immune responses. In this review, an appraisal of the current understanding of vitamin D–mediated immune regulation is presented that emphasizes progress towards its clinical application as well as the manner in which emerging models of normal immune function may facilitate a more complete understanding of its physiologic significance.

In recent years, the prevalence of type 2 diabetes has increased alarmingly worldwide, giving diabetes the dimension of an epidemic. Striking parallel increases in the prevalence of obesity reflect the importance of body fatness as a contributing factor to diabetes incidence. Moreover, it has been estimated that up to 75% of the risk of type 2 diabetes is attributable to obesity. Recent clinical trials and observational epidemiologic studies demonstrate the efficacy of lifestyle changes, including decreased energy intake, decreased fat intake, and weight loss, as well as regular participation in physical activity, in improving insulin sensitivity (SI) and reducing the risk of diabetes. This review evaluates evidence of the effect of diet on insulin resistance, insulin secretion, and glucose tolerance, and reflects on directions for future work toward primary prevention of type 2 diabetes.

The macular region of the primate retina is yellow in color due to the presence of the macular pigment, composed of two dietary xanthophylls, lutein and zeaxanthin, and another xanthophyll, meso-zeaxanthin. The latter is presumably formed from either lutein or zeaxanthin in the retina. By absorbing blue-light, the macular pigment protects the underlying photoreceptor cell layer from light damage, possibly initiated by the formation of reactive oxygen species during a photosensitized reaction. There is ample epidemiological evidence that the amount of macular pigment is inversely associated with the incidence of age-related macular degeneration, an irreversible process that is the major cause of blindness in the elderly. The macular pigment can be increased in primates by either increasing the intake of foods that are rich in lutein and zeaxanthin, such as dark-green leafy vegetables, or by supplementation with lutein or zeaxanthin. Although increasing the intake of lutein or zeaxanthin might prove to be protective against the development of age-related macular degeneration, a causative relationship has yet to be experimentally demonstrated.

Certain diets cause a marked reduction in milk fat production in ruminants. Commonly referred to as milk fat depression (MFD), the mechanism involves an interrelationship between rumen microbial processes and tissue metabolism. Numerous theories to explain this interrelationship have been proposed and investigations offer little support for theories that are based on a limitation in the supply of lipogenic precursors. Rather, the basis involves alterations in rumen biohydrogenation of dietary polyunsaturated fatty acids and a specific inhibition of mammary synthesis of milk fat. The biohydrogenation theory proposes that under certain dietary conditions, typical pathways of rumen biohydrogenation are altered to produce unique fatty acid intermediates that inhibit milk fat synthesis. Trans-10, cis-12 conjugated linoleic acid (CLA) has been identified as one example that is correlated with the reduction in milk fat. Investigations with pure isomers have shown that trans-10, cis-12 CLA is a potent inhibitor of milk fat synthesis, and similar to diet-induced MFD, the mechanism involves a coordinated reduction in mRNA abundance for key enzymes involved in the biochemical pathways of fat synthesis. A more complete identification of these naturally produced inhibitors of fat synthesis and delineation of cellular mechanisms may offer broader opportunities for application and understanding of the regulation of lipid metabolism.

Intestinal epithelial cell turnover (proliferation, migration, differentiation, and apoptosis) and gut barrier functions are dynamic processes that are markedly affected by nutritional status, the route of feeding, and the adequacy of specific nutrients in the diet. Emerging studies are defining potential therapeutic roles for specific nutrients and diet-derived compounds (including arginine, glutamate, glutamine, glutathione, glycine, vitamin A, zinc, and specific lipids) in gut mucosal turnover, repair, adaptation after massive bowel resection, and barrier function. The role and regulation of endogenous bowel flora in generating short-chain fatty acids from diet-derived fiber and other diet-derived compounds and the effects of these agents on gut function are increasingly being elucidated. Results of these investigations should define new nutritional methods for trophic and cytoprotective effects on the intestine in conditions such as inflammatory bowel disease, malnutrition, and short bowel syndrome.

