Biomedicine & Pharmacotherapy 109 (2019) 417–428

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Dietary composition modulates impact of food-added monosodium T

glutamate on behaviour, metabolic status and cerebral cortical morphology
in mice
A.Y. Onaolapoa, I. Odetundeb, A.S. Akintolab, M.O. Ogundejic, A. Ajaod, A.Y. Obelawoe,
⁎
O.J. Onaolapoe,
a
Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho, Oyo State, Nigeria
b
Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho, Oyo State, Nigeria
c
Department of Chemical Pathology, LAUTECH Teaching Hospital, Osogbo, Osun State, Nigeria
d
Department of Morbid Anatomy and Histopathology, LAUTECH Teaching Hospital, Osogbo, Osun State, Nigeria
e
Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University of Technology, Osogbo, Osun State, Nigeria

A R T I C LE I N FO A B S T R A C T

Keywords: Effects of food-added monosodium glutamate (MSG) on neurobehaviour, serum biochemical parameters, mal-
Behaviour ondialdehyde (MDA) levels, and changes in cerebral cortex, liver and kidney morphology were assessed in mice
Brain fed standard diet (SD) or high-fat diet (HFD). Animals were assigned to 8 groups [SD control, HFD control, and
Dysmetabolism six groups fed MSG plus SD or HFD at 0.1, 0.2 and 0.4 g/kg of feed]. Animals were fed for 8 weeks, behavioural
Dyslipidaemia
tests were conducted, and blood was taken for estimation of biochemical parameters and MDA level. Whole
Diet
Food additive
brain was homogenised for neurochemical assays, while the cerebrum, liver and kidneys were processed for
histology.
In groups fed MSG/SD, there was a decrease in weight gain, increase in food-intake, an increase in loco-
motion, a decrease in rearing/grooming, and a decrease in anxiety-response. Also observed were derangements
in biochemical parameters, increased MDA, and alteration of renal morphology. Compared to HFD, MSG/HFD
groups had reduction in weight gain, food-intake, grooming and anxiety-response, an increase in locomotion,
and improved memory. Protection against biochemical derangements and HFD-induced organ injuries were also
observed. In conclusion, the findings suggest that possible interactions that may occur between dietary con-
stituents and MSG are determinants of the effects of food-added MSG in mice.

1. Introduction
Flavour-enhancers constitute a category of food additives which are
of crucial culinary and industrial importance worldwide. The fact that
many industrially-prepared foods are made attractive to consumers by
the addition of flavour-enhancers implies that humans continually in-
gest them. Therefore, there is an ever-increasing interest in the under-
standing of their effects on the body. Flavour-enhancers increase the
sensory perception of food via the activation of distinct sensory sys-
tems, including the olfactory, gustatory, and trigeminal. Also, the sti-
mulation of the sensory systems is linked to the interactions of different
properties of food such as food texture (chewiness, crunchiness or
creaminess) and fat composition/content of food; properties which di-
rectly or indirectly influence the perception of flavour. There have been
reports that the fat content of food may influence the release and
retention of flavour [1–3]. However, the influence of dietary fat content
on other possible interactions between flavour-enhancers and the body
remains incompletely explored.
Monosodium glutamate (MSG) is a flavour-enhancer which has been
used for decades to improve the acceptability and palatability of a large
number of foods [4,5]. Presently, it is one of the most widely used food
additives, and an important component of several food seasonings.
Despite MSG’s widespread use, it has continued to be trailed by con-
troversies regarding possible or potentially-deleterious effects on a
number of body organs [6–12]). However, a significant number of
studies and/or reports also reiterate its safety, with regulatory agencies
maintaining its GRAS (Generally Recognized as Safe) status, specifically
when it is added to food [13,14]. Most studies that reported deleterious
effects of MSG were conducted using laboratory animals, with MSG
being administered by gavage, as oral bolus, or systemically. Till date, it

⁎
Corresponding author.
E-mail addresses: ayonaolapo@lautech.edu.ng (A.Y. Onaolapo), ojonaolapo@lautech.edu.ng (O.J. Onaolapo).

