Effects of a caloric restriction weight loss diet on tryptophan

Eur J Nutr
DOI 10.1007/s00394-014-0690-3
ORIGINAL CONTRIBUTION
Effects of a caloric restriction weight loss diet on tryptophan
metabolism and inflammatory biomarkers in overweight adults
Barbara Strasser • Ken Berger • Dietmar Fuchs
Received: 10 January 2014 / Accepted: 20 March 2014
Ó Springer-Verlag Berlin Heidelberg 2014
Abstract
Purpose Recent data suggest that chronic low-grade
inflammation, a characteristic of obesity, is associated with
altered tryptophan (Trp) and tyrosine (Tyr) metabolism and
plays a role in neuropsychiatric symptoms. The present
study assessed the effect of an extreme short-term diet on
Trp breakdown and inflammatory biomarkers in overweight adults.
Methods Thirty-eight overweight participants (16
women, 22 men; average body mass index: 29 kg/m2,
mean age 52.8 years) were randomized into two diet
groups: a very low kcal diet group (VLCD; Ø 600 kcal/
day, n = 21) and a low kcal diet group (LCD; Ø
1,200 kcal/day, n = 17). Assays included the measurement
of Trp, kynurenine (Kyn), and their ratio, neopterin,
phenylalanine (Phe), Tyr, as biologic markers; leptin,
plasma insulin, glucose, and homeostatic model assessment-insulin resistance; and interleukin 6, tumor necrosis
factor alpha, and C-reactive protein, as biochemical and
inflammatory markers at baseline and after 2 weeks of
treatment.
Results Weight loss diet lowered leptin levels in both
groups by 46 %, although not reaching significance. Trp
and Kyn decreased significantly by 21 and 16 % for VLCD
and by 15 and 17 % for the LCD group, respectively. A
significant reduction in Phe was only seen after VLCD.
B. Strasser (&) K. Berger
Institute for Nutritional Sciences and Physiology, University for
Health Sciences, Medical Informatics and Technology, Eduard
Wallnoefer-Zentrum 1, 6060 Hall in Tirol, Austria
e-mail: [email protected]
D. Fuchs
Division of Biological Chemistry, Biocenter, Medical University
Innsbruck, Innsbruck, Austria
Inflammatory biomarkers, neopterin, and Tyr were not
significantly altered during the study period. Leptin was
significantly correlated with Trp breakdown before and
after the intervention (P \ 0.02).
Conclusions Since disturbed metabolism of Trp affects
biosynthesis of serotonin and might be associated with
increased susceptibility for mood disturbances and carbohydrate craving, strategies to supplement Trp while dieting
could be highly useful in treating uncontrolled weight gain
or in preventing neuropsychiatric symptoms.
Keywords
Mood
Diet Leptin Tryptophan Inflammation Introduction
Both overweight and obesity are characterized by the
accumulation of body fat mostly due to over nutrition and a
lack of physical exercise. Obesity is an important risk
factor for low-grade inflammation, which is thought to
partly explain the excess risk of cardiovascular disease
associated with obesity [1]. It is proposed that hypertrophied adipocytes with large triglyceride stores will have a
high lipolytic rate. They will produce more leptin and less
adiponectin, two important adipokines that influence
inflammation and overall carbohydrate and lipid metabolism [2]. Several adipocytokines, including interleukin 6
(IL-6) and tumor necrosis factor alpha (TNF-a), are produced in adipose tissue and induce hepatic production of
C-reactive protein (CRP) [3].
As a precursor for serotonin and melatonin, the essential
amino acid tryptophan (Trp) is a key player in caloric
intake regulation [4]. Tryptophan can be metabolized
through different pathways, a major route being the
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Eur J Nutr
kynurenine (Kyn) pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated
by inflammatory molecules. Thus, the Kyn pathway is
often systematically up-regulated when the immune
response is activated. Over nutrition leads to an excess
intake of Trp as component of proteins [4, 5]. Obesityrelated systemic inflammation has been associated with the
development of the metabolic syndrome. Thereby, the Kyn
pathway is induced [6], and the ratio of Kyn to Trp concentrations reflects the Trp breakdown rate and elevation of
which is often linked with conditions of inflammation [7].
