Annual Review of Nutrition - Volume 42, 2022

After a long career at the National Center for Health Statistics, I retired and joined the Stanford Prevention Research Center as an unpaid associate. I was once described by a former US Food and Drug Administration commissioner as “one of the great epidemiologists.” The chair of the Harvard nutrition department, speaking on National Public Radio, once described my research as “rubbish.” Both may be exaggerations. Here I address some of the events that led to these contrasting descriptions. I also address the extent to which the so-called Matilda effect may have influenced my career. Are women in science on an equal footing with men? The Matilda effect suggests not. Unlike the Matthew effect for scientists, whereby those of higher prestige accrue a disproportionate share of recognition and rewards, the Matilda effect proposes that women scientists are systematically undervalued and underrecognized. I could never get a faculty job and was often treated like an underling. Nonetheless I persevered to publish highly cited research on several high-profile and sometimes controversial topics. Though overt sexism in science and workplaces has diminished over the course of my career, progress toward eliminating unconscious bias has been slower. The Matthew and Matilda effects are still powerful forces that distort incentives and rewards in science.

Glucose-dependent insulinotropic polypeptide (GIP) is released from the upper small intestine in response to food intake and contributes to the postprandial control of nutrient disposition, including of sugars and fats. Long neglected as a potential therapeutic target, the GIPR axis has received increasing interest recently, with the emerging data demonstrating the metabolically favorable outcomes of adding GIPR agonism to GLP-1 receptor agonists in people with type 2 diabetes and obesity. This review examines the physiology of the GIP axis, from the mechanisms underlying GIP secretion from the intestine to its action on target tissues and therapeutic development.

The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.

The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population.

Nonalcoholic fatty liver disease (NAFLD), a spectrum of metabolic liver disease associated with obesity, ranges from relatively benign hepatic steatosis to nonalcoholic steatohepatitis (NASH). The latter is characterized by persistent liver injury, inflammation, and liver fibrosis, which collectively increase the risk for end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. Recent work has shed new light on the pathophysiology of NAFLD/NASH, particularly the role of genetic, epigenetic, and dietary factors and metabolic dysfunctions in other tissues in driving excess hepatic fat accumulation and liver injury. In parallel, single-cell RNA sequencing studies have revealed unprecedented details of the molecular nature of liver cell heterogeneity, intrahepatic cross talk, and disease-associated reprogramming of the liver immune and stromal vascular microenvironment. This review covers the recent advances in these areas, the emerging concepts of NASH pathogenesis, and potential new therapeutic opportunities.

Diet influences onset, progression, and severity of several chronic diseases, including heart failure, diabetes, steatohepatitis, and a subset of cancers. The prevalence and clinical burden of these obesity-linked diseases has risen over the past two decades. These metabolic disorders are driven by ectopic lipid deposition in tissues not suited for fat storage, leading to lipotoxic disruption of cell function and survival. Sphingolipids such as ceramides are among the most deleterious and bioactive metabolites that accrue, as they participate in selective insulin resistance, dyslipidemia, oxidative stress and apoptosis. This review discusses our current understanding of biochemical pathways controlling ceramide synthesis, production and action; influences of diet on ceramide levels; application of circulating ceramides as clinical biomarkers of metabolic disease; and molecular mechanisms linking ceramides to altered metabolism and survival of cells. Development of nutritional or pharmacological strategies to lower ceramides could have therapeutic value in a wide range of prevalent diseases.

The microbial community colonizing the gastrointestinal tract, collectively termed the gut microbiota, is an important element of the host organism due to its impact on multiple aspects of health. The digestion of food, secretion of immunostimulatory molecules, performance of chemical reactions in the intestine, and production of metabolites by the microbiota contribute to host homeostasis and disease. Recent discoveries indicate that these major functions are not constantly performed over the course of a day, but rather undergo diurnal fluctuations due to compositional and biogeographical oscillations in the microbiota. Here, we summarize the characteristics and origins of diurnal microbiome rhythms as well as their functional consequences for the circadian biology of the host. We describe the major known pathways of circadian host-microbiome communication and discuss possible implications of altered diurnal microbiome rhythms for human disease.

