Annual Review of Nutrition - Volume 28, 2008

The sustained effort to witness and participate in the targeted translation of nutritional science and policy forms the structure of this narrative. The memoir starts with an early career-directing experience with nutrition and cholera and proceeds with a long thread of interest in folic acid malabsorption as one of the determinants of nutritional anemia in Asia and the tropics. The thread continues with the relationship of folate and associated vitamins to brain function and aging as a prototype of the study of the interface of aging biology and nutritional biology. My current interest in world hunger and famine and their impact on human security may circle back to studies of the great Bengal famine and the first Bangladesh survey of malnutrition.

We assess the existence, mechanism, and functions of less-than-maximal coupling efficiency of mitochondrial oxidative phosphorylation and its potential as a target for future antiobesity interventions. Coupling efficiency is the proportion of oxygen consumption used to make adenosine triphosphate (ATP) and do useful work. High coupling efficiency may lead to fat deposition; low coupling efficiency to a decrease in fat stores. We review obligatory and facultative energy expenditure and the role of a futile cycle of proton pumping and proton leak across the mitochondrial inner membrane in dissipating energy. Basal proton conductance is catalyzed primarily by the adenine nucleotide translocase but can be mimicked by chemical uncouplers. Inducible proton conductance is catalyzed by specific uncoupling proteins. We discuss the opportunities and pitfalls of targeting these processes as a treatment for obesity by decreasing coupling efficiency and increasing energy expenditure, either directly or through central mechanisms of energy homeostasis.

Intestinal glucose absorption comprises two components. One is classical active absorption mediated by the Na⁺/glucose cotransporter. The other is a diffusive component, formerly attributed to paracellular flow. Recent evidence, however, indicates that the diffusive component is mediated by the transient insertion of glucose transporter type 2 (GLUT2) into the apical membrane. This apical GLUT2 pathway of intestinal sugar absorption is present in species from insect to human, providing a major route at high sugar concentrations. The pathway is regulated by rapid trafficking of GLUT2 to the apical membrane induced by glucose during assimilation of a meal. Apical GLUT2 is therefore a target for multiple short-term and long-term nutrient-sensing mechanisms. These include regulation by a newly recognized pathway of calcium absorption through the nonclassical neuroendocrine l-type channel Cav1.3 operating during digestion, activation of intestinal sweet taste receptors by natural sugars and artificial sweeteners, paracrine and endocrine hormones, especially insulin and GLP-2, and stress. Permanent apical GLUT2, resulting in increased sugar absorption, is a characteristic of experimental diabetes and of insulin-resistant states induced by fructose and fat. The nutritional consequences of apical and basolateral GLUT2 regulation are discussed in the context of Western diet, processed foods containing artificial sweeteners, obesity, and diabetes.

Cystic fibrosis (CF) is the most common lethal inherited disorder among Caucasians and results from mutation in the gene encoding the CF transmembrane conductance regulator. In addition to its multisystem clinical effects, the disease is characterized by increased proinflammatory mediators and oxidant stress, and systemic redox imbalance with reduced glutathione (GSH), together with alterations in circulating and tissue (n-6) and (n-3) fatty acids, particularly a decrease in docosahexaenoic acid. The metabolism of phospholipids and fatty acids is closely related to GSH through the methionine-homocysteine cycle, in which choline via betaine provides methyl groups to regenerate S-adenosylmethionine, important in generating phosphatidylcholine and amino acid precursors for GSH. Current research focuses both on fatty acid supplementations to normalize altered (n-6) to (n-3) fatty acid balance and decrease generation of (n-6) fatty acid-derived inflammatory mediators, and strategies to improve oxidant defenses and redox balance. However, further research is needed before such strategies can be included in clinical care of individuals with CF.

Fatty acid–binding proteins (FABPs) are abundant intracellular proteins that bind long-chain fatty acids with high affinity. Nine separate mammalian FABPs have been identified, and their tertiary structures are highly conserved. The FABPs have unique tissue-specific distributions that have long suggested functional differences among them. In the last decade, considerable progress has been made in understanding the specific functions of the FABPs and, in some cases, their mechanisms of action at the molecular level. The FABPs appear to be involved in the extranuclear compartments of the cell by trafficking their ligands within the cytosol via interactions with organelle membranes and specific proteins. Several members of the FABP family have been shown to function directly in the regulation of cognate nuclear transcription factor activity via ligand-dependent translocation to the nucleus. This review will focus on these emerging functions and mechanisms of the FABPs, highlighting the unique functional properties of each as well as the similarities among them.

The development of a single-celled fertilized egg, through the blastocyst stage of a ball of cells and the embryonic stage when almost all organ systems begin to develop, and finally to the fetal stage where growth and physiological maturation occurs, is a complex and multifaceted process. A change in metabolism during gestation, especially when organogenesis occurs, can lead to abnormal development and congenital defects. Although many studies have described the roles of specific proteins in development, the roles of specific lipids, such as sterols, have not been studied as intensely. Sterol's functions in development range from being a structural component of membranes to regulating the patterning of the forebrain through sonic hedgehog to regulating expression of key proteins involved in metabolic processes. This review focuses on the roles of sterols in embryonic and fetal development and metabolism. Potential sources of cholesterol for the fetus and embryo are also discussed.

