John D. Fernstrom

Tyrosine, Phenylalanine, and Catecholamine Synthesis and Function in the Brain

Aromatic amino acids in the brain function as precursors for the monoamine neurotransmitters serotonin (substrate tryptophan) and the catecholamines [dopamine, norepinephrine, epinephrine; substrate tyrosine (Tyr)]. Unlike almost all other neurotransmitter biosynthetic pathways, the rates of synthesis of serotonin and catecholamines in the brain are sensitive to local substrate concentrations, particularly in the ranges normally found in vivo. As a consequence, physiologic factors that influence brain pools of these amino acids, notably diet, influence their rates of conversion to neurotransmitter products, with functional consequences. This review focuses on Tyr and phenylalanine (Phe). Elevating brain Tyr concentrations stimulates catecholamine production, an effect exclusive to actively firing neurons. Increasing the amount of protein ingested, acutely (single meal) or chronically (intake over several days), raises brain Tyr concentrations and stimulates catecholamine synthesis. Phe, like Tyr, is a substrate for Tyr hydroxylase, the enzyme catalyzing the rate-limiting step in catecholamine synthesis. Tyr is the preferred substrate; consequently, unless Tyr concentrations are abnormally low, variations in Phe concentration do not affect catecholamine synthesis. Unlike Tyr, Phe does not demonstrate substrate inhibition. Hence, high concentrations of Phe do not inhibit catecholamine synthesis and probably are not responsible for the low production of catecholamines in subjects with phenylketonuria. Whereas neuronal catecholamine release varies directly with Tyr-induced changes in catecholamine synthesis, and brain functions linked pharmacologically to catecholamine neurons are predictably altered, the physiologic functions that utilize the link between Tyr supply and catecholamine synthesis/release are presently unknown. An attractive candidate is the passive monitoring of protein intake to influence protein-seeking behavior.

A Wearable Electronic System for Objective Dietary Assessment

Dietary reporting by individuals is subject to error (1–3). Therefore, a research program has been initiated to develop a small electronic device to record food intake automatically. This device, which contains a miniature camera, a microphone, and several other sensors, can be worn on a lanyard around the neck. It collects visual data immediately in front of the participant and stores them on a memory card in the device. The data are transferred regularly to the dietitian’s computer for further processing and analysis. The device is designed to be almost completely passive to the participant, and thus hopefully will not intrude on or alter the participant’s eating activities. In addition to this function, in the future the device will have other functions, such as the measurement of physical activity, human behavior, and environmental exposure (e.g., pollutants).

Vitamin D Status and Response to Vitamin D3 in Obese vs. Non-obese African American Children

Background: Serum 25‐hydroxyvitamin D (25(OH)D) is low in obese adults.

Introduction to the symposium

This issue of the Journal contains the proceedings of a symposium, held in Tokyo, Japan, 11–13 September 2008, to honor the discovery a century ago by Kikunae Ikeda, a physical chemist at Tokyo Imperial University, of the active taste principle in a seaweed favored by the Japanese in cooking. The structure of this tastant turned out to be simple, the sodium salt of glutamic acid (monosodium glutamate; MSG). This taste was termed umami (a Japanese word) and is similar to the taste described in English as ‘‘meaty’’ or ‘‘savory.’’ Umami is found as a dominant taste in ripe tomatoes and ripened cheeses such as parmesan. Hence, a pasta meat sauce sprinkled with parmesan or pizza represent clear examples of the umami taste in Western cuisines. It has been just a decade since the International Glutamate Technical Committee (IGTC) last sponsored a major symposium on glutamate (1), which normally might be considered a rather short period of time, given that glutamate might not be expected to be the focus of fervent research activity. The interval between the first and second symposia was 20 y (2). But, as the organizing committee proceeded to construct the 2008 symposium, it quickly became apparent that a robust area of research had budded and flowered in the decade since the last symposium, focused largely on umami taste. The most parsimonious explanation for the increased pace of research is that, since the last symposium, molecular biology intersected with taste biology, with remarkable consequences (3–5). Whereas the notion of taste glutamate (GLU) receptors was in evidence at the last IGTC symposium, data were few, and the molecular biology effort had not begun. The present symposium and proceedings reflect the explosion of taste studies and data since Ikeda’s seminal work. Early studies that led to the demonstration of a specific taste for MSG (umami), based on psychophysical and electrophysiologic approaches, are discussed first (6, 7). Then, a series of articles expands on this issue and, through the lens of molecular biology, reveals the multiple taste receptors for MSG, their underlying transduction mechanisms, their responsiveness to various taste molecules, and the hallmark feature of umami taste, the synergism between MSG and nucleotide monophosphates. (As originally identified by Ikeda, MSG is not the only molecule in foods that imparts the umami taste; nucleotide monophosphates not only induce the umami taste but synergize or amplify the umami taste imparted by MSG) (8– 12). Other articles consider the variability of umami taste among animals and humans [a specific ageusia for umami has been identified in humans (13)] and begin to link this variability to mutations in putative umami receptor genes (14–18). Not surprisingly, given the new molecular toolbox, taste investigators also wondered if umami taste receptors might be found outside of the oral cavity, farther down in the gut. This interest was stimulated by earlier work that suggested that luminal GLU stimulated vagal afferent (sensory) fibers (19), which suggested the existence of some type of transduction mechanism. This issue has been taken up by several groups, and as described in several articles, GLU receptors have now been identified in various portions of the stomach and intestines, and potential physiologic functions have begun to be examined (20, 21). It is of interest that a similar approach has also been undertaken for sweet receptors, with remarkable results; this research was also reported in the symposium (22, 23). Although, understandably, the symposium was dominated by excitement over umami receptors, other areas of GLU research were no less interesting. Functional magnetic resonance imaging studies of the human brain response to umami taste were presented, which showed that brain regions that process taste stimuli (primary, secondary, and tertiary taste cortex and related areas) exhibit characteristic increases in activity when umami is tasted, that taste synergism occurs when MSG and nucleotides are applied to the tongue, and that the cortical responses are further enhanced when umami and nucleotides are paired with consonant smells (eg, vegetable) and diminished when subjects are told they are tasting MSG (thus showing cognitive bias at the cellular level) (24, 25). Clearly, the ultimate perception of the umami taste by the brain involves more than just the taste receptors themselves. Other presentations considered the use of MSG in food in attempts to improve the appetite, food intake, and health of elderly subjects (26). Another role for dietary glutamate in gut function that was discussed at the symposium was metabolic, and this discussion focused on recent findings that almost all glutamate consumed in food, free and protein-bound, is used by the gut to generate energy (27, 28). Dietary glutamate is an important energy substrate in this organ (29). Other metabolic aspects of glutamate that were discussed included functions in hepatocytes and b cells (30, 31). Additionally, 2 presentations involved the metabolic handling of glutamate in the brain (32, 33). This latter issue has been of interest from the dietary perspective, because several decades ago, dietary MSG was proposed to enter blood, cross into brain, and adversely affect neuronal communica-

