Brain tryptophan concentrations and serotonin synthesis ... · raise brain tryptophan and serotonin 2 h later. Brain tryptophan concentrations and serotonin synthesis are thus responsive
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Brain tryptophan concentrations and serotonin synthesisremain responsive to food consumption after the ingestionof sequential meals13
Madelyn H Fernstrom and John D Fernstrom
ABSTRACT The response of brain tryptophan concentra-tion and serotonin synthesis to the ingestion of two sequentialmeals was examined in rats. Fasted rats ingested a carbohy-
drate meal followed 2 h later by a protein-containing meal andwere examined 2 or 4 h after the first meal. Other rats ingesteda protein meal first, followed by a carbohydrate meal. Whenthe carbohydrate meal was fed first, brain tryptophan concen-
trations and serotonin synthesis increased at 2 h; these changeswere reversed at 4 h if the second meal contained protein.When the protein meal was fed first, there were no changes inbrain tryptophan or serotonin at 2 h, and a second carbohydratemeal at 2 h did not raise brain tryptophan or serotonin 2 h later.Carbohydrate ingestion 3 h after a protein meal, however, didraise brain tryptophan and serotonin 2 h later. Brain tryptophan
concentrations and serotonin synthesis are thus responsive tothe sequential ingestion of protein and carbohydrate meals ifthere is a sufficient interval between meals. Am J Clin Nutr
1995;61 :312-9
KEY WORDS Tryptophan, serotonin, brain, rat, diet, di-
etary protein, plasma amino acids, large neutral amino acids
Introduction
The synthesis and release of serotonin by brain neurons is
rapidly influenced by the local tryptophan (Trp) concentration
( 1 , 2). Brain Trp concentrations, in turn, appear to reflect Trpuptake from the circulation; uptake occurs via a transportcarrier, located at the blood-brain barrier (the brain capillaryendothelial cells). The carrier is shared between Trp and sev-
eral other large neutral amino acids (LNAAs) and is competi-tive (3). Changes in the blood concentration of Trp or any of
the other LNAAs can thus alter competition at the transport
sites and thereby influence Trp uptake into brain and brain Trp
concentrations (1).
The ingestion of food is one of the most potent physiological
processes to alter the blood concentrations of Trp and its
rosine, and phenylalanine). By this mechanism, food ingestion
influences serotonin synthesis in brain. It has been observedthat the ingestion of a largely carbohydrate, protein-free meal[the fat content is not important (4)] by fasting rats rapidlyraises brain Trp concentrations and stimulates serotonin syn-
thesis, whereas the consumption of a protein-containing meal
(typically 18-40% protein by wt) fails to raise brain Trp
concentrations or to stimulate serotonin synthesis, despite very
large increments in serum Trp concentrations (1). The carbo-hydrate meal is known to produce its effects on brain Trp and
serotonin via insulin secretion (5), which raises serum Trp
concentrations and lowers the serum concentrations of the
other LNAAs, thereby giving Trp a competitive advantage forbrain transport (1). The protein-containing meal fails to raisebrain Trp concentrations because its ingestion causes serum
Trp concentrations and the concentrations of its transport com-petitors to rise by proportionally similar amounts, resulting in
no net change in competition for uptake. Meal-induced changesin brain Trp concentrations thus appear to be predicted by thealterations produced by the meal in the serum concentration ofTrp relative to that of the other LNAAs, a relationship thatcan be simply expressed as a serum ratio of the Trp con-centration to the sum of the concentrations of the other
LNAAs (Trp/ILNAA); this ratio rises when carbohydrates
are ingested and fails to change after the consumption of
protein-containing meals (1).Over the past decade, the recognition that single meals can
influence serum LNAA concentrations, and thus ultimatelybrain serotonin synthesis, has led to the suggestion that thebrain may use this metabolic and neurochemical cascade tomonitor the recent history of carbohydrate and/or protein
consumption. Indeed, in some hypotheses of macronutrientappetite regulation, brain Trp concentrations and serotonin
synthesis are viewed as fluctuating from meal to meal as a
function of the protein and carbohydrate contents of themeal (6, 7). These food-induced neurochemical changes are
then said to be used by the brain to decide the macronutrient
selection at the next meal.
