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.

Little is known about the effects on the skeleton of laparoscopic Roux-en-Y gastric bypass (LRGB) surgery for morbid obesity and subsequent weight loss. We compared 25 patients who had undergone LRGB 11 +/- 3 months previously with 30 obese controls matched for age, gender, and menopausal status. Compared with obese controls, patients post LRGB had significantly lower weight (92 +/- 16 vs. 133 +/- 20 kg; P < 0.001) and body mass index (31 +/- 5 vs. 48 +/- 7 kg/m(2); P < 0.001). Markers of bone turnover were significantly elevated in patients post LRGB compared with controls (urinary N-telopeptide cross-linked collagen type 1, 93 +/- 38 vs. 24 +/- 11 nmol bone collagen equivalents per mmol creatinine; and osteocalcin, 11.6 +/- 3.4 vs. 7.6 +/- 3.6 ng/ml; both P < 0.001). Fifteen patients were studied prospectively for an average of 9 months after LRGB. They lost 37 +/- 9 kg and had a 29 +/- 8% fall in body mass index (both P < 0.001). Urinary N-telopeptide cross-linked collagen type 1 increased by 174 +/- 168% at 3 months (P < 0.01) and 319 +/- 187% at 9 months (P < 0.01). Bone mineral density decreased significantly at the total hip (7.8 +/- 4.8%; P < 0.001), trochanter (9.3 +/- 5.7%; P < 0.001), and total body (1.6 +/- 2.0%; P < 0.05), with significant decreases in bone mineral content at these sites. In summary, within 3 to 9 months after LRGB, morbidly obese patients have an increase in bone resorption associated with a decrease in bone mass. Additional studies are needed to examine these findings over the longer term.

Brain serotonin cocentrations at 1 p.m. were significantly elevated 1 hour after rats received a dose of L-tryptophan (12.5 milligrams per kilogram. intraperitoneally) smaller than one-twentieth of the normal daily dietary intake. Plasma and brain tryptophan levels were elevated 10 to 60 minutes after the injection, but they never exceeded the concentrationis that occur nocturnally in untreated aninmals as result of their normal 24-hour rhythms. These data suggest that physiological changes in plasma tryptophan concentration influenice brain serotonin levels.

Branched-chain amino acids (BCAAs) influence brain function by modifying large, neutral amino acid (LNAA) transport at the blood-brain barrier. Transport is shared by several LNAAs, notably the BCAAs and the aromatic amino acids (ArAAs), and is competitive. Consequently, when plasma BCAA concentrations rise, which can occur in response to food ingestion or BCAA administration, or with the onset of certain metabolic diseases (e.g., uncontrolled diabetes), brain BCAA concentrations rise, and ArAA concentrations decline. Such effects occur acutely and chronically. Such reductions in brain ArAA concentrations have functional consequences: biochemically, they reduce the synthesis and the release of neurotransmitters derived from ArAAs, notably serotonin (from tryptophan) and catecholamines (from tyrosine and phenylalanine). The functional effects of such neurochemical changes include altered hormonal function, blood pressure, and affective state. Although the BCAAs thus have biochemical and functional effects in the brain, few attempts have been made to characterize time-course or dose-response relations for such effects. And, no studies have attempted to identify levels of BCAA intake that might produce adverse effects on the brain. The only "model" of very high BCAA exposure is a very rare genetic disorder, maple syrup urine disease, a feature of which is substantial brain dysfunction but that probably cannot serve as a useful model for excessive BCAA intake by normal individuals. Given the known biochemical and functional effects of the BCAAs, it should be a straightforward exercise to design studies to assess dose-response relations for biochemical and functional effects and, in this context, to explore for adverse effect thresholds.

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In the rat, the injection of insulin or the consumption of carbohydrate causes sequential increases in the concentrations of tryptophan in the plasma and the brain and of serotonin in the brain. Serotonin-containing neurons may thus participate in systems whereby the rat brain integrates information about the metabolic state in its relation to control of homeostatis and behavior.

When plasma tryptophan is elevated by the injection of tryptophan or insulin, or by the consumption of carbohydrates, brain tryptophan and serotonin also rise; however, when even larger elevations of plasma tryptophan are produced by the ingestion of protein-containing diets, brain tryptophan and serotonin do not change. The main determinant of brain tryptophan and serotonin concentrations does not appear to be plasma tryptophan alone, but the ratio of this amino acid to other plasma neutral amino acids (that is, tyrosine, phenylalanine, leucine, isoleucine, and valine) that compete with it for uptake into the brain.We have shown that when plasma tryptophan concentrations rise in rats receiving low doses of tryptophan ( I ) or subconvulsive doses of insulin (2), or in rats consuming a carbohydrate diet (3), brain tryptophan and serotonin concentrations also increase. Such variations in amine concentration reflect the general dependence of the rate of serotonin formation on the degree of saturation of tryptophan hydroxylase, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis ( 4 ) . We suggested that the brain tryptophan elevations were direct responses to the increases in plasma tryptophan, and that, generally, any perturbations which increased plasma tryptophan would similarly increase brain tryptophan and serotonin (3). Since dietary protein should elevate plasma tryptophan both by eliciting insulin secretion and by providing new tryptophan, we anticipated (3) that its consumption should also elevate brain tryptophan and serotonin.We now report that the elective consumption of protein-containing diets may or may not be followed by increases in brain tryptophan and 5-hydroxyindoles, and that this effect of food consumption on the brain is best corre- lated not with plasma tryptophan concentration, per se, but with the ratio of plasma tryptophan to five other neutral amino acids that presumably compete with it for uptake into the brain.Male Sprague-Dawley rats (Charles River Breeding Laboratories) were housed as described in (3). At 9 p.m. the evening before an experiment, the rats were placed in clean cages and deprived of food. Between noon and 3 p.m. the next day, groups of six to eight animals were given free access to one of the following diets: (i) diet 1, a carbohydrate diet (3); (ii) diet 2, diet 1 supplemented with 18 percent casein, dry weight; (iii) diet 3, diet 1 supplemented with an artificial amino acid mixture similar to casein in amino acid content (5), 18 percent dry weigh; (iv) diet 3, but lacking specific amino acids as described below. In all experiments, animals consumed approximately 5 to 7 g of food during the first hour and 3 to 5 g during the second hour. Control rats were fasted and were killed at the beginning of the first hour of the experiment (0-hour control), or 1 or 2 hours later (1-hour and 2-hour controls, respectively). Experimental rats were killed 1 or 2 hours after diet presentation. Blood and brains were collected and prepared as described (3...

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.