Annual Review of Nutrition - Volume 29, 2009

Given the very difficult odyssey of my early years, who could have imagined the incredible and successful journey that constituted my life path after age 13? I was born into a Jewish family in Breslau, Germany, right before the rise of Nazism and Hitler's election. After Kristallnacht, when my father was taken to Buchenwald Concentration Camp, we had to leave Germany as soon as possible. The first opportunity came in May of 1939, when we boarded the SS St. Louis bound for Havana, Cuba. Almost all passengers were denied entrance into Cuba, and the ship had to go back to Europe, where I ended up in France. In December of 1939, during World War II, I was fortunate to be able to leave France. This time I made it to Cuba, where my father was already in residence. A year later, my entire family was allowed into the United States. I took advantage of all the educational resources in this land of opportunity. I graduated valedictorian of my high school class and earned a four-year scholarship to Rutgers University, where I obtained a Bachelor of Science degree. I went on to earn a Master's degree from the University of Connecticut and finally a PhD from the University of Illinois. Within two months after graduating from Illinois, I was hired as an assistant professor of nutritional biochemistry at Rutgers, where I enjoyed a most productive research and teaching career. My PhD research involved tryptophan and niacin metabolism in the chick, and upon arrival at Rutgers I continued amino acid studies with the goal of assessing the essential amino acid requirements for egg production. This research was crowned with success and was followed with amino acid requirement studies for maintenance and for growth in rabbits, and ultimately with a reevaluation of requirements in adult humans. An outgrowth of the maintenance requirements led to a series of investigations into the metabolism of histidine, histamine, and carnosine (a histidine-containing dipeptide). Histamine, we found, plays an important role in wound healing and stress management. Pyridoxal phosphate is the cofactor for the enzyme histidine decarboxylase required for histamine synthesis and similarly serves as a cofactor for hydroxytryptophan decarboxylase, the enzyme that is part of the pathway to serotonin synthesis. Investigations into these pathways led to interesting findings: brain concentrations of serotonin could be increased by supplementing the diet of rats with tryptophan and pyridoxine; the elevated brain serotonin levels had behavioral consequences. Alcohol craving, addiction, and withdrawal symptoms are affected by serotonin concentrations in the brain, and alleviation of these conditions can be achieved with simultaneous administration of serotonin and dopamine agonists. In the midst of our early amino acid studies, we serendipitously also became involved with lipid metabolism in relation to atherosclerosis and blood cholesterol in a chicken model. This work led to the recognition that soluble fibers, like pectin, had strong cholesterol-lowering properties that were beneficial in lowering the incidence of coronary plaque formation. The research success that I have enjoyed has been coupled with the gift of three accomplished children who are making important contributions as professionals in their fields of endeavor. My wife and I are also blessed with 10 wonderful grandchildren, our pride and joy!

The role of dietary protein in weight loss and weight maintenance encompasses influences on crucial targets for body weight regulation, namely satiety, thermogenesis, energy efficiency, and body composition. Protein-induced satiety may be mainly due to oxidation of amino acids fed in excess, especially in diets with “incomplete” proteins. Protein-induced energy expenditure may be due to protein and urea synthesis and to gluconeogenesis; “complete” proteins having all essential amino acids show larger increases in energy expenditure than do lower-quality proteins. With respect to adverse effects, no protein-induced effects are observed on net bone balance or on calcium balance in young adults and elderly persons. Dietary protein even increases bone mineral mass and reduces incidence of osteoporotic fracture. During weight loss, nitrogen intake positively affects calcium balance and consequent preservation of bone mineral content. Sulphur-containing amino acids cause a blood pressure–raising effect by loss of nephron mass. Subjects with obesity, metabolic syndrome, and type 2 diabetes are particularly susceptible groups. This review provides an overview of how sustaining absolute protein intake affects metabolic targets for weight loss and weight maintenance during negative energy balance, i.e., sustaining satiety and energy expenditure and sparing fat-free mass, resulting in energy inefficiency. However, the long-term relationship between net protein synthesis and sparing fat-free mass remains to be elucidated.