The intestinal barrier is essential in early life to prevent infection, inflammation, and food allergies. It consists of microbiota, a mucus layer, an epithelial layer, and the immune system. Microbial metabolites, the mucus, antimicrobial peptides, and secretory immunoglobulin A (sIgA) protect the intestinal mucosa against infection. The complex interplay between these functionalities of the intestinal barrier is crucial in early life by supporting homeostasis, development of the intestinal immune system, and long-term gut health. Exclusive breastfeeding is highly recommended during the first 6 months. When breastfeeding is not possible, milk-based infant formulas are a safe alternative. Breast milk contains many bioactive components that help to establish the intestinal microbiota and influence the development of the intestinal epithelium and the immune system. Importantly, breastfeeding lowers the risk for intestinal and respiratory tract infections. Here we review all aspects of intestinal barrier function and the nutritional components that impact its functionality in early life, such asmicronutrients, bioactive milk proteins, milk lipids, and human milk oligosaccharides. These components are present in breast milk and can be added to milk-based infant formulas to support gut health and immunity.

The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces paradoxical increases in energy intake and expenditure and limits fat deposition while reducing tissue and circulating lipids and enhancing overall insulin sensitivity. In the years following the original 1993 report, a comprehensive effort has been made to understand the nutrient sensing and signaling systems linking reduced dietary methionine to the behavioral, physiological, biochemical, and transcriptional components of the response. Recent work has shown that transcriptional activation of hepatic fibroblast growth factor 21 (FGF21) is a key event linking the MR diet to many but not all components of its metabolic phenotype. These findings raise the interesting possibility of developing therapeutic, MR-based diets that produce the beneficial effects of FGF21 by nutritionally modulating its transcription and release.

Biological sex is a fundamental source of phenotypic variability across species. Males and females have different nutritional needs and exhibit differences in nutrient digestion and utilization, leading to different health outcomes throughout life. With personalized nutrition gaining popularity in scientific research and clinical practice, it is important to understand the fundamentals of sex differences in nutrition research. Here, we review key studies that investigate sex dimorphism in nutrition research: sex differences in nutrient intake and metabolism, sex-dimorphic response in nutrient-restricted conditions, and sex differences in diet and gut microbiome interactions. Within each area above, factors from sex chromosomes, sex hormones, and sex-specific loci are highlighted.

Long noncoding RNAs (lncRNAs) are sensitive to changing environments and play key roles in health and disease. Emerging evidence indicates that lncRNAs regulate gene expression to shape metabolic processes in response to changing nutritional cues. Here we review various lncRNAs sensitive to fasting, feeding, and high-fat diet in key metabolic tissues (liver, adipose, and muscle), highlighting regulatory mechanisms that trigger expression changes of lncRNAs themselves, and how these lncRNAs regulate gene expression of key metabolic genes in specific cell types or across tissues. Determining how lncRNAs respond to changes in nutrition is critical for our understanding of the complex downstream cascades following dietary changes and can shape how we treat metabolic disease. Furthermore, investigating sex biases that might influence lncRNA-regulated responses will likely reveal contributions toward the observed disparities between the sexes in metabolic diseases.

Ferroptosis is a type of regulated cell death characterized by an excessive lipid peroxidation of cellular membranes caused by the disruption of the antioxidant defense system and/or an imbalanced cellular metabolism. Ferroptosis differentiates from other forms of regulated cell death in that several metabolic pathways and nutritional aspects, including endogenous antioxidants (such as coenzyme Q10, vitamin E, and di/tetrahydrobiopterin), iron handling, energy sensing, selenium utilization, amino acids, and fatty acids, directly regulate the cells’ sensitivity to lipid peroxidation and ferroptosis. As hallmarks of ferroptosis have been documented in a variety of diseases, including neurodegeneration, acute organ injury, and therapy-resistant tumors, the modulation of ferroptosis using pharmacological tools or by metabolic reprogramming holds great potential for the treatment of ferroptosis-associated diseases and cancer therapy. Hence, this review focuses on the regulation of ferroptosis by metabolic and nutritional cues and discusses the potential of nutritional interventions for therapy by targeting ferroptosis.