Data indicate significant relationships between cytokineinduced alterations of Trp and Kyn and the occurrence of
neuropsychiatric symptoms that are associated with a
variety of chronic inflammatory conditions [7, 8].
Weight loss in obese individuals has been shown to
improve or prevent many of the aforementioned conditions.
Bariatric surgical intervention in patients with adiposity
was found not to improve tryptophan breakdown rates and
other signs of immune activation and inflammation [4],
whereas caloric restriction is known to be a strong activator
of protective metabolic pathways, thereby leading to lower
blood pressure, improved blood lipids, and reduced
inflammatory markers, including CRP [9]. Still, little is
known about the effects of an extreme short-term hypocaloric diet on Trp metabolism and changes in inflammatory biomarkers. The present study assessed the effect of
a 2-week caloric restriction weight loss diet on Trp
breakdown, leptin, and inflammatory biomarkers in overweight adults.
Methods
Study population
We randomized 27 overweight and 11 obese participants
(22 men and 16 women, mean age 52.8 ± 9.1 years) from
the health center Lanserhof, Innsbruck–Lans, into two diet
groups: a very low kcal diet group (VLCD; Ø 600 kcal/
day) and a low kcal diet group (LCD; Ø 1,200 kcal/day).
Only healthy subjects with BMI [ 25 kg/m2 between the
ages of 35 and 70 years were accepted for the study. A
physician performed physical examinations on all subjects
before the study. Subjects were excluded if they consume
any anti-inflammatory drugs (e.g., ibuprofen or aspirin) or
supplements (such as antioxidants or fish-oil capsules).
None from either group was involved in regular training
programs. Measurements of energy intake, body composition, and biologic markers were conducted in all subjects
before and after a 2-week energy restriction intervention
period.
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The Ethics Committee at the Medical University Innsbruck approved the study protocol. The purpose, nature,
and potential risks of the study were explained to the
participants before obtaining their written consent.
Dietary program
Prior to the study, all subjects kept a 3-day food record.
Subjects of LCD and subjects of VLCD were placed on a
1,200- and 600-kcal diet per day, respectively. Subjects
were instructed on portion sizes and how to record dietary
intake using a daily dietary protocol. Compliance with the
diet was measured in all subjects by random 24-h dietary
recalls. The dietary menu was based on 50 energy percent
carbohydrates, 30 energy percent proteins, and 20 energy
percent fat.
Anthropometric measurements
Measures of participants’ weight and height were obtained
using standardized methods. Body mass index (BMI) has
been calculated as body weight in kilograms divided by
height in meters squared. Prior to and at the end of the
study, all subjects were tested for body fat (in percent of
body weight) and muscle mass (kg) using the bioelectrical
impedance analysis method (BodyComp v 8.5, MEDI-CAL
Health care).
Laboratory determinations
Fasting blood samples were collected between 8:00 a.m.
and 9:30 a.m. for the measurement of serum inflammatory
markers and selected amino acids relevant for neurotransmitter biochemistry. Samples were stored at -80 °C until
thawed for biologic assays. Serum concentrations of IL-6
and TNF-a were assayed by ELISA (R&D Systems, Biomedica, Vienna, Austria). CRP was measured by immunoturbidimetric method Tina-quant (gen.3) on analyzer
Roche/Modular (Roche Diagnostics, Basel, Switzerland).
Leptin was measured by ELISA (R&D Systems). Inter- and
intraassay variability was reliable \10 %. Plasma insulin
was measured by ELISA (Mercodia, Uppsala, Sweden),
plasma glucose by the glucose hexokinase method.
Homeostatic model assessment-insulin resistance (HOMAIR) was calculated using the formula by Mathews et al.
