Annual Review of Nutrition - Volume 32, 2012

In this biographical article, I describe the evolution of my career in nutrition from an early period as an animal nutritionist interested in amino acid metabolism and genetic variation in nutrient requirements to an involvement in human nutrition and international public health. The career changes were in some respects a mirror of the evolution of nutritional science in my lifetime. I spent my entire career at Cornell University in what I think of as three distinct phases. As a researcher and teacher in the Poultry Science Department, I was able to do research in animal nutrition and witness the rapid industrialization of the production of poultry meat and eggs, helped by the findings of the era of nutrient discovery in nutritional science. Later I had the opportunity to lead the reorganization of human nutrition at Cornell during a period when research in nutritional science turned away from identifying new nutrients and became increasingly concerned with the roles of diet and chronic disease. During this period my research focus evolved as I became interested in aspects of international nutrition problems, particularly the influence of parasitic infections on child health and nutrition. I also became involved nationally in nutrition issues through participation in organizations such as the National Nutrition Consortium, the Food and Nutrition Board, and National Institutes of Health study sections at a time of great ferment in nutrition about the relationship of dietary patterns to health. Finally, I became provost of Cornell University and involved in the administration of a major research university. I describe my career in the context of my origins and early education springing from life on a sustainable family farm in rural Illinois.

The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease.

Mathematical modeling of human energy regulation and body weight change has recently reached the level of sophistication required for accurate predictions. Mathematical models are beginning to provide a quantitative framework for integrating experimental data in humans and thereby help us better understand the dynamic imbalances of energy and macronutrients that give rise to changes in body weight and composition. This review provides an overview of the various approaches that have been used to model body weight dynamics and energy regulation in humans, highlights several insights that these models have provided, and suggests how mathematical models can serve as a guide for future experimental research.

In recent years, increasing awareness of hypomagnesemia has resulted in clinical trials that associate this mineral deficiency with diabetes, metabolic syndrome, and drug therapies for cancer and cardiovascular diseases. However, diagnostic testing for tissue deficiency of magnesium still presents a challenge. Investigations of animal and cellular responses to magnesium deficiency have found evidence of complex proinflammatory pathways that may lead to greater understanding of mediators of the pathobiology in neuronal, cardiovascular, intestinal, renal, and hematological tissues. The roles of free radicals, cytokines, neuropeptides, endotoxin, endogenous antioxidants, and vascular permeability, and interventions to limit the inflammatory response associated with these parameters, are outlined in basic studies of magnesium deficiency. It is hoped that this limited review of inflammation associated with some diseases complicated by magnesium deficiency will prompt greater awareness by clinicians and other health providers and in turn increase efforts to prevent and treat this disorder.

The discovery of multiple selenoproteins has raised tantalizing questions about their role in maintaining normal cellular function. Unfortunately, many of these remain inadequately investigated. While they have a role in maintaining redox balance, other functions are becoming increasingly recognized. As the roles of these selenoproteins are further characterized, a better understanding of the true physiological significance of this trace element will arise. This knowledge will be essential in defining optimum intakes to achieve cellular homeostasis in order to optimize health, including a reduction in cancer, for diverse populations. Human variation in the response to selenium likely reflects significant interactions between the type and amounts of selenium consumed with the genome and a host of environmental factors including the totality of the diet, as discussed in this review.

Maternal adaptations during pregnancy and lactation appear to provide calcium to fetus and neonate without relying on vitamin D or calcitriol. Consequently, the blood calcium, calciotropic hormones, and skeleton appear normal at birth in the offspring of mothers who are severely vitamin D deficient or who lack calcitriol or its receptor. It remains unclear whether skeletal or extraskeletal problems will develop postnatally from exposure to vitamin D deficiency in utero. During the neonatal period, calcitriol-stimulated intestinal calcium absorption becomes the dominant mechanism of calcium delivery. The vitamin D–deficient neonate is at risk to develop hypocalcemia, rickets, and possibly extraskeletal disorders (e.g., type 1 diabetes). Breastfed babies are at higher risk of vitamin D deficiency because normally little vitamin D or 25-hydroxyvitamin D passes into breast milk. Dosing recommendations during pregnancy and lactation should ensure that the baby is born vitamin D sufficient and maintained that way during infancy and beyond.

The chromophore of all known visual pigments consists of 11-cis-retinal (derived from either vitamin A1 or A2) or a hydroxylated derivative, bound to a protein (opsin) via a Schiff base. Absorption of a photon results in photoisomerization of the chromophore to all-trans-retinal and conversion of the visual pigment to the signaling form. Regeneration of the 11-cis-retinal occurs in an adjacent tissue and involves several enzymes, several water-soluble retinoid-binding proteins, and intra- and intercellular diffusional processes. Rod photoreceptor cells depend completely on the output of 11-cis-retinal from adjacent retinal pigment epithelial (RPE) cells. Cone photoreceptors cells can use 11-cis-retinal from the RPE and from a second more poorly characterized cycle, which appears to involve adjacent Müller (glial) cells. Recent progress in the characterization of rod and cone visual cycle components and reactions will result in the development of approaches to the amelioration of blinding eye diseases associated with visual cycle defects.

Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its function has remained elusive. Recent evidence implicates a role of LPL in the brain in two processes: (a) the regulation of energy balance and body weight and (b) cognition. Mice with neuron-specific deletion of LPL have increases in food intake that lead to obesity, and then reductions in energy expenditure that further contribute to and sustain the phenotype. In other mice with LPL deficiency rescued from neonatal lethality by somatic gene transfer wherein LPL in the brain remains absent, altered cognition ensues. Taking into consideration data that associate LPL mutations with Alzheimer's disease, a role for LPL in learning and memory seems likely. Overall, the time is ripe for new insights into how LPL-mediated lipoprotein metabolism in the brain impacts CNS processes and systems biology.

High-density lipoprotein (HDL) levels are inversely associated with coronary heart disease due to HDL's ability to transport excess cholesterol in arterial macrophages to the liver for excretion [i.e., reverse cholesterol transport (RCT)]. However, recent advances highlight additional atheroprotective roles for HDL beyond bulk cholesterol removal from cells through RCT. By promoting cellular free cholesterol (FC) efflux, HDL and its apolipoproteins (apoA-I and apoE) decrease plasma membrane FC and lipid raft content in immune and hematopoietic stem cells, decreasing inflammatory and cell proliferation signaling pathways. HDL and apoA-I also dampen inflammatory signaling pathways independent of cellular FC efflux. In addition, HDL lipid and protein cargo provide protection against parasitic and bacterial infection, endothelial damage, and oxidant toxicity. Here, current knowledge is reviewed regarding the role of HDL and its apolipoproteins in regulating cellular cholesterol homeostasis, highlighting recent advances on novel functions and mechanisms by which HDLs regulate inflammation and hematopoiesis.

Nutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical to facilitate transition of nutritional sciences from population-based to individual-based criteria for nutritional research, assessment, and management. This review addresses progress in making these approaches manageable for nutrition research. Important concept developments concerning the exposome, predictive health, and complex pathobiology serve to emphasize the central role of diet and nutrition in integrated biosystems models of health and disease. Improved analytic tools and databases for targeted and nontargeted metabolic profiling, along with bioinformatics, pathway mapping, and computational modeling, are now used for nutrition research on diet, metabolism, microbiome, and health associations. These new developments enable metabolome-wide association studies (MWAS) and provide a foundation for nutritional metabolomics, along with genomics, epigenomics, and health phenotyping, to support the integrated models required for personalized diet and nutrition forecasting.

Omega-3 polyunsaturated fatty acids (PUFAs) are essential to health, and deficiencies in these PUFAs are linked to chronic disease. Although important insights into the diverse biological roles of PUFAs have been made, the mechanistic basis underlying their protective actions is still emerging. Studies over the past decade have elucidated that omega-3 PUFAs are enzymatically converted into bioactive autacoids that have inflammation-resolving properties. Among these, resolvins have emerged as an important family that has potent and stereospecific immunomodulatory roles, elucidation of which has contributed to a growing body of literature demonstrating that resolution of acute inflammation is an active process. In addition to their direct interactions with immune cells, resolvins have effects on nonimmune cells as well, suggesting a much broader role in biological systems than originally appreciated. In this review, we describe the endogenous biosynthesis and immunomodulatory actions of resolvins and highlight their emerging roles in health and disease.

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is a protein with several suggested functions. Although the first discovery of this molecule as a pre-B-cell colony-enhancing factor suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide generation has considerably widened its potential biological activities. Although originally thought to be produced in adipose tissue (i.e., adipocytes and infiltrating macrophages), its production seems to involve other cells and tissues such as skeletal muscle, liver, immune cells, cardiomyocytes, and the brain. Visfatin/NAMPT has both intracellular and extracellular effects influencing several signaling pathways. Its broad spectrum of effects is mirrored by its potential involvement in a wide range of disorders including human immunodeficiency virus infection, septicemia, myocardial failure, atherosclerosis, metabolic disorders, inflammatory diseases, malignancies, and neurodegenerative disorders and aging. Moreover, studies on visfatin/NAMPT in atherosclerotic disorders suggest a rather complex role of this molecule in pathophysiology, potentially mediating both adaptive and maladaptive responses.

Type 2 diabetes (T2D) is thought to arise from the complex interplay of both genetic and environmental factors. Since the advent of genome-wide association studies (GWAS), we have seen considerable progress in our understanding of the role that genetics and gene-environment interactions play in the development of T2D. Recent work suggests that the adverse effect of several T2D loci may be abolished or at least attenuated by higher physical activity levels or healthy lifestyle, whereas low physical activity and dietary factors characterizing a Western dietary pattern may augment it. However, there still remain inconsistencies warranting further investigation. Lack of statistical power and measurement errors for the environmental factors continue to challenge our efforts for characterizing interactions. Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS. Agnostic approaches to the discovery of gene and environment interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges. Nonetheless, continued investment in gene-environment interaction studies through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors.

