Annual Review of Nutrition - Volume 30, 2010

I review here some key developments of personal and professional interest, with special reference to total parenteral nutrition (TPN), an area in which I have been involved from 1937 until recently. As a result of basic and biomedical science advances achieved in university and industrial laboratories in numerous countries, many essential nutrients were identified, synthesized, produced, and provided to patients in safe and effective forms both enterally and parenterally. This period also saw important developments in analytic instrumentation. I have had the privilege of seeing major advances in nutrition during my lifetime, and it is my belief and my hope for the future that with the advent of bowel transplants and tissue growth from cells, TPN will be a temporary measure rather than a lifetime regimen.

Intramuscular triacylglycerol (IMTG) is both a dynamic fat-storage depot that can expand during periods of elevated lipid availability and a fatty acid source that can be utilized during periods of increased energy expenditure in active individuals. Although many studies have investigated the lifestyle determinants of IMTG content, the results are far from consistent, and studies attempting to unravel the mechanisms behind IMTG metabolism are in their infancy. The limited evidence available suggests that the enzymes responsible for skeletal muscle lipolysis and IMTG synthesis play an important role in determining the fate of fatty acids and therefore the concentration of lipid metabolites and insulin sensitivity of skeletal muscle. This review provides a summary of current knowledge on the effects of acute and chronic exercise as well as energy intake and macronutrient composition of the diet upon the metabolism of IMTG and the implications for metabolic health.

Carotenoids affect a rich variety of physiological functions in nature and are beneficial for human health, serving as antioxidants in lipophilic environments and blue light filters in the macula of human retina. These dietary compounds also serve as precursors of a unique set of apo-carotenoid cleavage products, including retinoids. Although knowledge about retinoid biology has tremendously increased, the metabolism of retinoids' parent precursors remains poorly understood. Recently, molecular players in carotenoid metabolism have been identified and biochemically characterized. Moreover, mutations in their corresponding genes impair carotenoid metabolism and induce various pathologies in animal models. Polymorphisms in these genes alter carotenoid and retinoid homeostasis in humans as well. This review summarizes our current knowledge about the molecular/biochemical basis of carotenoid metabolism and particularly the physiological role of carotenoids in retinoid-dependent physiological processes.

The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.G. Mackenzie, and G. Kikuchi. These studies revealed mitochondria as the site of oxidation of one-carbon donors such as serine, glycine, sarcosine, and dimethylglycine. Subsequent work from these laboratories and others demonstrated the participation of folate coenzymes and folate-dependent enzymes in these mitochondrial processes. Biochemical and molecular genetic approaches in the 1980s and 1990s identified many of the enzymes involved and revealed an interdependence of cytoplasmic and mitochondrial one-carbon metabolism. These studies led to the development of a model of eukaryotic one-carbon metabolism that comprises parallel cytosolic and mitochondrial pathways, connected by one-carbon donors such as serine, glycine, and formate. Sequencing of the human and other mammalian genomes has facilitated identification of the enzymes that participate in this intercompartmental one-carbon metabolism, and animal models are beginning to clarify the roles of the cytoplasmic and mitochondrial isozymes of these enzymes. Identifying the mitochondrial transporters for the one-carbon donors and elucidating how flux through these pathways is controlled are two areas ripe for exploration.

Maternal micronutrient requirements during pregnancy increase to meet the physiologic changes in gestation and fetal demands for growth and development. Maternal micronutrient deficiencies are high and coexist in many settings, likely influencing birth and newborn outcomes. The only recommendation for pregnancy currently exists for iron and folic acid use. Evidence is convincing that maternal iron supplementation will improve birth weight and perhaps gestational length. In one randomized trial, iron supplementation during pregnancy reduced child mortality in the offspring compared with the control group. Few other single micronutrients given antenatally, including vitamin A, zinc, and folic acid, have been systematically shown to confer such a benefit. A meta-analysis of 12 trials of multiple micronutrient supplementation compared with iron-folic acid reveals an overall 11% reduction in low birth weight but no effect on preterm birth and perinatal or neonatal survival. Currently, data are unconvincing for replacing supplementation of antenatal iron-folic acid with multiple micronutrients.

Iron and its homeostasis are intimately tied to the inflammatory response. The adaptation to iron deficiency, which confers resistance to infection and improves the inflammatory condition, underlies what is probably the most obvious link: the anemia of inflammation or chronic disease. A large number of stimulatory inputs must be integrated to tightly control iron homeostasis during the inflammatory response. In order to understand the pathways of iron trafficking and how they are regulated, this article presents a brief overview of iron homeostasis. A major focus is on the regulation of the peptide hormone hepcidin during the inflammatory response and how its function contributes to the process of iron withdrawal. The review also summarizes new and emerging information about other iron metabolic regulators and effectors that contribute to the inflammatory response. Potential benefits of treatment to ameliorate the hypoferremic condition promoted by inflammation are also considered.

