Annual Review of Nutrition - Volume 34, 2014

Long-chain fatty acyl-coenzyme As (CoAs) are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids such as triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs toward or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway arose early during evolution of eukaryotic cells, when it appears to have been involved in the response to glucose starvation and perhaps also in monitoring the output of the newly acquired mitochondria. Due to the advent of hormonal regulation of glucose homeostasis, glucose starvation is a less frequent event for mammalian cells than for single-celled eukaryotes. Nevertheless, the AMPK system has been preserved in mammals where, by monitoring cellular AMP:adenosine triphosphate (ATP) and adenosine diphosphate (ADP):ATP ratios and balancing the rates of catabolism and ATP consumption, it maintains energy homeostasis at a cell-autonomous level. In addition, hormones involved in maintaining energy balance at the whole-body level interact with AMPK in the hypothalamus. AMPK is activated by two widely used clinical drugs, metformin and aspirin, and also by many natural products of plants that are either derived from traditional medicines or are promoted as “nutraceuticals.”

The ability of adipose tissue to adapt to a changing nutrient environment is critical to the maintenance of metabolic control. Nutrient excess and deficiency alter the shape of adipose tissue drastically and trigger many events that are collectively known as adipose tissue remodeling. Remodeling of adipose tissue involves more than adipocytes and is controlled by an extensive network of stromal cells and extracellular matrix proteins. Prominent players in this process are adipose tissue macrophages, which are a specialized leukocyte present in lean and obese states that contributes to adipose tissue inflammation. The interest in adipose tissue remodeling has been accelerated by the current epidemic of obesity and the chronic generation of signals that lead to expansion of adipose tissue. It is clear that evidence of dysfunctional remodeling events is a hallmark of obesity associated with metabolic disease. This review summarizes and highlights the recent work in this area and provides a framework in which to consider how adipose tissue macrophages contribute to the remodeling events in lean and obese states. Advancing our understanding of the involvement of macrophages in adipose tissue remodeling will promote one aspect of the new field of “immunometabolism,” which connects control systems developed for regulation of immunity with those that control metabolism. It will also provide insight into how physiologic and pathophysiologic remodeling differs in adipose tissue and identify potential nodes for intervention to break the link between obesity and disease.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-β) superfamily of signaling molecules. In addition to protean roles in embryonic development, germ-line specification, and cellular differentiation, a central role in iron homeostasis has recently been demonstrated for certain BMPs. Specifically, BMP6 serves to relate hepatic iron stores to the hepatocellular expression of the iron-regulatory hormone hepcidin. This regulation occurs via cellular SMAD-signaling molecules and is strongly modulated by the BMP coreceptor hemojuvelin (HJV). Mutations in certain genes influencing signaling to hepcidin via the BMP/SMAD pathway are associated with human disorders of iron metabolism, such as hereditary hemochromatosis and iron-refractory iron-deficiency anemia. Evidence suggests that signals in addition to iron stores influence hepcidin expression via the BMP/SMAD pathway. This review summarizes the details of BMP/SMAD signaling, with a particular focus on its role in iron homeostasis and iron-related diseases.

Given their similar physiochemical properties, it is a logical postulate that iron and copper metabolism are intertwined. Indeed, iron-copper interactions were first documented over a century ago, but the homeostatic effects of one on the other has not been elucidated at a molecular level to date. Recent experimental work has, however, begun to provide mechanistic insight into how copper influences iron metabolism. During iron deficiency, elevated copper levels are observed in the intestinal mucosa, liver, and blood. Copper accumulation and/or redistribution within enterocytes may influence iron transport, and high hepatic copper may enhance biosynthesis of a circulating ferroxidase, which potentiates iron release from stores. Moreover, emerging evidence has documented direct effects of copper on the expression and activity of the iron-regulatory hormone hepcidin. This review summarizes current experimental work in this field, with a focus on molecular aspects of iron-copper interplay and how these interactions relate to various disease states.

Vitamin D deficiency is prevalent throughout the world, and growing evidence supports a requirement for optimal vitamin D levels for the healthy developing and adult brain. Vitamin D has important roles in proliferation and differentiation, calcium signaling within the brain, and neurotrophic and neuroprotective actions; it may also alter neurotransmission and synaptic plasticity. Recent experimental studies highlight the impact that vitamin D deficiency has on brain function in health and disease. In addition, results from recent animal studies suggest that vitamin D deficiency during adulthood may exacerbate underlying brain disorders and/or worsen recovery from brain stressors. An increasing number of epidemiological studies indicate that vitamin D deficiency is associated with a wide range of neuropsychiatric disorders and neurodegenerative diseases. Vitamin D supplementation is readily available and affordable, and this review highlights the need for further research.

