Annual Review of Nutrition - Volume 41, 2021

After I studied medicine, my career took an early and unusual course when I was offered a clinical research post in Jamaica dealing with childhood malnutrition, of which I knew nothing. My subsequent nutritional explorations allowed gastrointestinal and metabolic analyses to have an impact on several public health policies. The biggest challenges came from unexpected political demands: coping with poor school performers in the Caribbean; addressing UK public health initiatives in health education; breaking the siege of Sarajevo; developing a Food Standards Agency as a sudden need for Tony Blair as incoming prime minister; dealing with widespread bovine spongiform encephalopathy in Europe; and responding to a United Nations request to assess global malnutrition. This last task revealed the need for a lifelong approach to nutrition, which also encompassed pregnancy. But perhaps the biggest challenge was establishing the criteria for obesity assessment, management, and prevention for policy makers across the globe.

The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status. They facilitate recycling pathways and nitrogen trafficking necessary for catabolism, and they influence redox state and oxidative capacity by altering TCA cycle intermediate concentrations. These functions vary widely by tissue and play emerging roles in disease. This article reviews the roles of anaplerosis and cataplerosis in various tissues and discusses how they alter carbon transitions, and highlights their contribution to mechanisms of disease.

Ketone bodies play significant roles in organismal energy homeostasis, serving as oxidative fuels, modulators of redox potential, lipogenic precursors, and signals, primarily during states of low carbohydrate availability. Efforts to enhance wellness and ameliorate disease via nutritional, chronobiological, and pharmacological interventions have markedly intensified interest in ketone body metabolism. The two ketone body redox partners, acetoacetate and D-β-hydroxybutyrate, serve distinct metabolic and signaling roles in biological systems. We discuss the pleiotropic roles played by both of these ketones in health and disease. While enthusiasm is warranted, prudent procession through therapeutic applications of ketogenic and ketone therapies is also advised, as a range of metabolic and signaling consequences continue to emerge. Organ-specific and cell-type-specific effects of ketone bodies are important to consider as prospective therapeutic and wellness applications increase.

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.

Vitamin A, acting through its metabolite, all-trans-retinoic acid, is a potent transcriptional regulator affecting expression levels of hundreds of genes through retinoic acid response elements present within these genes. However, the literature is replete with claims that consider vitamin A to be an antioxidant vitamin, like vitamins C and E. This apparent contradiction in the understanding of how vitamin A acts mechanistically within the body is a major focus of this review. Vitamin E, which is generally understood to act as a lipophilic antioxidant protecting polyunsaturated fatty acids present in membranes, is often proposed to be a transcriptional regulator. The evaluation of this claim is another focus of the review. We conclude that vitamin A is an indirect antioxidant, whose indirect function is to transcriptionally regulate a number of genes involved in mediating the body's canonical antioxidant responses. Vitamin E, in addition to being a direct antioxidant, prevents the increase of peroxidized lipids that alter both metabolic pathways and gene expression profiles within tissues and cells. However, there is little compelling evidence that vitamin E has a direct transcriptional mechanism like that of vitamin A. Thus, we propose that the term antioxidant not be applied to vitamin A, and we discourage the use of the term transcriptional mediator when discussing vitamin E.

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency.

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid–containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like moleculesinclude palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation.

Proper timing of critical care nutrition has long been a matter of controversy. Critical illness waxes and wanes in stages, creating a dynamic flux in energy needs that we have only begun to examine. Furthermore, response to nutrition support likely differs greatly at the level of the individual patient in regard to genetic status, disease stage, comorbidities, and more. We review the observational and randomized literature concerning timing in nutrition support, discuss mechanisms of harm in feeding critically ill patients, and highlight the role of precision nutrition for moving the literature beyond the realm of blunt population averages into one that accounts for the patient-specific complexities of critical illness and host genetics.

Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO, were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring. Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. In addition, bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity,but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited.