https://doi.org/10.1016/j.biopha.2018.10.172
Received 17 July 2018; Received in revised form 20 October 2018; Accepted 30 October 2018
0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
A.Y. Onaolapo et al.
is argued that the effects reported by such studies could not be directly
extrapolated to humans, largely because humans only consume MSG as
a food-added seasoning. Hence, the terminology ‘food-added MSG’
tends to be used to depict this difference [14].
While previous studies have examined how the presence of MSG
may [4,15–17], or may not [18] modulate food taste or flavour; the
possible wider effects of adding MSG to food, and how the composition
of the diet may modulate such effects remains to be examined. Fol-
lowing the publication of a previous article [11] depicting the possible
deleterious effects of orally administered MSG, we considered it im-
portant to investigate the possible effects of food-added MSG on me-
tabolic indices (body weight, food intake, glucose levels and lipid
profile), biochemical indices (blood levels of urea/creatinine, alanine
transaminase and aspartate transaminase), alterations in brain beha-
viour/neurochemistry, and changes in morphology (of the brain, liver
and kidneys). Also, how dietary composition (standard rodent chow
versus high-fat diet) could modulate these effects needed to be in-
vestigated. Therefore, we tested the hypotheses that a) food-added MSG
has significant behavioural, biochemical and morphological effects in
mice, b) dietary composition significantly influences the behavioural,
metabolic and morphologic effects of food-added MSG in mice.
2. Methods
2.1. Chemicals
Food-grade monosodium glutamate (Ajinomoto®, 99% purity) was
used for this study. Assay kits for lipid profile (total cholesterol, tri-
glyceride, and lipoproteins), liver function tests (alanine transaminase
and aspartate transaminase) and kidney function tests (urea and crea-
tinine) was from Randox Laboratories (Crumlin, Co. Antrim, UK). Lipid
peroxidation (malondialdehyde assay kits) was from Biovision Inc.
(Milpitas, CA, USA). Kits were obtained and refrigerated until used. All
other chemicals were analytical grade.
2.2. Animals
Adult male Swiss mice (Empire Breeders, Osogbo, Osun State,
Nigeria) were used for this study. Mice were housed in groups of five in
plastic cages that were located in temperature-controlled quarters
(22–25 °Celsius) with lights on/off at 7.00 a.m/p.m. All procedures
were conducted in compliance with approved institutional protocols
and within the provisions for animal care and use prescribed in the
scientific procedures on living animals, European Council Directive
(EU2010/63).
2.3. Diet
All animals were fed the commercially-available standard rodent
chow (29% protein, 11% fat, 58% carbohydrate) from weaning. At the
beginning of the experimental period, animals were either fed standard
chow (29% protein, 11% fat, 58% carbohydrate) or high fat diet (18%
protein, 44% fat, 36% carbohydrate) which was compounded from
palm olein and vegetable shortening (hydrogenated). Monosodium
glutamate was incorporated into the standard diet or high fat diet at
0.1, 0.2 and 0.4 g /kg of food, and administered ad libitum for a period
of eight weeks. Mice had access to food and tap water ad libitum except
during behavioural tests.
2.4. Experimental method
Eighty male, juvenile mice weighing between 13–15 g each were
randomly assigned into eight groups of ten (n = 10) animals each. Mice
were grouped as follows (Table 1), normal control (standard diet), high
fat control (High fat diet), six groups of animals that were fed mono-
sodium glutamate incorporated (standard or high fat) diet at 0.1 g
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Biomedicine & Pharmacotherapy 109 (2019) 417–428
(0.01%), 0.2 g (0.02%) and 0.4 g/kg (0.04%) of monosodium glutamate
in feed. Body weight was measured daily (7.00 a.m., before feeding)
using a weighing balance (Mettler Toledo Type BD6000, Greifensee,
Switzerland). Animals were fed standard diet, high fat diet or MSG-
containing diet daily for a period of eight weeks. At the end of the
experimental period (day 57), animals were exposed to the open field,
elevated plus maze, Y-maze and radial-arm maze respectively. After
behavioural tests, animals were fasted overnight (Day 58), following
which blood was taken from the tail vein for estimation of glucose le-
vels by the glucose oxidase method [19,20]. Mice in all groups were
then observed for changes in their physical characteristics and then
sacrificed by cervical dislocation. Serum from blood taken via an intra-
cardiac puncture was used for estimation of lipid parameters (total
cholesterol, low density lipoprotein, high density lipoprotein and tri-
glyceride), acetylcholinesterase levels, lipid peroxidation (mal-
ondialdehyde) levels, glutamate levels and biochemical parameters of
liver and kidney function. The liver and kidneys were dissected out,
observed grossly, weighed and then fixed in 10% neutral buffered
formalin. Sections of the liver and kidney were processed for paraffin-
embedding, cut at 5 μm and stained with haematoxylin and eosin for
general histological study. The brain was either processed for histology
or homogenised for assessment of acetylcholinesterase activity, lipid
peroxidation status and glutamate levels.
2.5. Blood collection and brain homogenisation
Blood sample collected from each mouse was used for the estima-
tion of different biochemical parameters. Sample collected into un-
heparinised bottles were allowed to clot, and then centrifuged at
3500 rpm for 10 min using a general centrifuge (Uniscope SM112,
Surgifriend Medicals, England) to separate serum from cells, as pre-
viously described [21,22]. The serum was either assayed immediately
or stored at −20 °C until used.
Within 24 h of the completion of the behavioural tests, animals were
sacrificed by cervical dislocation. Brains (whole) were dissected out,
blotted dry and weighed. A 10% brain homogenate was then prepared
with ice-cold phosphate buffered saline using a Teflon-glass homo-
geniser. The homogenate was centrifuged at 5000 rpm (4 °C) for
15 min, and used to measure glutamate levels, acetylcholinesterase
activity, and lipid peroxidation levels.
2.5.1. Metabolic indices
Biochemical parameters of liver function, including alanine and
aspartate transaminases (ALT and AST) were assessed using their re-
spective assay kits. AST and ALT were assayed by measuring the con-
centration of oxaloacetate hydrazone and the pyruvate hydrazones re-
sulting from 2, 4-dinitrophenyl-hydrazine respectively. Colour change
was measured at 546 nm [12,19,20]. Total cholesterol (TC), triglycer-
ides (TG), high density lipoprotein (HDL-C) and low density lipoprotein
(LDL-C) in serum were analysed using commercially-available kits ac-
cording to the instructions of the manufacturer.
2.5.1.1. Atherogenic index. Atherogenic index was calculated using the
formula below:
(Total cholesterol − HDL Cholesterol ) x HDL Cholesterol
2.5.2. Lipid peroxidation (Malondialdehyde)
Lipid peroxidation was assessed by measuring the level of mal-
ondialdehyde (MDA) in serum samples using the thiobarbituric acid-
reactive species (TBARs). Reactive substances of thiobarbituric acid
combine with free MDA in blood or tissue to produce a coloured
complex (TBAR-MDA adducts) which is then measured at an absor-
bance of 532 nm. The MDA concentration is expressed as nmol/L [23].
A.Y. Onaolapo et al. Biomedicine & Pharmacotherapy 109 (2019) 417–428