In addition to providing complete postnatal nutrition, breast milk is a complex biofluid that delivers bioactive components for the growth and development of the intestinal and immune systems. Lactation is a unique opportunity to understand the role of diet in shaping the intestinal environment including the infant microbiome. Of considerable interest is the diversity and abundance of milk glycans that are energetically costly for the mammary gland to produce yet indigestible by infants. Milk glycans comprise free oligosaccharides, glycoproteins, glycopeptides, and glycolipids. Emerging technological advances are enabling more comprehensive, sensitive, and rapid analyses of these different classes of milk glycans. Understanding the impact of inter- and intraindividual glycan diversity on function is an important step toward interventions aimed at improving health and preventing disease. This review discusses the state of technology for glycan analysis and how specific structure-function knowledge is enhancing our understanding of early nutrition in the neonate.

Hydrogen sulfide (H2S) has emerged as an important signaling molecule with beneficial effects on various cellular processes affecting, for example, cardiovascular and neurological functions. The physiological importance of H2S is motivating efforts to develop strategies for modulating its levels. However, advancement in the field of H2S-based therapeutics is hampered by fundamental gaps in our knowledge of how H2S is regulated, its mechanism of action, and its molecular targets. This review provides an overview of sulfur metabolism; describes recent progress that has shed light on the mechanism of H2S as a signaling molecule; and examines nutritional regulation of sulfur metabolism, which pertains to health and disease.

Hypoxia develops in white adipose tissue in obese mice, resulting in changes in adipocyte function that may underpin the dysregulation that leads to obesity-associated disorders. Whether hypoxia occurs in adipose tissue in human obesity is unclear, with recent studies contradicting earlier reports that this was the case. Adipocytes, both murine and human, exhibit extensive functional changes in culture in response to hypoxia, which alters the expression of up to 1,300 genes. These include genes encoding key adipokines such as leptin, interleukin (IL)-6, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2), which are upregulated, and adiponectin, which is downregulated. Hypoxia also inhibits the expression of genes linked to oxidative metabolism while stimulating the expression of genes associated with glycolysis. Glucose uptake and lactate release by adipocytes are both stimulated by hypoxia, and insulin sensitivity falls. Preadipocytes and macrophages in adipose tissue also respond to hypoxia. The hypoxia-signaling pathway may provide a new target for the treatment of obesity-associated disorders.

Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross talk between the gastrointestinal tract, which senses the incoming meal; the pancreas, which produces glycemic counterregulatory hormones; and the brain, which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide, as well as the pancreatic hormone amylin, on energy balance and glycemic control.

The cytochrome P450s (CYPs) represent a highly divergent class of enzymes involved in the oxidation of organic compounds. A subgroup of CYPs metabolize ω3-arachidonic and linoleic acids and ω6-docosahexaenoic and eicosapentaenoic polyunsaturated fatty acids (PUFAs) into a series of related biologically active mediators. Over the past 20 years, increasing evidence has emerged for a role of these PUFA-derived mediators in physiological and pathophysiological processes in the vasculature, during inflammation, and in the regulation of metabolism. With recent technological advances and increased availability of lipid mass spectroscopy, we are now starting to discern the patterns of these CYP-PUFA products in health and disease. These analyses not only are revealing the diverse spectrum of lipid nutrients regulated by CYPs, but also clearly indicate that the balance of these mediators changes with dietary intake of different PUFA classes. These findings suggest that we are only just beginning to understand all of the relevant lipid species produced by CYP pathways. Moreover, we are still a long way from understanding the nature and presence of their receptors, their tissue expression, and the pathophysiological processes they regulate. This review highlights these future issues in the context of lipid-metabolizing CYP enzymes, focusing particularly on the CYP450 family of epoxygenases and the lipid mediators they produce.

CD36 (cluster of differentiation 36) is a scavenger receptor that functions in high-affinity tissue uptake of long-chain fatty acids (FAs) and contributes under excessive fat supply to lipid accumulation and metabolic dysfunction. This review describes recent evidence regarding the CD36 FA binding site and a potential mechanism for FA transfer. It also presents the view that CD36 and FA signaling coordinate fat utilization, a view that is based on newly identified CD36 actions that involve oral fat perception, intestinal fat absorption, secretion of the peptides cholecystokinin and secretin, regulation of hepatic lipoprotein output, activation of beta oxidation by muscle, and regulation of the production of the FA-derived bioactive eicosanoids. Thus abnormalities of fat metabolism and the associated pathology might involve dysfunction of CD36-mediated signal transduction in addition to the changes in FA uptake.