Iron deficiency (ID) is the most common micronutrient deficiency in the world, with consequences of ID and ID anemia (IDA) in young children including behavioral and cognitive deficits. In turn, lead exposure is one of the most common environmental toxicants affecting children. Elevated blood lead levels (BLLs) in young children are also associated with behavioral and cognitive deficits. The metabolic and physiological connections between iron and lead, including a common route of entry into the body and similar neural targets, suggest a considerable overlap in their effects on functional outcomes. Very few studies have examined the existence of increased susceptibility to lead neurotoxicity in children with ID, but there is evidence that ID and BLL are independently associated with cognition and behavior. Children's susceptibility to both ID and elevated BLLs will likely depend on the timing and severity of both exposures, something that should be investigated systematically.

The human body cannot actively excrete excess iron. As a consequence, iron absorption must be strictly regulated to ensure adequate iron uptake and prevent toxic iron accumulation. Iron absorption is controlled chiefly by hepcidin, the iron-regulatory hormone. Produced by the liver and secreted into the circulation, hepcidin regulates iron metabolism by inhibiting iron release from cells, including duodenal enterocytes, which mediate the absorption of dietary iron. Hepcidin production increases in response to iron loading and decreases in iron deficiency. Such regulation of hepcidin expression serves to modulate iron absorption to meet body iron demand. This review discusses the proteins that orchestrate hepatic hepcidin production and iron absorption by the intestine. Emphasis is placed on the proteins that directly sense iron and how they coordinate and fine-tune the molecular, cellular, and physiologic responses to iron deficiency and overload.

Extensive research within the past two decades has revealed that obesity, a major risk factor for type 2 diabetes, atherosclerosis, cancer, and other chronic diseases, is a proinflammatory disease. Several spices have been shown to exhibit activity against obesity through antioxidant and anti-inflammatory mechanisms. Among them, curcumin, a yellow pigment derived from the spice turmeric (an essential component of curry powder), has been investigated most extensively as a treatment for obesity and obesity-related metabolic diseases. Curcumin directly interacts with adipocytes, pancreatic cells, hepatic stellate cells, macrophages, and muscle cells. There, it suppresses the proinflammatory transcription factors nuclear factor-kappa B, signal transducer and activators of transcription-3, and Wnt/β-catenin, and it activates peroxisome proliferator-activated receptor-γ and Nrf2 cell-signaling pathways, thus leading to the downregulation of adipokines, including tumor necrosis factor, interleukin-6, resistin, leptin, and monocyte chemotactic protein-1, and the upregulation of adiponectin and other gene products. These curcumin-induced alterations reverse insulin resistance, hyperglycemia, hyperlipidemia, and other symptoms linked to obesity. Other structurally homologous nutraceuticals, derived from red chili, cinnamon, cloves, black pepper, and ginger, also exhibit effects against obesity and insulin resistance.

The vitamin A metabolite all-trans-retinoic acid (RA) regulates multiple biological processes by virtue of its ability to regulate gene expression. It thus plays critical roles in embryonic development and is involved in regulating growth, remodeling, and metabolic responses in adult tissues. RA can also suppress carcinoma cell growth and is currently used in treatment of some cancers. Growth inhibition by RA may be exerted by induction of differentiation, cell cycle arrest, or apoptosis, or by a combination of these activities. Paradoxically, in the context of some cells, RA not only fails to inhibit growth but, instead, enhances proliferation and survival. This review focuses on the involvement of RA in regulating apoptotic responses. It includes brief overviews of transcriptional signaling by RA and of apoptotic pathways, and then addresses available information on the mechanisms by which RA induces apoptosis or, conversely, inhibits cell death and enhances survival.

The mammalian target of rapamycin (mTOR) pathway coordinates cell growth in response to nutrient availability. Increasing evidence points to a role for mTOR to also direct whole-body energy balance in response to micronutrient as well as hormonal cues. This positions mTOR as a key central integrator of acute and chronic changes in fuel status. Energy balance is affected by mTOR in several organ systems, including the hypothalamus, where the pathway can modulate feeding. We propose that a greater understanding of this nutrient-sensitive pathway may open the door to more intelligent, effective diet design based on the effects of micronutrients on specific signaling pathways.

Deposition of fat in the fetus increases exponentially with gestational age, reaching its maximal rate—around 7 g/day or 90% of energy deposition—at term. In late pregnancy, many women consuming contemporary Western diets may not be able to meet the fetal demand for n-3 long chain polyunsaturated fatty acids (LCPUFAs) from the diet alone. Numerous mechanisms have evolved to protect human offspring from extreme variation or deficiency in the maternal diet during pregnancy. Maternal adipose tissue is an important source of LCPUFA. Temporal changes in placental function are synchronized with maternal metabolic and physiological changes to ensure a continuous supply of n-3 and n-6 LCPUFA-enriched fat to the fetus. LCPUFA storage in fetal adipose tissue provides an important source of LCPUFA during the critical first months of postnatal life. An appreciation of these adaptations is important in any nutritional strategy designed to improve the availability of fatty acids to the fetus.