Appealing though such hypotheses are, they involve a majorassumption regarding food intake and serotonin synthesis,namely that brain Trp uptake and serotonin synthesis can vary
1 From the Departments of Psychiatry, Pharmacology, and Behavioral
Neuroscience, University of Pittsburgh School of Medicine.2 Supported by a grant from the National Institutes of Health (HD24730)
and an NIMH Research Scientist Award (MH00254) to JDF.
3 Address reprint requests to MH Fernstrom, Department of Psychiatry,
University of Pittsburgh School of Medicine, Western Psychiatric Institute
and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213.
FIGURE 1. Effect of ingesting sequential meals of carbohydrates or
carbohydrates and 40% protein on brain tryptophan (Trp) concentrations
and 5-hydroxytryptophan (SHiP) synthesis. A, cerebral cortex; B, hypo-
thalamus. At 2 h: open bar = fasted; shaded bar carbohydrate meal. At
4 h: open bar = fasted; shaded bar two sequential carbohydrate meals;
black bar = carbohydrate meal followed by protein meal. * ,D < 0.05, ** P< 0.01 vs fasted groups at 2 h (t test). * �P < 0.05, ** P < 0.01 vs fastedvalues at 4 h (Newman-Keuls test). .1 ± SEM; n = 7/group.
In this study all animals rapidly consumed all of the food at
both meals. The ingestion of any of the meal pairs raised serum
Trp concentrations significantly over fasting values (Table 1).As in the initial experiments, the ingestion of two sequentialcarbohydrate meals caused the serum Trp/ILNAA to rise
(Table 1). Cortical and hypothalamic Trp concentrations and
TABLE 1
5-Hi? synthesis rates were also significantly elevated above
fasting control values. Also analogous to the first study, inges-tion of an initial carbohydrate meal followed by a 40% protein
meal caused the serum Trp/ILNAA, brain Trp concentrations,
and 5-Hi? synthesis to be at or below fasting control values
(Table 1). The failure of the ratio to exceed fasting values,despite the rise in serum Trp concentrations, was attributable to
the large increase in the serum concentrations of the other
LNAAS. Between these two endpoints, the serum Trp/ILNAAand each of the brain variables could be seen to fall gradually
from the highest values, obtained after two meals of carbohy-
drates, to the lowest values, obtained after ingestion of carbo-
hydrates followed by 40% protein. Of particular note, the
serum Trp/ILNAA and cortical and hypothalamic Trp and5-HTP concentrations were as high when carbohydrates were
followed by a 6% protein meal as the values obtained when two
meals of carbohydrates were ingested. At 12% protein, the
serum Trp/ILNAA and cortical Trp concentrations were sig-
nificantly elevated above fasting concentrations, but hypotha-
lamic Trp and cortical and hypothalamic 5-HTP accumulation
rates were not. At 24% protein, the serum Trp/ILNAA was not
significantly elevated over control values, because the second
meal elevated the serum concentrations of the other LNAAs by
almost as much, proportionally, as the serum Trp concentration
(Table 1). Brain Trp concentrations and 5-HTP synthesis were
also at fasting values. From these studies it is apparent that
when a protein-containing meal is consumed 2 h after a car-
bohydrate meal, the protein content of the second meal must
contain >6% protein to lower Trp concentrations and 5-HTP
synthesis rates in the brain.
Another series of studies examined the ability of a second
meal of carbohydrates to increase the serum Trp/ILNAA and
brain Trp and 5-Hi? concentrations after an initial meal con-
taming protein. As a preliminary step in this study, we evalu-ated the effects of single meals containing different amounts of
protein on the serum Trp/ILNAA, and on cortical and hypo-
thalamic concentrations of Trp and 5-I-ITP synthesis. As antic-
ipated, a single meal of carbohydrates caused all of thesevariables to rise significantly 2 h later (Table 2). Smaller but
nonetheless significant increases were also evident after inges-
Changes in tryptophan (Trp) concentrations and 5-hydroxytryptophan (5-HTP) synthesis rate in cerebral cortex and hypothalamus in rats ingesting a
carbohydrate (CHO) meal followed by a protein-containing meal’
Group Serum lipSerumLNAA
Serum Trp/�LNAA
Trp 5-HTP
Cortex Hypothalamus Cortex Hypothalamus
pjnollL p.snolIL nmol/g �i.molJg protein ng/g p.g/g protein
‘ .1 ± SE. Groups of seven male rats, fasted overnight, ingested at 0 h either no food or 4 g dry wt of one of the diets indicated in the table (all 4 g was
consumed); 90 mm thereafter, all rats received NSD-1015 and were killed 30 mm later. LNAA, large neutral amino acids; CHO, carbohydrate.