Understanding the molecular mechanisms that inform how diet and dietary supplements influence health and disease is an active research area. One such mechanism concerns the role of diet in modulating the activity and function of microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that are involved in posttranscriptional gene silencing and have been shown to control gene expression in diverse biological processes including development, differentiation, cell proliferation, metabolism, and inflammation as well as in human diseases. Recent evidence described in this review highlights how dietary factors may influence cancer, cardiovascular disease, type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease through modulation of miRNA expression. Additionally, circulating miRNAs are emerging as putative biomarkers of disease, susceptibility, and perhaps dietary exposure. Research needs to move beyond associations in cells and animals to understanding the direct effects of diet and dietary supplements on miRNA expression and function in human health and disease.

Extensive human and animal model data show that nutrition and other environmental influences during critical periods of embryonic, fetal, and early postnatal life can affect the development of body weight regulatory pathways, with permanent consequences for risk of obesity. Epigenetic processes are widely viewed as a leading mechanism to explain the lifelong persistence of such “developmental programming” of energy balance. Despite meaningful progress in recent years, however, significant research obstacles impede our ability to test this hypothesis. Accordingly, this review attempts to summarize progress toward answering the following outstanding questions: Is epigenetic dysregulation a major cause of human obesity? In what cells/tissues is epigenetic regulation most important for energy balance? Does developmental programming of human body weight regulation occur via epigenetic mechanisms? Do epigenetic mechanisms have a greater impact on food intake or energy expenditure? Does epigenetic inheritance contribute to transgenerational patterns of obesity? In each case, significant obstacles and suggested approaches to surmounting them are elaborated.

Plasma levels of triacylglycerols and diacylglycerols, the lipoproteins that transport them, and proteins involved in their absorption from the intestinal lumen fluctuate in a circadian manner. These changes are likely controlled by clock genes expressed in the intestine that are probably synchronized by neuronal and humoral signals from the suprachiasmatic nuclei, which constitute a master clock entrained by light signals from the eyes and from the environment, e.g., food availability. Acute changes in circadian rhythms—e.g., due to nonsynchronous work schedules or a transcontinental flight—may trigger intestinal discomfort. Chronic disruptions in circadian control mechanisms may predispose the individual to irritable bowel syndrome, gastroesophageal reflux disease, and peptic ulcer disease. A more detailed understanding of the molecular mechanisms underlying temporal changes in intestinal activity might allow us to identify novel targets for developing therapeutic approaches to these disorders.

Calcium and bone metabolism remain key concerns for space travelers, and ground-based models of space flight have provided a vast literature to complement the smaller set of reports from flight studies. Increased bone resorption and largely unchanged bone formation result in the loss of calcium and bone mineral during space flight, which alters the endocrine regulation of calcium metabolism. Physical, pharmacologic, and nutritional means have been used to counteract these changes. In 2012, heavy resistance exercise plus good nutritional and vitamin D status were demonstrated to reduce loss of bone mineral density on long-duration International Space Station missions. Uncertainty continues to exist, however, as to whether the bone is as strong after flight as it was before flight and whether nutritional and exercise prescriptions can be optimized during space flight. Findings from these studies not only will help future space explorers but also will broaden our understanding of the regulation of bone and calcium homeostasis on Earth.

Decisions related to a spectrum of nutrition-related public health and clinical concerns must consider many factors and are best informed by evaluating the totality and quality of the evidence. Systematic review (SR) is a structured process to evaluate, compare, and synthesize relevant evidence for the SR-specific question(s). Applications of SR are exemplified here through the discussion of four case studies: research agendas, nutrient reference intakes, dietary guidance, and practice guidelines. Concerns that SR cannot be effectively applied to nutrition evidence because of the lack of an unexposed comparator and the complex homeostasis in nutrition are discussed. Central to understanding the applicability of SR is its flexibility in defining key inclusion criteria and rigorous elements as appropriate for the SR-specific question(s). Through the reduction of bias and random error by explicit, reproducible, comprehensive, and rigorous examination of all of the evidence, SR informs the scientific judgment needed for sound evidence-based public health nutrition.

Launching a new food/dietary supplement into the US market can be a confusing process to those unfamiliar with the food industry. Industry capability and product specifications are initial determinants of whether a candidate product can be manufactured in a reproducible manner and whether pilot production can be brought up to the market scale. Regulatory issues determine how a product can be produced and marketed; the primary federal institutions involved in regulations are the US Department of Agriculture, the Food and Drug Administration, and the Federal Trade Commission. A primary distinction is made between food and drugs, and no product may enter the food market if it is in part or whole a drug. Product safety is a major concern, and myriad regulations govern the determination of safety. New foods/dietary supplements are often marketed by health claims or structure/function claims, and there are specific regulations pertaining to claims. Not understanding the regulatory issues involved in developing a new product or failing to comply with associated regulations can have legal and financial repercussions.