This review analyzes the evidence presented to support the role of organs other than the liver and kidney to release substantial amounts of glucose into the mammalian blood circulation. The evidence includes (a) the identification of gluconeogenic enzyme activities in various organs, especially the small intestine, (b) levels of mRNA for the same enzymes, and (c) measurements of gluconeogenic flux in the small intestine. The latter would be the definite proof of extrahepatic, extrarenal glucose production. We critically evaluate the radioactive and stable isotopic techniques used to measure intestinal gluconeogenesis. We also simulate the impact of unavoidable measurement errors on apparent rates of intestinal gluconeogenesis. We conclude that there is so far no credible evidence to support the concept that glucose can be produced by the intestine or by muscle.

New brain synapses form when a postsynaptic structure, the dendritic spine, interacts with a presynaptic terminal. Brain synapses and dendritic spines, membrane-rich structures, are depleted in Alzheimer's disease, as are some circulating compounds needed for synthesizing phosphatides, the major constituents of synaptic membranes. Animals given three of these compounds, all nutrients—uridine, the omega-3 polyunsaturated fatty acid docosahexaenoic acid, and choline—develop increased levels of brain phosphatides and of proteins that are concentrated within synaptic membranes (e.g., PSD-95, synapsin-1), improved cognition, and enhanced neurotransmitter release. The nutrients work by increasing the substrate-saturation of low-affinity enzymes that synthesize the phosphatides. Moreover, uridine and its nucleotide metabolites activate brain P2Y receptors, which control neuronal differentiation and synaptic protein synthesis. A preparation containing these compounds is being tested for treating Alzheimer's disease.

Recent interest in vitamin K has been motivated by evidence of physiological roles beyond that of coagulation. Vitamin K and vitamin K–dependent (VKD) proteins may be involved in regulation of calcification, energy metabolism, and inflammation. However, the evidence for many of these proposed roles in the maintenance of health is equivocal. There is also an emerging viewpoint that the biochemical function of vitamin K may extend beyond that of a cofactor for the VKD carboxylation of glutamyl residues (Glus) to carboxylated Glus in VKD proteins.

Higher vitamin D exposure is hypothesized to prevent several cancers, possibly through genomic effects modulated by the vitamin D receptor (VDR), and autocrine/paracrine metabolism of the VDR's ligand, 1α,25-(OH)2-vitamin D. Herein we review the background and evidence to date on associations between polymorphisms in VDR and selected genes in the vitamin D pathway in relation to colorectal, breast, and prostate cancer. Although most studies to date have examined only a few VDR polymorphisms, more are beginning to comprehensively investigate polymorphisms in the VDR as well as in other vitamin D pathway genes, such as the vitamin D–binding protein gene (Gc) and CYP27B1 and CYP24A1, which code for enzymes that, respectively, synthesize and degrade 1α,25-(OH)2-vitamin D. Currently, there is no strong, consistent epidemiologic evidence for substantial influences of single variants in vitamin D pathway genes on risk for colorectal, breast, or prostate cancer, but promising leads are developing.

Recent years have brought a paradigm shift for the role of the essential trace element zinc in immunity. Although its function as a structural component of many enzymes has been known for decades, current experimental evidence points to an additional function of the concentration of free or loosely bound zinc ions as an intracellular signal. The activity of virtually all immune cells is modulated by zinc in vitro and in vivo. In this review, we discuss the interactions of zinc with major signaling pathways that regulate immune cell activity, and the implications of zinc deficiency or supplementation on zinc signaling as the molecular basis for an effect of zinc on immune cell function.