[10]. Neopterin concentrations were measured by ELISA
(BRAHMS Diagnostics, Hennigsdorf, Germany). Serum
concentrations of free Trp and Kyn as well as concentrations of phenylalanine (Phe) and tyrosine (Tyr) were
determined by high-performance liquid chromatography,
as described elsewhere [11]. The ratios of Kyn/Trp and
Eur J Nutr
Table 1 Anthropometric characteristics before and after a 2-week
very low kcal diet (VLCD) or low kcal die (LCD) in 38 overweight
subjects (mean ± SD)
VLCD
(n = 21)
LCD
(n = 17)
Table 2 Biologic markers before and after a 2-week very low kcal
diet (VLCD) or low kcal die (LCD) in 38 overweight subjects
(mean ± SD)
P#
VLCD
(n = 21)
LCD
(n = 17)
CRP (mg/L)
BMI (kg/m2)
Before
29.0 ± 4.35
After
28.1 ± 4.07*
28.84 ± 4.26
27.9 ± 4.16*
n.s.
BW (kg)
Before
5.32 ± 0.63
5.17 ± 0.80
After
4.94 ± 0.67
5.14 ± 0.59
P*
n.s.
n.s.
IL-6 (pg/mL)
Before
87.3 ± 20.4
89.1 ± 17.6
After
84.5 ± 19.6*
86.3 ± 16.7*
n.s.
BF (%)
Before
34.3 ± 6.02
30.3 ± 8.60
After
32.1 ± 6.12*
28.6 ± 8.99*
Before
29.8 ± 7.92
33.3 ± 6.35
After
29.9 ± 8.10
33.2 ± 6.37
Before
9.27 ± 19.5
11.1 ± 17.0
After
9.41 ± 12.9
20.8 ± 38.9
P*
n.s.
n.s.
TNF-a (pg/mL)
n.s.
MM (kg)
Before
7.90 ± 13.5
8.41 ± 19.9
After
3.16 ± 1.69
18.2 ± 37.9
P*
n.s.
n.s.
Leptin (ng/mL)
n.s.
BMI body mass index, BW body weight, BF (%) percentage body fat,
MM muscle mass, n.s. not significant
* Difference in each group before and after a 2-week caloric
restriction diet; * P \ 0.05, statistically significant
#
Difference between groups at baseline and after a 2-week caloric
restriction diet
Phe/Tyr were calculated as indexes of Trp breakdown and
phenylalanine hydroxylase (PAH) activity, respectively.
Statistical analysis
All statistical analyses were carried out using SPSS Statistics 20.0 for Windows. Normal distribution of all measures was controlled by the Kolmogorov–Smirnov test.
Differences between groups were analyzed by the unpaired
t test. For non-normal distribution, the Mann–Whitney
U test was used. Differences within groups were analyzed
by the paired t test. For non-normal distribution, the Wilcoxon test was used. We used Spearman’s rank correlation
coefficient to assess the relationship between two variables.
P values below 0.05 were considered statistically
significant.
Results
Before
11.6 ± 13.0
11.9 ± 13.9
After
6.36 ± 7.18
6.35 ± 6.30
P*
n.s.
n.s.
Glucose (mg/dL)
Before
110 ± 21.67
113 – 21.4
After
106 ± 26.2
101 – 20.0
P*
n.s.
0.04
HOMA-IR
Before
4.36 ± 10.6
5.56 ± 12.16
After
6.59 ± 19.0
8.96 ± 15.94
P*
n.s.
n.s.
Before
51.4 – 8.71
51.1 – 8.16
After
40.8 – 7.64
43.4 – 10.3
P*
0.003
0.04
Before
2.31 – 0.55
2.56 – 0.77
After
1.94 – 0.56
2.13 – 0.57
P*
0.05
0.05
Tryptophan (lmol/L)
Kynurenine (lmol/L)
Kyn/Trp (lmol/mmol)
Before
45.8 ± 13.0
50.9 ± 16.6
After
48.9 ± 16.1
49.7 ± 9.60
P*
n.s.
n.s.
Neopterin (nmol/L)
Before
7.63 ± 3.41
7.54 ± 2.28
After
7.37 ± 2.60
7.14 ± 1.83
P*
n.s.
n.s.