An abundant metal in the human body, iron is essential for key biological pathways including oxygen transport, DNA metabolism, and mitochondrial function. Most iron is bound to heme but it can also be incorporated into iron-sulfur clusters or bind directly to proteins. Iron's capacity to cycle between Fe²⁺ and Fe³⁺ contributes to its biological utility but also renders it toxic in excess. Heme is an iron-containing tetrapyrrole essential for diverse biological functions including gas transport and sensing, oxidative metabolism, and xenobiotic detoxification. Like iron, heme is essential yet toxic in excess. As such, both iron and heme homeostasis are tightly regulated. Here we discuss molecular and physiologic aspects of iron and heme metabolism. We focus on dietary absorption; cellular import; utilization; and export, recycling, and elimination, emphasizing studies published in recent years. We end with a discussion on current challenges and needs in the field of iron and heme biology.

This review traces the discoveries that led to the recognition of selenium (Se) as an essential nutrient and discusses Se-responsive diseases in animals and humans in the context of current understanding of the molecular mechanisms of their pathogeneses. The article includes a comprehensive analysis of dietary sources, nutritional utilization, metabolic functions, and dietary requirements of Se across various species. We also compare the function and regulation of selenogenomes and selenoproteomes among rodents, food animals, and humans. The review addresses the metabolic impacts of high dietary Se intakes in different species and recent revelations of Se metabolites, means of increasing Se status, and the recycling of Se in food systems and ecosystems. Finally, research needs are identified for supporting basic science and practical applications of dietary Se in food, nutrition, and health across species.

Numerous association studies and findings from a controlled feeding trial have led to the suggestion that “processed” foods are bad for health. Processing technologies and food formulation are essential for food preservation and provide access to safe, nutritious, affordable, appealing and sustainable foods for millions globally. However, food processing at any level can also cause negative health consequences that result from thermal destruction of vitamins; formation of toxins such as acrylamide; or excessive intakes of salt, sugar, and fat. Research on ultraprocessed foods centers on food composition and formulation. In addition, many modern food formulations can have poor nutritional quality and higher energy density. We outline the role of processing in the provision of a safe and secure food supply and explore the characteristics of processed foods that promote greater energy intake. Despite the potential for negative health effects, food processing and formulation represent an opportunity to apply the latest developments in technology and ingredient innovation to improve the food supply by creating foods that decrease the risk of overeating.

National dietary surveillance produces dietary intake data used for various purposes including development and evaluation of national policies in food and nutrition. Since 2000, What We Eat in America, the dietary component of the National Health and Nutrition Examination Survey, has collected dietary data and reported on the dietary intake of the US population. Continual innovations are required to improve methods of data collection, quality, and relevance. This review article evaluates the strengths and limitations of current and newer methods in national dietary data collection, underscoring the use of technology and emerging technology applications. We offer four objectives for national dietary surveillance that serve as guiding principles in the evaluation. Moving forward, national dietary surveillance must take advantage of new technologies for their potential in enhanced efficiency and objectivity in data operations while continuing to collect accurate dietary information that is standardized, validated, and publicly transparent.

For three decades, the US Public Health Service has recommended that all persons capable of becoming pregnant consume 400 μg/day of folic acid (FA) to prevent neural tube defects (NTDs). The neural tube forms by 28 days after conception. Fortification can be an effective NTD prevention strategy in populations with limited access to folic acid foods and/or supplements. This review describes the status of mandatory FA fortification among countries that fortify (n = 71) and the research describing the impact of those programs on NTD rates (up to 78% reduction), blood folate concentrations [red blood cell folate concentrations increased ∼1.47-fold (95% CI, 1.27, 1.70) following fortification], and other health outcomes. Across settings, high-quality studies such as those with randomized exposures (e.g., randomized controlled trials, Mendelian randomization studies) are needed to elucidate interactions of FA with vitamin B12 as well as expanded biomarker testing.

Population-based solutions are needed to stabilize and then reverse the continued upward trends in obesity prevalence in the US population and worldwide. This review focuses on the related, urgent issue of disparities in obesity prevalence affecting US racial/ethnic minority and other socially marginalized populations. The review provides background on these disparities from a health equity perspective and highlights evidence of progress in equity-focused obesity efforts. Five recommendations for advancing equity efforts are offered as potential approaches to build on progress to date: (a) give equity issues higher priority, (b) adopt a health equity lens, (c) strengthen approaches by using health equity frameworks, (d) broaden the types of policies considered, and (e) emphasize implementation science concepts and tools. Potential challenges and opportunities are identified, including the prospect of longer-term, transformative solutions that integrate global and national initiatives to address obesity, undernutrition, and climate change.