The lipin proteins are evolutionarily conserved proteins with roles in lipid metabolism and disease. There are three lipin protein family members in mammals and one or two orthologs in plants, invertebrates, and single-celled eukaryotes. Studies in yeast and mouse led to the identification of two distinct molecular functions of lipin proteins. Lipin proteins have phosphatidate phosphatase activity and catalyze the formation of diacylglycerol in the glycerol-3-phosphate pathway, implicating them in the regulation of triglyceride and phospholipid biosynthesis. Mammalian lipin proteins also possess transcriptional coactivator activity and have been implicated in the regulation of metabolic gene expression. Here we review key findings in the field that demonstrate roles for lipin family members in metabolic homeostasis and in rare human diseases, and we examine evidence implicating genetic variations in lipin genes in common metabolic dysregulation such as obesity, hyperinsulinemia, hypertension, and type 2 diabetes.

The metabolic syndrome is a clustering of cardiovascular risk factors, including insulin resistance, abdominal obesity, dyslipidemia, and hypertension, and is associated with other comorbidities such as a proinflammatory state and nonalcoholic fatty liver disease (NAFLD). Its prevalence is high, especially among developed countries, and mainly reflects overnutrition and sedentary lifestyle. Moreover, the developing countries are not spared, as obesity and its related problems such as the metabolic syndrome are increasing quickly. We review the potential primary role of skeletal muscle insulin resistance in the pathophysiology of the metabolic syndrome, showing that in lean, young, insulin-resistant individuals, impaired muscle glucose transport and glycogen synthesis redirect energy derived from carbohydrate into hepatic de novo lipogenesis, promoting the development of atherogenic dyslipidemia and NAFLD. The demonstration of a link between skeletal muscle insulin resistance and the metabolic syndrome offers opportunities in targeting early defects in muscle insulin action in order to counteract the development of the disease and its related complications.

Through cultural innovation and changes in habitat and ecology, there have been a number of major dietary shifts in human evolution, including meat eating, cooking, and those associated with plant and animal domestication. The identification of signatures of adaptations to such dietary changes in the genome of extant primates (including humans) may shed light not only on the evolutionary history of our species, but also on the mechanisms that underlie common metabolic diseases in modern human populations. In this review, we provide a brief overview of the major dietary shifts that occurred during hominin evolution, and we discuss the methods and approaches used to identify signals of natural selection in patterns of sequence variation. We then review the results of studies aimed at detecting the genetic loci that played a major role in dietary adaptations and conclude by outlining the potential of future studies in this area.

There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and to place these studies in a broader life-course context.

Microarray technology permits the interrogation of nearly all expressed genes under a wide range of conditions. Patterns of gene expression in response to obesity and diabetes have yielded important insights into the pathogenesis of diabetes and its relationship to obesity. In muscle, microarray studies have motivated research into mitochondrial function. In adipose tissue, clues have pointed to the importance of inflammation in obesity. New adipocyte-derived hormones involved in insulin resistance have been found; a notable example is retinol binding protein 4. In liver, genes responsive to master regulators of lipid metabolism have been identified. In β-cells, genes involved in cell survival, cell proliferation, and insulin secretion have been identified. These studies have greatly expanded our understanding of mechanisms underlying the pathogenesis of obesity-induced diabetes. When combined with genetic information, microarray data can be used to construct causal network models linking gene expression with disease.

The incidence and severity of hypertension are affected by nutritional status and intake of many nutrients. Excessive energy intake and obesity are major causes of hypertension. Obesity is associated with increased activity of the renin-angiotensin-aldosterone and sympathetic nervous systems, possibly other mineralcorticoid activity, insulin resistance, salt-sensitive hypertension and excess salt intake, and reduced kidney function. High sodium chloride intake strongly predisposes to hypertension. Increased alcohol consumption may acutely elevate blood pressure. High intakes of potassium, polyunsaturated fatty acids, and protein, along with exercise and possibly vitamin D, may reduce blood pressure. Less-conclusive studies suggest that amino acids, tea, green coffee bean extract, dark chocolate, and foods high in nitrates may reduce blood pressure. Short-term studies indicate that specialized diets may prevent or ameliorate mild hypertension; most notable are the Dietary Approaches to Stop Hypertension (DASH) diet, which is high in fruits, vegetables, and low-fat dairy products, and the DASH low-sodium diet. Long-term compliance to these diets remains a major concern.

Pica, the purposive consumption of nonfood substances, is a millennia-old nutritional enigma. Its worldwide ubiquity, prevalence among pregnant women and children, and association with both positive and negative health outcomes, especially micronutrient deficiencies, underscore the importance of understanding this behavior. Multiple proposed etiologies of pica are reviewed, including cultural expectations, psychological stress, hunger, dyspepsia, micronutrient deficiencies (Fe, Zn, and Ca), and protection against toxins and pathogens. Currently available data, although limited, best support the protection hypothesis as a cause of most types of pica, although some evidence suggests that pagophagy (ice consumption) may occur during iron deficiency. It is possible that the binding capacity of pica substances explains the association with micronutrient deficiencies; earth, starch, etc. may render micronutrients in ingesta unavailable for absorption. Increased research efforts are warranted and must be hypothesis driven, interdisciplinary, and permit the testing of multiple causal inferences.

Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed, as well as the possible exploitation of ECS components as novel drug targets for therapeutic intervention in eating disorders.