Phenylalanine (lmol/L)
Before
67.3 – 10.1
61.0 ± 9.17
After
60.2 – 9.23
59.64 ± 8.73
P*
0.02
n.s.
Tyrosine (lmol/L)
At study entry, both caloric restriction diet groups had
similar profiles for body composition, summarized in
Table 1. Under diet, body weight and percentage body fat
decreased significantly in both groups, but there was no
significant difference observed between groups. Subjects in
VLCD and LCD lost 2.75 ± 1.60 kg (mean water loss
0.7 kg) and 2.80 ± 1.33 kg (mean water loss 1.0 kg) body
weight and 2.14 ± 1.49 and 1.72 ± 1.33 % body fat,
Before
54.1 ± 9.87
52.7 ± 11.6
After
50.0 ± 9.01
48.9 ± 7.72
P*
n.s.
n.s.
All differences between groups at baseline and after a 2-week caloric restriction diet
were not significant
CRP C-reactive protein, IL-6 interleukin 6, Kyn/Trp kynurenine/tryptophan, n.s. not
significant
* Difference in each group before and after a 2-week caloric restriction diet
Significant differences of concentrations within groups are indicated in bold
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Fig. 1 Amino acid
concentrations before and after
a 2-week very low kcal diet
(VLCD) or low kcal die (LCD)
in 38 overweight subjects. Data
are shown in mean ± SD;
P \ 0.05, statistically
significant; n.s. not significant
respectively. There were no significant changes of muscle
mass for both groups.
Data for biologic markers are shown in Table 2. Fasting
blood glucose declined significantly (P \ 0.05) in the LCD
group with no significant changes in insulin sensitivity in
both groups after 2 weeks of caloric restriction. Weight
loss diet lowered leptin levels in both groups, although not
reaching the level of significance. Inflammatory biomarkers were not significantly altered during the trial, although
there was a tendency toward an increase in IL-6 and TNF-a
in the LCD group. Trp and Kyn concentrations decreased
significantly by 21 and 16 % for VLCD and by 15 and
17 % for the LCD group, respectively, with no significant
difference between groups. The ratio of Kyn/Trp concentrations did not change significantly in both groups. A
significant reduction in Phe concentrations was only seen
after VLCD. Neopterin and Tyr levels remained unchanged
during the trial (Fig. 1).
At baseline, there was a significant positive relationship
between the BMI of participants and serum concentrations
of leptin, CRP, and Kyn. In addition, there was a trend for a
positive relationship between muscle mass and Trp concentrations. Leptin was significantly positive correlated
with serum TNF-a (r = 0.33, P \ 0.05) and CRP
(r = 0.36, P \ 0.03) before the intervention; however, no
correlation with inflammatory markers was seen after
2 weeks of caloric restriction. Further, leptin was significantly correlated with tryptophan breakdown (Kyn/Trp)
before and after the intervention (r = 0.39, P \ 0.02 and
r = 0.43, P \ 0.01, respectively). Collectively, neopterin
concentrations were significantly positive correlated with
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Kyn/Trp and Phe/Tyr concentrations, the latter being
indicative for PAH activity.