Table 1
Experimental methodology.
Groups Bodyweight/food intake Behavioural tests Biochemical tests Neurochemical test Organ morphology

Control diet YES YES YES YES YES

SD/MSG 0.1 YES YES YES YES YES
SD/MSG 0.2 YES YES YES YES YES
SD/MSG 0.4 YES YES YES YES YES
HFD YES YES YES YES YES
HFD/MSG 0.1 YES YES YES YES YES
HFD/MSG 0.2 YES YES YES YES YES
HFD/MSG 0.4 YES YES YES YES YES

SD: Standard diet, HFD: high fat diet, MSG: monosodium glutamate at 0.1, 0.2 and 0.4 g/kg of feed. Number of animals/group = 10.

2.5.3. Glutamate assay
Commercially available glutamate assay kit (Biovision Inc.,
Milpitas, CA, USA) was used to assay brain glutamate levels using
methods that had been previously described [11,12,71]. The glutamate
assay kit provided a sensitive method for measuring glutamate con-
centration in the sample.
2.5.4. Acetylcholinesterase activity
Brain acetylcholinesterase activity was determined using the com-
mercially available acetylcholinesterase assay kit, following the in-
structions of the manufacturer. Colour change was measured at an
absorbance of 412 nm. The results were expressed as nmol per micro-
gram (nmol/mg).
3.2. Effect of food added MSG on food intake
Fig. 1 (lower panel) shows the effect of food-added MSG on food
intake. Two-factor ANOVA revealed a significant main effect of MSG
dose (F (3,72) = 935, p < 0.001), diet (F (1,72) = 8597, p < 0.001)
and significant interaction between MSG dose and diet (F
(3,72) = 1953, p < 0.001). Pairwise comparisons of the effect of MSG
on food intake revealed a significant increase in the percentage food
intake with HFD, MSG/SD at 0.1, 0.2 and 0.4 g/kg and MSG/HFD at
0.1, 0.2 and 0.4 g/kg 4 compared to the mice fed standard diet. Com-
pared to HFD, there was a significant decrease in food intake with
MSG/HFD 0.1, 0.2 and 0.4 g/kg.
3.3. Behavioural tests