The association of malnutrition with surgical morbidity and mortality is well recognized. The question of whether this relationship is causal or simply an association in sick patients has been hotly debated. The field of nutrition support has grown out of the belief that correcting malnutrition will modify associated risks for poor outcome. It has been easier to substantiate this belief in some clinical situations than in others. The evidence for nutrition support during the perioperative period is reviewed and recommendations are made about where nutrition support is most useful and where it may be counterproductive. Some of the important unanswered questions about perioperative nutrition support are raised.

The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.

Microorganisms have successfully adapted to changes in food production, processing, and preservation techniques, resulting in a number of new and emerging foodborne pathogens and the re-emergence of organisms that have been problematic in the past. To protect public health, science must meet the challenges that result from the remarkable adaptability of foodborne pathogens. However, not all of the challenges of preventing foodborne illness reside in the realm of science. Food safety policy must evolve in reponse to new scientific understanding of hazards in the food supply and an ever-changing food processing industry. The laws, regulations, and organizations comprising the food safety system frequently lag behind current scientific knowledge of the risks posed by foodborne pathogens. Future systemic changes to enhance food safety will require better understanding of risks associated with specific pathogens occurring in the food supply and the costs and benefits of implementing mitigation strategies.

An evolutionary perspective is used to elucidate the etiology of the current epidemic of type 2 diabetes estimated at 151 million people. Our primate legacy, fossil hominid, and hunting-gathering lifestyles selected for adaptive metabolically thrifty genotypes and phenotypes are rendered deleterious through modern lifestyles that increase energy input and reduce output. The processes of modernization or globalization include the availability and abundance of calorically dense/low-fiber/high-glycemic foods and the adoption of sedentary Western lifestyles, leading to obesity among both children and adults in developed and developing countries. These trends are projected to continue for a number of decades.

In the postgenomic era of biology, much attention has been given to functional genomics, or the relation between genes and higher levels of organization in the cell. The latter are typically represented as mRNA, protein, or organic metabolite complements. The theme of this review is that the operational unit of function in complex biological systems is more properly seen as the fully assembled metabolic pathway in the whole organism. Due to the connectivity, interactions, and complexity of metabolic pathways, the measurement of components is an inadequate method for predicting phenotype. Measurement of the outputs of pathways (molecular fluxes) involves different tools than static measures of components, however. Here, we review recently developed stable isotope-mass spectrometric tools for measuring fluxes through metabolic pathways in vivo, focusing on the response to dietary macronutrients (carbohydrates and fats). Methods discussed include measurement of lipid dynamics, DNA replication, hepatic assembly of lipoproteins, and long-lived protein synthesis. Measuring fluxes through multiple pathways concurrently allows regulatory themes to emerge. Use of ²H2O-labeling is emerging as a particularly powerful approach for multiple concurrent biosynthetic flux measurements. Several examples demonstrate that pathway flux results are often unexpected and not predicted by classic biochemistry or the expression of genes and proteins.

Bone mass is maintained constant between puberty and menopause by the balance between osteoblast and osteoclast activity. The existence of a hormonal control of osteoblast activity has been speculated for years by analogy to osteoclast biology. Through the search for such humoral signal(s) regulating bone formation, leptin has been identified as a strong inhibitor of bone formation. Furthermore, intracerebroventricular infusion of leptin has shown that the effect of this adipocyte-derived hormone on bone is mediated via a brain relay. Subsequent studies have led to the identification of hypothalamic groups of neurons involved in leptin's antiosteogenic function. In addition, those neurons or neuronal pathways are distinct from neurons responsible for the regulation of energy metabolism. Finally, the peripheral mediator of leptin's antiosteogenic function has been identified as the sympathetic nervous system. Sympathomimetics administered to mice decreased bone formation and bone mass. Conversely, β-blockers increased bone formation and bone mass and blunted the bone loss induced by ovariectomy.