Diet and nutrition are intricately related to cancer prevention, growth, and treatment response. Preclinical rodent models are a cornerstone to biomedical research and remain instrumental in our understanding of the relationship between cancer and diet and in the development of effective therapeutics. However, the success rate of translating promising findings from the bench to the bedside is suboptimal. Well-designed rodent models will be crucial to improving the impact basic science has on clinical treatment options. This review discusses essential experimental factors to consider when designing a preclinical cancer model with an emphasis on incorporatingthese models into studies interrogating diet, nutrition, and metabolism. The aims of this review are to (a) provide insight into relevant considerations when designing cancer models for obesity, nutrition, and metabolism research; (b) identify common pitfalls when selecting a rodent model; and (c) discuss strengths and limitations of available preclinical models.

Because breastfeeding provides optimal nutrition and other benefits for infants (e.g., lower risk of infectious disease) and benefits for mothers (e.g., less postpartum bleeding), many organizations recommend that healthy infants be exclusively breastfed for 4 to 6 months in the United States and 6 months internationally. Recommendations related to how long breastfeeding should continue, however, are inconsistent. The objective of this article is to review the literature related to evidence for benefits of breastfeeding beyond 1 year for mothers and infants. In summary, human milk represents a good source of nutrients and immune components beyond 1 year. Some studies point toward lower infant mortality in undernourished children breastfed for >1 year, and prolonged breastfeeding increases interbirth intervals. Data on other outcomes (e.g., growth, diarrhea, obesity, and maternal weight loss) are inconsistent, often lacking sufficient control for confounding variables. There is a substantial need for rigorous, prospective, mixed-methods, cross-cultural research on this topic.

Two factors intrinsic to health are diet and sleep. These two behaviors may well influence one another. Indeed, that insufficient sleep adversely impacts dietary intakes is well documented. On the other hand, diet may influence sleep via melatonin and its biosynthesis from tryptophan. Experimental data exist indicating that provision of specific foods rich in tryptophan or melatonin can improve sleep quality. Whole diets rich in fruits, vegetables, legumes, and other sources of dietary tryptophan and melatonin have been shown to predict favorable sleep outcomes. Although clinical trials are needed to confirm a causal impact of dietary patterns on sleep and elucidate underlying mechanisms, available data illustrate a cyclical relation between these lifestyle factors. We recommend adopting a healthful diet to improve sleep, which may further promote sustained favorable dietary practices.

This review aims to summarize the effects of intermittent fasting on markers of cardiometabolic health in humans. All forms of fasting reviewed here—alternate-day fasting (ADF), the 5:2 diet, and time-restricted eating (TRE)—produced mild to moderate weight loss (1–8% from baseline) and consistent reductions in energy intake (10–30% from baseline). These regimens may benefit cardiometabolic health by decreasing blood pressure, insulin resistance, and oxidative stress. Low-density lipoprotein cholesterol and triglyceride levels are also lowered, but findings are variable. Other health benefits, such as improved appetite regulation and favorable changes in the diversity of the gut microbiome, have also been demonstrated, but evidence for these effects is limited. Intermittent fasting is generally safe and does not result in energy level disturbances or increased disordered eating behaviors. In summary, intermittent fasting is a safe diet therapy that can produce clinically significant weight loss (>5%) and improve several markers of metabolic health in individuals with obesity.

We review the evolutionary origins of the human diet and the effects of ecology economy on the dietary proportion of plants and animals. Humans eat more meat than other apes, a consequence of hunting and gathering, which arose ∼2.5 Mya with the genus Homo. Paleolithic diets likely included a balance of plant and animal foods and would have been remarkably variable across time and space. A plant/animal food balance of 50/50% prevails among contemporary warm-climate hunter-gatherers, but these proportions vary widely. Societies in cold climates, and those that depend more on fishing or pastoralism, tend to eat more meat. Warm-climate foragers, and groups that engage in some farming, tend to eat more plants. We present a case study of the wild food diet of the Hadza, a community of hunter-gatherers in northern Tanzania, whose diet is high in fiber, adequate in protein, and remarkably variable over monthly timescales.