Research advances defining how zinc is transported into and out of cells and organelles have increased exponentially within the past five years. Research has progressed through application of molecular techniques including genomic analysis, cell transfection, RNA interference, kinetic analysis of ion transport, and application of cell and animal models including knockout mice. The knowledge base has increased for most of 10 members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family. Relative to the handling of dietary zinc is the involvement of ZnT1, ZIP4, and ZIP5 in intestinal zinc transport, involvement of ZIP10 and ZnT1 in renal zinc reabsorption, and the roles of ZIP5, ZnT2, and ZnT1 in pancreatic release of endogenous zinc. These events are major factors in regulation of zinc homeostasis. Other salient findings are the involvement of ZnT2 in lactation, ZIP14 in the hypozincemia of inflammation, ZIP6, ZIP7, and ZIP10 in metastatic breast cancer, and ZnT8 in insulin processing and as an autoantigen in diabetes.

The rapid growth of infant brains places an exceptionally high demand on the supply of nutrients from the diet, particularly for preterm infants. Sialic acid (Sia) is an essential component of brain gangliosides and the polysialic acid (polySia) chains that modify neural cell adhesion molecules (NCAM). Sia levels are high in human breast milk, predominately as N-acetylneuraminic acid (Neu5Ac). In contrast, infant formulas contain a low level of Sia consisting of both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). Neu5Gc is implicated in some human inflammatory diseases. Brain gangliosides and polysialylated NCAM play crucial roles in cell-to-cell interactions, neuronal outgrowth, modifying synaptic connectivity, and memory formation. In piglets, a diet rich in Sia increases the level of brain Sia and the expression of two learning-related genes and enhances learning and memory. The purpose of this review is to summarize the evidence showing the importance of dietary Sia as an essential nutrient for brain development and cognition.

Sustainable lifestyle modifications in diet and physical activity are the initial, and often the primary, component in the management of diabetes and the metabolic syndrome. An energy-prudent diet, coupled with moderate levels of physical activity, favorably affects several parameters of the metabolic syndrome and delays the onset of diabetic complications. Weight loss, albeit not an absolute prerequisite for improvement, is a major determinant and maximizes effectiveness. Adopting a healthy lifestyle pattern requires a series of long-term behavioral changes, but evidence to date indicates low long-term adherence to diet and physical activity recommendations. This calls for greater research and public health efforts focusing on strategies to facilitate behavior modification.

The structure, size, stability, and functionality of lipid rafts are still in debate, but recent techniques allowing direct visualization have characterized them in a wide range of cell types. Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. However, it is not clear whether dietary polyunsaturated fatty acids (PUFAs) are incorporated into raft lipids or whether their low affinity to cholesterol disallows this and causes phase separation from rafts and displacement of raft proteins. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Although there is increasing evidence to suggest that membrane microdomains, and their modulation, have an impact in health and disease, it is too early to judge whether modulation of lipid rafts is responsible for the immunomodulatory effects of n-3 PUFA. In addition to dietary fatty acids, gangliosides and cholesterol may also modulate microdomains in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth by n-3 PUFA. The roles of fatty acids and gangliosides in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require clarification, particularly with respect to the contribution of lipid rafts. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are only just emerging, but compelling evidence indicates the growing importance of membrane microdomains in health and disease.

Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living.

Taste is a chemical sense that aids in the detection of nutrients and guides food choice. A limited number of primary qualities comprise taste. Accumulating evidence has raised a question about whether fat should be among them. Most evidence indicates triacylglycerol is not an effective taste stimulus, though it clearly contributes sensory properties to foods by carrying flavor compounds and altering texture. However, there is increasing anatomical, electrophysiological, animal behavior, imaging, metabolic, and psychophysical evidence that free fatty acids are detectable when non-taste cues are minimized. Free fatty acids varying in saturation and chain length are detectable, suggesting the presence of multiple transduction mechanisms and/or a nonspecific mechanism in the oral cavity. However, confirmation of “fatty” as a taste primary will require additional studies that verify these observations are taste specific. Oral exposure to free fatty acids likely serves as a warning signal to discourage intake and influences lipid metabolism.