Although baseline requirements for nicotinamide adenine dinucleotide (NAD⁺) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD⁺ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD⁺ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD⁺ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

In this article, we review the evidence that dietary protein has a positive influence on bone health, reduces hip fracture risk, and promotes postfracture recovery, and we consider the molecular, cellular, and endocrine bases of the interactions that link protein and calcium metabolism, including effects via IGF-1 and PTH. In addition, we consider the roles of amino acid–sensing mechanisms in coupling dietary protein intake to metabolic change as well as the central role of calcium-sensing receptors (CaRs) in the control of calcium metabolism. Finally, we consider how recently identified broad-spectrum amino acid–sensing receptors from class 3 of the G-protein coupled receptor superfamily including, remarkably, the CaR itself may contribute to the impact of dietary protein on bone.

Dietary selenium intake is regarded as an important factor in determining optimal health and susceptibility to disease. Therefore, it is critical to understand the interaction between selenium intake and molecular events at the genetic and cellular level. This article addresses two facets of this interaction. The first facet is how genomics is contributing to understanding the molecular mechanisms by which selenium affects cell function through selenoproteins and downstream targets of Se supply in other metabolic pathways. The contribution of transgenic animals in this field is emphasized, and the more recent studies using transcriptomics are discussed. The second facet is the extent to which single nucleotide polymorphisms (SNPs) in genes encoding selenoproteins and components of the selenoprotein synthetic machinery affect individual dietary requirements for optimal health. The state of knowledge of known functional SNPs in selenoprotein genes is presented, and a strategy for future studies is discussed.

Calcium is an essential ion in all organisms and participates in a variety of structural and functional roles. Calcium (re)absorption occurs in epithelia, including the intestine, kidney, mammary glands, placenta, and gills of fish. Its transport is regulated by a complex array of processes that are mediated by hormonal, developmental, and physiological factors involving the gastrointestinal tract, bone, kidney, and the parathyroids. Here we review the calcium transport mechanisms—paracellular, which is energy independent, and transcellular, which is energy dependent—primarily focusing on the intestine. We provide a new perspective on the facilitated diffusion and vesicular transport models to account for the emerging concepts on transcellular calcium transport. Finally, we discuss how 1,25(OH)2D3 and parathyroid hormone regulate calcium transport.

The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/ferroportin system to connect the control networks for systemic and cellular iron balance.

The ability to link dietary consumption of prebiotic food ingredients and probiotic microorganisms to health benefits rests, in part, on our ability to identify both the extent to which these factors alter human microbiome activity and/or structure and the ability to engage eukaryotic cells necessary to transduce signals originating from the microbiome. The human microbiome consists of bacterial, archaeal, and fungal components that reside in mucosal surfaces of the gut, the airways, and the urogenital tract. Characterization of the symbiotic nature of the relationship between eukaryotic cells and the bacterial and archaeal components of the microbiota has revealed significant contributions in energy balance, bowel function, immunologic function, sensory perception, glycemic control, and blood pressure regulation. Elucidating the complex interactions between the microbiota and their associated epithelial, immune, and neural cells may provide mechanistic insights and a rational basis for our belief that dietary consumption of probiotic microorganisms and prebiotics produces health benefits.

The appropriate function of insulin-producing pancreatic β-cells is crucial for the regulation of glucose homeostasis, and its impairment leads to diabetes mellitus, the most common metabolic disorder in man. In addition to glucose, the major nutrient factor, inputs from the nervous system, humoral components, and cell-cell communication within the islet of Langerhans act together to guarantee the release of appropriate amounts of insulin in response to changes in blood glucose levels. Data obtained within the past decade in several laboratories have revitalized controversy over the autocrine feedback action of secreted insulin on β-cell function. Although insulin historically has been suggested to exert a negative effect on β-cells, recent data provide evidence for a positive role of insulin in transcription, translation, ion flux, insulin secretion, proliferation, and β-cell survival. Current insights on the role of insulin on pancreatic β-cell function are discussed.

Malonyl-CoA can be formed within the mitochondria, peroxisomes, and cytosol of mammalian cells. Besides being an intermediate in the pathways of de novo fatty acid biosynthesis and fatty acid elongation, malonyl-CoA has an important signaling function through its allosteric inhibition of carnitine palmitoyltransferase 1, the enzyme that normally exerts flux control over mitochondrial β-oxidation. Malonyl-CoA is rapidly turned over in mammalian cells, and the activities of acetyl-CoA carboxylase and malonyl-CoA decarboxylase are important determinants of its cytosolic concentration. It is now recognized that malonyl-CoA participates in a diverse range of physiological or pathological responses and systems. These include the ketogenic response of the liver to fasting and diabetes, carbohydrate versus fat fuel selection in muscle tissues, metabolic changes in muscle during contracture, alterations in fatty acid metabolism during cardiac ischemia and postischemic reperfusion, stimulation of B cell insulin secretion by glucose, and the hypothalamic control of appetite.