Discussion
The present study assessed the effect of an extreme
2-week caloric restriction weight loss diet on Trp and Kyn
concentrations and inflammatory biomarkers in overweight adults. The associations of obesity and leptin with
cardiovascular, endocrine, and inflammatory processes
have been described. Leptin is responsible for energy
regulation and satiety, thus is strongly correlated to body
fat [12]. A reduction in elevated leptin concentrations in
the circulation can improve blood lipid levels, blood
pressure, and insulin sensitivity [13]. In our study, caloric
restriction diet lowered leptin levels in overweight adults
by 46 %, whereas inflammation and insulin sensitivity
remained unchanged. The aim of a recent study was to
investigate the effect of a 12-week very low caloric diet
(800 kcal/d) on insulin sensitivity and inflammatory
parameters in obese subjects [14]. In this study by Oberhauser et al. [14] despite a significant decrease in leptin
levels and improvement of insulin sensitivity, biomarkers
of inflammation did not change throughout the study
period, suggesting that inflammation is not a major contributor to the development of insulin resistance. On the
other hand, hyperinsulinemia per se can produce an
increase in plasma IL-6 and TNF-a [15], and this can
potentially contribute to the low-grade inflammation seen
in obesity. Thus, one possible reason for the mean
Eur J Nutr
increases in TNF-a and IL-6 in the LCD after 2 weeks of
treatment might be the rise in fasting plasma insulin
(?83 %) observed only in the LCD group. In our study,
baseline BMI was positively associated with leptin, CRP,
and Kyn concentrations, while leptin levels were positively correlated with serum TNF-a, CRP and with Kyn/
Trp, reflecting tryptophan breakdown. However, with the
exception of the relationship between leptin and Kyn/Trp,
these associations disappeared after 2 weeks of caloric
restriction diet, supporting the hypothesis that chronic
low-grade inflammation is associated with altered Trp
metabolism. In addition to its function in metabolic control, leptin has been recognized as a more complex hormone involved in regulating stress responses in the
hypothalamic–pituitary–adrenal (HPA) axis. A large
population-based study found a fourfold increased risk for
depressed mood in men with elevated leptin levels [16].
Trp concentrations decreased significantly with a caloric
restriction weight loss diet, and lowest Trp concentrations
were observed in the group of individuals with the lowest
calorie intake. The decline of Trp levels can be referred to
its reduced intake during caloric restriction diet; it was
unrelated to the immune activation status of individuals,
which remained unchanged. There was also no increase or
decrease in neopterin concentrations, which usually
accompany changes of Kyn/Trp during inflammatory
conditions [17]. Data correspond well to earlier findings
that different diet forms did not influence serum neopterin
concentrations [18].
Disturbed metabolism of Trp affects biosynthesis of
neurotransmitter 5-hydroxytryptamine (5-HT) [19], and it
appears to be associated with an increased susceptibility for
depression [17, 20]. Because Trp is precursor in various
biochemical pathways, e.g., it is hydroxylated by tryptophan-5-hydroxylase (T5H) into the intermediate product
5-hydroxy-tryptophan, which by decarboxylation is further
converted to neurotransmitter 5-HT (serotonin), and
because substrate saturation of T5H is only about 50 %
[21], changes in plasma Trp levels may have an immediate
impact on brain serotonin levels. Such conclusion is further
supported by experiments using acute Trp depletion [22].
In addition, Trp competes with the other large neutral
amino acids (LNAA) valine, leucine, isoleucine, Tyr, and
Phe for transport across the blood–brain barrier. Since
plasma amino acids change in obese persons on hypocaloric diet, a decrease in Trp–LNAA ratio may further
influence serotonin synthesis [23]. Thus, the dietary intervention in our study would affect not only Trp concentrations but also other amino acids concentrations; still, the
Trp availability to the brain would decline. Evidence suggests that women appear more vulnerable than men both to
the diet-induced reductions in Trp and to its consequences
for brain serotonin function [19].
BMI
Diet
Weight
Craving
Loss
Leptin
Mood
TRP
Fig. 2 Vicious cycle underlying weight gain (yo–yo effect): possible
impact of a caloric restriction weight loss diet on mood and hence
carbohydrate craving leading to overweight, mediated by modulation
of tryptophan metabolism and leptin response
An association between mood disturbance, the inability
to lose or to stop gaining weight, and a craving for carbohydrates is manifested by many people who are overweight or are becoming so [24]. This tendency, to use
carbohydrate-rich foods, to feel better, is a frequent cause
of weight gain, the so-called yo–yo effect (Fig. 2). The
reasons for yo–yo dieting are complex and variable but
often include embarking upon a hypocaloric diet that was
initially too extreme. At first, the dieter may experience
elation at the thought of loss and pride of their rejection of
food. With time, however, the limits imposed by such
extreme diets cause effects such as depression or fatigue
that make the diet impossible to sustain. Ultimately, the
dieters revert to their old eating habits, now with the added
emotional effects of failing to lose weight by restrictive
diet. Such an emotional state leads many people to eating
more than they would have before dieting, causing them to
rapidly regain weight [25]. Diet-induced weight cycling
may contribute to dysregulation of metabolism [26] and
have long-term detrimental consequences for accumulation
of visceral adipose tissue [27]. However, a recent study by
researchers at Fred Hutchinson Cancer Research Center has
shown that a history of yo–yo dieting does not negatively
affect metabolism or the ability to lose weight long term
[28].