As ultraprocessed foods (i.e., foods composed of mostly cheap industrial sources of dietary energy and nutrients plus additives) have become more abundant in our food supply, rates of obesity and diet-related disease have increased simultaneously. Food addiction has emerged as a phenotype of significant empirical interest within the past decade, conceptualized most commonly as a substance-based addiction to ultraprocessed foods. We detail (a) how approaches used to understand substance-use disorders may be applicable for operationalizing food addiction, (b) evidence for the reinforcing potential of ingredients in ultraprocessed foods that may drive compulsive consumptions, (c) the utility of conceptualizing food addiction as a substance-use disorder versus a behavioral addiction, and (d) clinical and policy implications that may follow if ultraprocessed foods exhibit an addictive potential. Broadly, the existing literature suggests biological and behavioral parallels between food addiction and substance addictions, with ultraprocessed foods high in both added fat and refined carbohydrates being most implicated in addictive-like eating. Future research priorities are also discussed, including the need for longitudinal studies and the potential negative impact of addictive ultraprocessed foods on children.

Recent dietary reference intake workshops focusing on nutrient requirements in chronic disease populations have called attention to the potential adverse effects of chronic medication use on micronutrient status. Although this topic is mostly ill defined in the literature, several noteworthy drug–nutrient interactions (DNIs) are of clinical and public health significance. The purpose of this narrative review is to showcase classic examples of DNIs and their impact on micronutrient status, including those related to antidiabetic, anticoagulant, antihypertensive, antirheumatic, and gastric acid–suppressing medications. Purported DNIs related to other drug families, while relevant and worthy of discussion, are not included. Unlike previous publications, this review is primarily focused on DNIs that have sufficient evidence supporting their inclusion in US Food and Drug Administration labeling materials and/or professional guidelines. While the evidence is compelling, more high-quality research is needed to establish clear and quantitative relationships between chronic medication use and micronutrient status.

Cardiometabolic disease (CMD) is a leading cause of death worldwide and encompasses the inflammatory metabolic disorders of obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. Flavonoids are polyphenolic plant metabolites that are abundantly present in fruits and vegetables and have biologically relevant protective effects in a number of cardiometabolic disorders. Several epidemiological studies underscored a negative association between dietary flavonoid consumption and the propensity to develop CMD. Recent studies elucidated the contribution of the gut microbiota in metabolizing dietary intake as it relates to CMD. Importantly, the biological efficacy of flavonoids in humans and animal models alike is linked to the gut microbial community. Herein, we discuss the opportunities and challenges of leveraging flavonoid intake as a potential strategy to prevent and treat CMD in a gut microbe–dependent manner, with special emphasis on flavonoid-derived microbial metabolites.

The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds structurally diverse ligands and senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. The AhR is an ancient conserved protein and is widely expressed across different tissues in vertebrates and invertebrates. AhR signaling mediates a wide range of cellular functions in a ligand-, cell type–, species-, and context-specific manner. Dysregulation of AhR signaling is linked to many developmental defects and chronic diseases. In this review, we discuss the emerging role of AhR signaling in mediating bidirectional host–microbiome interactions. We also consider evidence showing the potential for the dietary/microbial enhancement ofhealth-promoting AhR ligands to improve clinical pathway management in the context of inflammatory bowel diseases and colon tumorigenesis.

The gut microbiome plays an integral role in health and disease, and diet is a major driver of its composition, diversity, and functional capacity. Given the dynamic development of the gut microbiome in infants and children, it is critical to address two major questions: (a) Can diet modify the composition, diversity, or function of the gut microbiome, and (b) will such modification affect functional/clinical outcomes including immune function, cognitive development, and overall health? We synthesize the evidence on the effect of nutritional interventions on the gut microbiome in infants and children across 26 studies. Findings indicate the need to study older children, assess the whole intestinal tract, and harmonize methods and interpretation of findings, which are critical for informing meaningful clinical and public health practice. These findings are relevant for precision health, may help identify windows of opportunity for intervention, and may inform the design and delivery of such interventions.