Nutrigenetics and nutrigenomics are nascent areas that are evolving quickly and riding on the wave of “personalized medicine” that is providing opportunities in the discovery and development of nutraceutical compounds. The human genome sequence and sequences of model organisms provide the equivalent of comprehensive blueprints and parts lists that describe dynamic networks and the bases for understanding their responses to external and internal perturbations. Unfolding the interrelationships among genes, gene products, and dietary habits is fundamental for identifying individuals who will benefit most from, or be placed at risk by, intervention strategies. More accurate assessment of the inputs to human health and the consequences of those inputs measured as accurate transcriptomic, proteomic, and metabolomic analyses would bring personalized health/diet to practice far faster than would waiting for a predictive knowledge of genetic variation. It is widely recognized that systems and network biology has the potential to increase our understanding of how nutrition influences metabolic pathways and homeostasis, how this regulation is disturbed in a diet-related disease, and to what extent individual genotypes contribute to such diseases.

A fundamental clinical problem in treating patients with chronic kidney disease (CKD) is designing their diets: an excess of protein leads to the accumulation of uremic toxins, whereas a diet insufficient in protein could lead to loss of lean body mass. The benefits of dietary protein restriction include reducing the accumulation of metabolic waste products that can suppress appetite and stimulate muscle protein wasting. There also is a potential for slowing the loss of kidney function. Unfortunately, advanced CKD is strongly associated with a protein wasting syndrome that is directly correlated with morbidity and mortality. Fortunately, the mechanisms underlying negative responses to an excess of dietary protein, including the causes of the wasting syndrome, are beginning to be understood. We have examined how dietary protein influences the mechanisms causing protein wasting, and we propose a framework for approaching the variable dietary protein requirements in patients with CKD or end-stage kidney disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance, obesity, and other features of metabolic syndrome and is known to be the most common cause for abnormal liver enzymes. The recent surge in the number of patients with NAFLD has been accompanied by an increase in research on potential treatment options, particularly weight loss and dietary interventions. Given the growing interest on the role of carbohydrates in the prevention and treatment of NAFLD, this review discusses the relationship between the amount of carbohydrates in the diet and effects on NAFLD, with special emphasis on a low-carbohydrate diet. We discuss the role of insulin resistance in the pathophysiology of NAFLD and provide an overview of various popular diets and their role as a treatment option for NAFLD. Additional large, longer-duration trials studying the efficacy of a low-carbohydrate diet in the treatment and prevention of NAFLD are eagerly awaited.

Arsenic, which is commonly found in drinking water, is a potent toxicant, but little is known about its effects on maternal health. Arsenic's modes of action include enzyme inhibition and oxidative stress as well as immune, endocrine, and epigenetic effects. A couple of studies reported increased blood pressure and anemia during pregnancy. Susceptibility to arsenic is dependent on the biomethylation, which occurs via one-carbon metabolism. Methylarsonic acid and dimethylarsinic acid are main metabolites in urine, and elevated methylarsonic acid is considered a general risk factor. Arsenic easily passes the placenta, and a few human studies indicate a moderately increased risk of impaired fetal growth and increased fetal and infant mortality. The fetus and infant are probably partly protected by the increased methylation of arsenic during pregnancy and lactation; the infant is also protected by low arsenic excretion in breast milk. Early-life exposure may induce changes that will become apparent much later in life.

Plant-based foods offer an array of nutrients that are essential for human nutrition and promote good health. However, the major staple crops of the world are often deficient in some of these nutrients. Traditional agricultural approaches can marginally enhance the nutritional value of some foods, but the advances in molecular biology are rapidly being exploited to engineer crops with enhanced key nutrients. Nutritional targets include elevated mineral content, improved fatty acid composition, increased amino acid levels, and heightened antioxidant levels. Unfortunately, in many cases the benefits of these “biofortified” crops to human nutrition have not been demonstrated.