Can nutrient supplements modify brain function

Over the past 40 y, several lines of investigation have shown that the chemistry and function of both the developing and the mature brain are influenced by diet. Examples are the effect of folate deficiency on neural tube development during early gestation, the influence of essential fatty acid deficiency during gestation and postnatal life on the development of visual function in infants, and the effects of tryptophan or tyrosine intake (alone or as a constituent of dietary protein) on the production of the brain neurotransmitters derived from them (serotonin and the catecholamines, respectively). Sometimes the functional effects are clear and the underlying biochemical mechanisms are not (as with folate and essential fatty acids); in other cases (such as the amino acids tyrosine and tryptophan), the biochemical effects are well understood, whereas the effect on brain function is not. Despite the incomplete knowledge base on the effects of such nutrients, investigators, physicians, and regulatory bodies have promoted the use of these nutrients in the treatment of disease. Typically, these nutrients have been given in doses above those believed to be required for normal health; after they have been given in pure form, unanticipated adverse effects have occasionally occurred. If this pharmacologic practice is to continue, it is important from a public safety standpoint that each nutrient be examined for potential toxicities so that appropriate purity standards can be developed and the risks weighed against the benefits when considering their use.

Large neutral amino acids: dietary effects on brain neurochemistry and function.

The ingestion of large neutral amino acids (LNAA), notably tryptophan, tyrosine and the branched-chain amino acids (BCAA), modifies tryptophan and tyrosine uptake into brain and their conversion to serotonin and catecholamines, respectively. The particular effect reflects the competitive nature of the transporter for LNAA at the blood–brain barrier. For example, raising blood tryptophan or tyrosine levels raises their uptake into brain, while raising blood BCAA levels lowers tryptophan and tyrosine uptake; serotonin and catecholamine synthesis in brain parallel the tryptophan and tyrosine changes. By changing blood LNAA levels, the ingestion of particular proteins causes surprisingly large variations in brain tryptophan uptake and serotonin synthesis, with minimal effects on tyrosine uptake and catecholamine synthesis. Such variations elicit predictable effects on mood, cognition and hormone secretion (prolactin, cortisol). The ingestion of mixtures of LNAA, particularly BCAA, lowers brain tryptophan uptake and serotonin synthesis. Though argued to improve physical performance by reducing serotonin function, such effects are generally considered modest at best. However, BCAA ingestion also lowers tyrosine uptake, and dopamine synthesis in brain. Increasing dopamine function in brain improves performance, suggesting that BCAA may fail to increase performance because dopamine is reduced. Conceivably, BCAA administered with tyrosine could prevent the decline in dopamine, while still eliciting a drop in serotonin. Such an LNAA mixture might thus prove an effective enhancer of physical performance. The thoughtful development and application of dietary proteins and LNAA mixtures may thus produce treatments with predictable and useful functional effects.