The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome.

Excess body weight due to obesity has traditionally been considered to have a positive effect on bone; however, more recent findings suggest that bone quality is compromised. Both obesity and caloric restriction increase fracture risk and are regulated by endocrine factors and cytokines that have direct and indirect effects on bone and calcium absorption. Weight reduction will decrease bone mass and mineral density, but this varies by the individual's age, gender, and adiposity. Dietary modifications, exercise, and medications have been shown to attenuate the bone loss associated with weight reduction. Future obesity and weight loss trials would benefit from assessment of key hormones, adipokine and gut peptides that regulate calcium absorption, and bone mineral density and quality by using sensitive techniques in high-risk populations.

Although obesity is a well-known risk factor for several cancers, its role on cancer survival is poorly understood. We conducted a systematic literature review to assess the current evidence evaluating the impact of body adiposity on the prognosis of the three most common obesity-related cancers: prostate, colorectal, and breast. We included 33 studies of breast cancer, six studies of prostate cancer, and eight studies of colo-rectal cancer. We note that the evidence overrepresents breast cancer survivorship research and is sparse for prostate and colorectal cancers. Overall, most studies support a relationship between body adiposity and site-specific mortality or cancer progression. However, most of the research was not specifically designed to study these outcomes and, therefore, several methodological issues should be considered before integrating their results to draw conclusions. Further research is urgently warranted to assess the long-term impact of obesity among the growing population of cancer survivors.

Frank Burr Mallory's landmark observation in 1911 on the histopathology of alcoholic liver disease (ALD) was the first identification of a link between inflammation and ALD. In this review, we summarize recent advances regarding the origins and roles of various inflammatory components in ALD. Metabolism of ethanol generates a number of metabolites, including acetate, reactive oxygen species, acetaldehyde, and epigenetic changes, that can induce inflammatory responses. Alcohol and its metabolites can also initiate and aggravate inflammatory conditions by promoting gut leakiness of microbial products, by sensitizing immune cells to stimulation, and by activating innate immune pathways, such as complement. Chronic alcohol consumption also sensitizes nonimmune cells, e.g., hepatocytes, to inflammatory signals and impairs their ability to respond to protective signals. Based on these advances, a number of inflammatory targets have been identified with potential for therapeutic intervention in ALD, presenting new opportunities and challenges for translational research.

This review discusses the results of randomized clinical trials of supplemental micronutrients for cancer prevention completed over the past 20 years, including trials of beta-carotene and retinol, vitamins C and E, selenium, folic acid, and vitamin D. Some trials observed significant reductions in risk, whereas others observed significant increases in risk of the primary cancer endpoint. In considering these trials, it appears that supplementation targeted to populations with low status of the nutrient of interest may prevent cancer, whereas supplementation in populations with higher status or to achieve pharmacological exposures may promote cancer. Observational epidemiologic evidence coupled with these trial results supports the concept of a U-shaped curve for micronutrients in relation to cancer prevention. Based on these data, nutrient supplements are not currently recommended for cancer prevention in the general population. The hypothesis that groups with low nutrient status may benefit from supplementation has yet to be formally tested.

With obesity affecting approximately 12.5 million American youth, population-level interventions are indicated to help support healthy behaviors. The purpose of this review is to provide a summary of population-level intervention strategies and specific intervention examples that illustrate ways to help prevent and control obesity in children through improving nutrition and physical activity behaviors. Information is summarized within the settings where children live, learn, and play (early care and education, school, community, health care, home). Intervention strategies are activities or changes intended to promote healthful behaviors in children. They were identified from (a) systematic reviews; (b) evidence- and expert consensus–based recommendations, guidelines, or standards from nongovernmental or federal agencies; and finally (c) peer-reviewed synthesis reviews. Intervention examples illustrate how at least one of the strategies was used in a particular setting. To identify interventions examples, we considered (a) peer-reviewed literature as well as (b) additional sources with research-tested and practice-based initiatives. Researchers and practitioners may use this review as they set priorities and promote integration across settings and to find research- and practice-tested intervention examples that can be replicated in their communities for childhood obesity prevention.

This review summarizes the current data on diabetes risk factors, prevalence, and prevention efforts in Asia and Asian migrant populations. Studies indicate that type 2 diabetes mellitus is a large and growing threat to public health in Asian populations. Furthermore, Asian subgroups (e.g., South Asians/Asian Indians, Chinese) have unique risk factor profiles for developing diabetes, which differ from other populations and between Asian ethnic groups. Lifestyle intervention programs are effective in preventing diabetes in Asians, as with other ethnicities. The strength of these findings is lessened by the lack of systematically collected data using objective measurements. Large epidemiologic studies of diabetes prevalence and risk factor profiles and translational trials identifying sustainable and culturally acceptable lifestyle programs for Asian subgroups are needed.