In the early 1930s, Banting and Best, the discoverers of insulin, found that choline could prevent the development of fatty liver disease (steatosis) in pancreatectomized dogs treated with insulin. Later work indicated that in rats and mice, diets deficient in labile methyl groups (choline, methionine, betaine, folate) produced fatty liver and that long-term administration of diets deficient in choline and methionine also caused hepatocellular carcinoma. These experiments not only linked steatosis and diabetes but also provided evidence, for the first time, of the importance of labile methyl group balance to maintain normal liver function. This conclusion is now amply supported by the observation of mice devoid of key enzymes of methionine and folate metabolism and in patients with severe deficiencies in these enzymes. Moreover, treatments with various methionine metabolites in experimental animal models of liver disease show hepatoprotective properties.

To maintain normal activity, single cells must assure that their energy needs and utilization are continuously matched. Likewise, multicellular organisms must constantly coordinate energy intake and expenditure to maintain energy homeostasis. The brain, and the hypothalamus in particular, plays a critical role in integrating and coordinating several types of signals, including hormones and nutrients, to guarantee such homeostasis. Like single cells, the hypothalamus also profits from intracellular pathways known to work as fuel sensors to maintain energy balance. One such pathway is the mammalian target of rapamycin (mTOR). mTOR integrates different sensory inputs to regulate protein synthesis rates in individual cells, and it has recently been implicated in the central nervous system to regulate food intake and body weight as well. This review provides an overview of the role of hypothalamic intracellular fuel sensors in the overall control of energy balance and discusses the potential contribution of these fuel-sensing mechanisms to the metabolic dysregulation associated with obesity.

Diet-related mutagenesis plays an etiologic role in chronic diseases, including cardiovascular disease and cancer. Many dietary mutagens are DNA reactive, leading to distinct spectra of base-pair substitution mutations and structural chromosome changes. Examples include aflatoxin B1, ochratoxin A, ptaquiloside, various pyrrolizidine alkaloids, heterocyclic amines including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene. However, endogenously or exogenously formed reactive species, inhibitors of topoisomerase II enzymes (e.g., flavonoids), of DNA repair (e.g., caffeine), or of the mitotic spindle (possibly acrylamide), also cause mutations, including structural chromosome changes and copy number variants. Genomic instability also results from inadequate nutrient intake (e.g., folate and selenium). Antimutagens include vitamin C, carotenoids, chlorophyllin, dietary fibers, and plant polyphenols acting through various mechanisms. Polymorphisms in genes for nutrient uptake, metabolism, and excretion will affect dietary intake in determining individual risk of disease development. Human studies utilizing nutrigenomic/nutrigenetic technologies will be essential to quantifying and overcoming diet-related mutagenesis.

Traits related to energy balance and obesity are exceptionally complex, with varying contributions of genetic susceptibility and interacting environmental factors. The use of mouse models has been a powerful driving force in understanding the genetic architecture of polygenic traits such as obesity. However, the use of mouse models for analysis of complex traits is at an important crossroad. Genome-wide association studies in humans are now leading to direct identification of obesity genes. In this review, we focus on three areas representing the current and future roles of mouse models regarding genetics of complex obesity. First, we summarize increasingly powerful ways to harness the strength of mouse models for discovery of genes affecting polygenic obesity. Second, we examine the status of using a systems biology approach to dissect the genetic architecture of obesity. And third, we explore the effects of recent findings indicating increasing levels of complexity in the nature of variation underlying, and the heritability of, complex traits such as obesity.

Post-translational modifications of histones are the subject of intensive investigations with the aim of decoding how they regulate, alone or in combination, chromatin structure, genomic stability, and gene expression. Major epigenetic programming events take place during gametogenesis and fetal development and are thought to have long-lasting consequences on adult health. Epidemiological and experimental studies have pointed toward maternal nutrition as a major player during prenatal development in influencing disease susceptibility later in life. Although the mechanisms underlying such observations are not well elucidated, epigenetic alterations of histones by particular maternal diets might be of central importance. Moreover, as much as dietary sources can influence epigenetic programming during pregnancy, they have started to be implicated in cancer chemoprevention, via the targeting of reversible epigenetic deregulations at the level of the histones.

Genetic sensitivity to the bitter taste of phenylthiocarbamide and 6-n-propylthiouracil (PROP) is a well-studied human trait. It has been hypothesized that this phenotype is a marker for individual differences in taste perception that influence food preferences and dietary behavior with subsequent links to body weight and chronic disease risk. Steady progress has been made over the past several decades in defining the involvement of this phenotype and its underlying gene, TAS2R38, in this complex behavioral pathway. However, more work needs to be done to fully determine its overall nutritional and health significance. The primary goal of this review is to assess our current understanding of the role of the PROP bitter taste phenotype in food selection and body weight in both children and adults. A brief history of the field is included and controversies surrounding the use of different PROP screening methods are addressed. The contribution of other receptors (both bitter and nonbitter) to human taste variation is also discussed.