Since serotoninergic mechanisms may reduce body
weight by accelerating the onset of satiety and increasing
metabolic rate besides suppressing excessive snacking of
carbohydrate-rich foods, Trp supplements during caloric
restriction weight loss diet could be highly useful in
treating obesity or uncontrolled weight gain. However,
there is limited evidence that Trp loading is effective as a
treatment for depression through its action of increasing
serotonin production [29]. Furthermore, Trp supplements
might have adverse effects in a context of chronic
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Eur J Nutr
inflammation when, e.g., the antiproliferative and Trpdepriving strategy of the immune system is counteracted
and metabolism of tumor cells or virus infected cells may
benefit from extra Trp [17, 30]. However, depressive mood
related to an inflammatory condition such as cancer,
infection, or autoimmune syndromes is certainly different
from the mood-lowering effect of lower Trp caused by a
caloric-restricted diet. In such situation, Trp supplements
can be regarded as rather safe.
Alternatively, physical exercise could be a potent stimulus to improve pro-inflammatory cytokines by lowering
and thereby enhancing Trp levels. For example, it was
found that an exercise intervention even without weight
loss lowers circulating IL-6 levels in lean and obese men
with and without type 2 diabetes [31]. Furthermore,
recently, it has been demonstrated that high-intensity aerobic training and aerobic exercise with resistance training,
but not low-intensity physical activity reduced inflammation in subjects with type 2 diabetes and the metabolic
syndrome [32]. Based on a recent meta-analysis, resistance
training has the power to significantly reduce resting levels
of CRP by 25 % independently from weight loss in sedentary healthy or overweight/obese adults and tends to
improve adiponektin and leptin profile with intensities
equal or greater than 80 % of one-repetition maximum
[33]. It seems that changes in body mass (fat loss, lean
body mass increase) may be an effective strategy for
reducing inflammatory milieu. In addition, exercise seems
to elevate the levels of Trp 4-mono-oxygenase, the enzyme
involved in the rate-limiting step in the synthesis of serotonin, and sends projections to the hippocampus that can
influence hippocampal activity [34]. It has also been found
that running can increase the levels of Trp in the hippocampus [35]. The increased availability of Trp might
enhance serotonin production and reduce depressive
symptoms in adults who have been diagnosed with mild to
moderate major depressive disorder [36]. Intriguingly, the
antidepressant effects of exercise can far outlast the period
of exercise [37].
Strengths and limitations
One strength of the study is that the physician who assessed
the clinical status of the subjects and the research nutritionist who assessed the outcomes did not know which
group the subjects were in. Limitations of the study include
short study intervention period, lack of data on mood, and
the effect of exercise on Trp metabolism. In addition, if an
obese person starts a weight loss program, at least temporarily in some individuals, the whole lifestyle shifts to a
healthier behavior, which often includes higher levels of
physical activity. Results from the Aerobic Center Longitudinal Study indicate that adults who are more satisfied
123
with their weight tend to engage in more physical activity
and have better health status regardless of BMI [38]. Further research is needed to investigate potential mechanisms
of how lifestyle interventions, such as increased exercise or
reduced calories and fat intake, affect Trp metabolism,
which might impact mood in overweight and obese
patients. Also, any potential positive effect of Trp supplements avoiding the yo–yo effect remains to be shown.
Conflict of interest On behalf of all authors, the corresponding
author states that there is no conflict of interest.
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