Effects of dietary polyunsaturated fatty acids on neuronal function

Diets deficient in linoleic acid (18∶2n−6), or that have unusual ratios of linoleic acid to α-linolenic acid (18∶3n−3) induce changes in the polyunsaturated fatty acid (PUFA) composition of neuronal and glial membranes. Such changes have been linked to alterations in retina and brain function. These functional effects are presumed to follow from the biochemical consequences of modifying membrane PUFA content; known effects include modifications in membrane fludity, in the activities of membrane-associated, functional proteins (transporters, receptors, enzymes), and in the production of important signaling molecules from oxygenated linoleic and α-linolenic acid derivatives. However, despite the demonstration that central nervous system function changes when dietary PUFA intake is altered, and that in general, membrane PUFA content influences membrane functions, little work has focused specifically on brain and retina to reveal the underlying biochemical bases for such effects. This review examines this issue, looking at known effects of dietary PUFA on neurons in both the central and peripheral nervous systems, and attempts to identify some approaches that might promote productive investigation into the underlying mechanisms relating changes in dietary PUFA intake to alterations in neuronal and overall nervous system functioning.

Dietary effects on brain serotonin synthesis: relationship to appetite regulation.

This review summarizes evidence showing that: 1) the synthesis of serotonin in the brain depends directly on the amount of tryptophan available to it from the circulation; 2) tryptophan uptake into brain depends on the blood levels not only of tryptophan, but also of other aromatic and branched-chain amino acids that compete with tryptophan for a common transport carrier into brain; and 3) dietary factors that influence the blood levels of tryptophan and these other amino acids can modify tryptophan uptake into brain, and consequently the rate of serotonin formation. Additionally, data are reviewed that attempt to show that appetite for protein and/or carbohydrates is dependent on the relationship between food intake, plasma amino acid pattern, brain tryptophan uptake, and serotonin synthesis.

Acute tryptophan depletion in bulimia: Effects on large neutral amino acids ☆

Acute tryptophan depletion, which may reduce brain serotonin synthesis in humans, was evaluated in bulimic and normal subjects assessing its effects on the plasma ratio of tryptophan to the sum of the other large, neutral amino acids (TRP/sigma LNAA). Thirteen bulimic and 9 control women ingested an amino acid mixture containing either 2.3 g (control mixture) or 0 g of tryptophan (active mixture), in combination with 100 g of the other amino acids. Six healthy male volunteers were also studied, using a similar mixture containing 4.6 g of tryptophan. Bulimic and control women both experienced sizable reductions in the plasma TRP/sigma LNAA ratio, compared to baseline values, for both the active mixture (10% of baseline) or the control mixture (45% of baseline). For bulimic women, the active mixture produced a significant increase in fatigue and a trend toward increased anxiety and indecisiveness. The control mixture did not maintain baseline TRP/sigma LNAA ratios so we identified a control amino acid mixture that does not cause a drop in the plasma TRP/sigma LNAA ratio when ingested (4.6 g tryptophan in combination with 100 g of other amino acids). An oral, tryptophan-deficient amino acid mixture produced acute, substantial reductions in the plasma TRP/sigma LNAA ratio in all subjects, suggesting that the treatment should reduce brain tryptophan uptake and serotonin synthesis. A control mixture containing tryptophan was also identified that maintains the plasma TRP/sigma LNAA ratio at pretreatment values.

Vitamin D Insufficiency in Preadolescent African-American Children

To determine the proportion of vitamin D insufficiency in 6- to 10-year-old preadolescent African-American children residing in Pittsburgh, Pennsylvania and to estimate their therapeutic response to vitamin D 400 IU/day for 1-month, an open-label pre- and post-comparison of vitamin D status following vitamin D 400 IU daily for 1 month during winter and early spring was conducted. Outcomes included serum calcium, phosphorus, albumin, 25 hydroxyvitamin D [25 (OH) D], 1, 25 dihydroxyvitamin D [1, 25 (OH) 2 D], parathyroid hormone (PTH), and markers of bone turnover (serum bone-specific alkaline phosphatase, osteocalcin, and urine n-telopeptide crosslinked collagen type 1 [NTX]). Dietary intake of vitamin D was assessed using a food frequency questionnaire. Forty-one of the 42 enrolled subjects (mean age: 8.9 ± 1.2 yrs [SD]) were analyzed, and 20/41 (49%) were vitamin D insufficient. Vitamin D insufficient group had a suggestive trend of being older (9.2 ± 1.0 years vs. 8.5 ± 1.3 years, p = 0.06) and more pubertally advanced (Tanner II: 7/20 vs. Tanner II: 1/21, p = 0.02). Mean dietary intake of vitamin D was 277 (146 IU/day (n = 41). Adequate intake for vitamin D (200 IU/day) was not met in 16/41 (39%); however, the dietary intake of vitamin D was not significantly different between the vitamin D insufficient and vitamin D sufficient groups.