2.3 Statistically significant vs no food values (Newman-Keuls test): 2 p < 0.01, �? p < 0.05.
4 Statistically significant vs no food values, P < 0.01 (ANOVA).
tion of the 6% protein meal (except for cortical Trp, which
increased but not significantly so in this experiment). Con-
sumption of the 12%, 24%, or 40% protein meals did not
elevate any of the brain variables above fasting control values,though ingestion of 12% protein did cause a small rise in theserum Trp/ILNAA. Also, the 40% protein meal caused noincrease over fasting values in the serum Trp/�LNAA despitethe large rise in serum Trp concentrations, because of thesubstantial increments in the serum concentrations of the otherLNAAs. Significant reductions in cortical and hypothalamic
concentrations of Trp also occurred (5-Hi? synthesis also
declined, but not significantly so).Other groups of fasted rats were then given an initial meal of
either carbohydrates or 6%, 12%, 24%, or 40% protein. Two
hours later a second meal was offered that consisted of carbo-hydrates only. The rats were killed 2 h after the second meal,
and had received NSD-1015 30 mm beforehand. As in theother studies, serum Trp concentrations rose after the ingestionof each of the meals (Table 3). The serum Trp/ILNAA and
cortical and hypothalamic concentrations of Tip and 5-HTP
were increased at the 4-h time point in animals consuming two
consecutive carbohydrate meals (Table 3). If the rats consumed
TABLE 3
6% protein as their first meal, the serum Trp/ILNAA and all of
the brain variables measured were almost as high after the
ingestion of the second carbohydrate meal as they were when
both meals had been carbohydrate. When the initial meal
contained 12% or 24% protein, the second (carbohydrate) meal
raised the serum Trp/ILNAA above fasting values, but cortical
and hypothalamic Trp concentrations were not significantly
increased, and 5-Hi? accumulation did not rise significantly
over fasting values (for cortex or hypothalamus). At 40%
protein, neither the serum Trp/ILNAA nor any of the brainvariables was significantly increased over fasting values (Table
3). The principal conclusion from these results is that a second
meal of carbohydrates, 2 h after an initial meal of 12-40%
protein, does not significantly increase brain Trp concentra-tions or serotonin synthesis.
A final series of studies was conducted to determine whether
a longer interval between the first and second meals would
allow a second carbohydrate meal to elevate brain Trp and
5-HTP after an initial meal of high protein content (24%
protein). An intermeal period of 3 h was selected. As a pre-
liminary step, we measured cortical and hypothalamic Trp
concentrations and 5-HTP synthesis 3 h after fasting rats re-
Changes in tryptophan (Tm) concentrations and 5-hydroxytryptophan (5-HiP) synthesis rate in cerebral cortex and hypothalamus in rats ingesting a
protein-containing meal followed by a carbohydrate (CHO) meal’
Group
Serum
Trp
Serum
LNAASerum Trp:
�LNAA
Trp 5-HTP
Cortex Hypothalamus Cortex Hypothalamus
pinoliL p.mol/L nmol/g pinolig protein ng/g pg/g protein
‘ .t ± SE. Groups of seven male rats, fasted overnight, ingested at 0 h either no food or 4 g dry wt of one of the diets indicated in the table (all 4 g was
consumed); 150 mm thereafter all rats received NSD-1015 and were killed 30 mm later. CHO, carbohydrate.
2 Statistically significant vs no food values, P < 0.01 (Newman-Keuls test).
3 Statistically significant vs no food values, P < 0.01 (ANOVA).
F 5#{149}474 26.16� 5.88� 8.89� 6.10� 25.79� 22.08�
‘ I ± SE. Groups of seven male rats, fasted overnight, ingested at 0 h 4 g dry wt of either 0% (CHO) or 24% protein. At 3 h the animals received a
second 4-g meal of protein or CHO; 90 mm thereafter all rats received NSD-1015 and were killed 30 mm later. Each rat consumed all of the first and second