2.6. Photomicrography 3.3.1. Locomotor activity

Sections of the cerebral cortex, liver and kidney were examined
using a Sellon-Olympus trinocular microscope (XSZ-107E, China) with
a digital camera (Canon Powershot 2500), and photomicrographs
taken.
2.7. Statistical analysis
Data was analysed using Chris Rorden’s ezANOVA for windows.
Hypothesis was tested using analysis of variance (ANOVA). We tested
the hypothesis that food-added MSG can significantly alter body
weight, food consumption, behaviour, blood glucose, lipid profile, lipid
peroxidation, glutamate levels, acetylcholinesterase activity and bio-
chemical parameters of hepatic and renal function in mice that are fed
standard or high fat diet. ANOVA was used to test effects of food-added
MSG on these parameters, while Tukey’s (HSD) test was used for post-
hoc analysis. Results were expressed as mean ± S.E.M, and p < 0.05
considered statistically-significant.
3. Results
3.1. Effect of food-added MSG on body weight
Fig. 2 (upper panel) shows the effect of food-added MSG on loco-
motor activity. Two-factor ANOVA revealed a significant main effect of
MSG dose (F (3,72) = 44.1, p < 0.001), diet (F (1,72) = 29.8,
p < 0.001), with no significant interaction between MSG dose and diet
(F (3,72) = 2.50, p < 0.070). Pairwise comparisons of the effect of
MSG on locomotor activity revealed a significant decrease with HFD
and MSG/HFD at 0.4 g/kg, and a significant increase with MSG/SD at
0.1 and 0.2 g/kg, and MSG/HFD at 0.1 g/kg, compared to the mice fed
standard diet. Compared to HFD, there was a significant increase in
locomotor activity with MSG/HFD at 0.1 and 0.2 g/kg.
3.3.2. Rearing activity
Fig. 2 (lower panel) shows the effect of food-added MSG on rearing.
Two-factor ANOVA revealed a significant main effect of MSG dose (F
(3,72) = 21.7, p < 0.001), no significant effect of diet (F
(1,72) = 2.89, p < 0.093) although interaction between MSG dose and
diet was significant (F (3,72) = 40.0, p < 0.001). Pairwise compar-
isons of the effect of MSG on rearing activity revealed a significant
decrease in rearing with HFD and MSG/SD at 0.1, 0.2 and 0.4 g/kg,
MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared to the mice fed standard
diet. Compared to HFD, there was a significant increase in rearing with
MSG/HFD at 0.1 and a decrease with MSG/HFD at 0.4 g/kg,

Fig. 1(Upper panel) shows the effect of food-added monosodium
glutamate (MSG) on body weight. Two-factor ANOVA revealed a sig-
nificant main effect of MSG dose (F (3,72) = 104, p < 0.001), diet
(standard vs. High fat diet) (F (1,72) = 320, p < 0.001) and significant
interaction between MSG dose and diet (F (3,72) = 65, p < 0.001).
Pairwise comparisons of the effect of MSG on body weight revealed a
significant decrease in the percentage weight gain with MSG/SD at
0.4 g/kg, and a significant increase with HFD and MSG/HFD at 0.1, 0.2
and 0.4 compared to the mice fed standard diet. Compared to HFD,
there was a significant decrease in body weight with MSG/HFD at 0.1,
0.2 and 0.4 g/kg.
3.3.3. Grooming behaviour
Fig. 3 shows the effect of food-added MSG on grooming. Two-factor
ANOVA revealed a significant main effect of MSG dose (F
(3,72) = 3.38, p < 0.0023), a significant effect of diet (F
(1,72) = 7.71, p < 0.007), with no significant interaction between
MSG dose and diet (F (3,72) = 0.311, p < 0.820). Pairwise compar-
isons of the effect of MSG on grooming behaviour revealed a significant
decrease in the grooming with HFD, MSG/SD at 0.1 and 0.4 g/kg and
with MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared to the mice fed
standard diet. Compared to HFD, there was a significant decrease in
grooming with MSG/HFD at 0.1 and 0.4 g/kg.

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A.Y. Onaolapo et al. Biomedicine & Pharmacotherapy 109 (2019) 417–428

Fig. 1. Effects of food-added monosodium glutamate on %

change in body weight. (upper panel) and % food intake
(lower panel) Each bar represents Mean ± S.E.M, *p < 0.05
significantly different from control diet, #p < 0.05 sig-
nificantly different from high fat diet, MSG: monosodium
glutamate, SD: standard diet, HFD: high fat diet, number of
animals/ group -10.

3.3.4. Anxiety-related behaviours

Fig. 4 shows the effect of food-added MSG on time spent in the open
arm (upper panel) and closed arm (lower panel) of the elevated plus
maze. Two-factor ANOVA of the effect of food-added MSG on open arm
time revealed a significant main effect of MSG dose (F (3,72) = 22.20,
p < 0.001), no significant effect of diet (F (1,72) = 0.175, p < 0.677)
with significant interactions between MSG dose and diet (F
(3,72) = 4.03, p < 0.010). Pairwise comparisons of the effect of MSG
on open arm time revealed a significant decrease in the open arm time
with HFD, and a significant increase with MSG/SD at 0.4 g/kg and with
MSG/HFD at 0.1, 0.2 and 0.4 g/kg, compared to the mice fed standard
diet. Compared to HFD, there was a significant increase in open arm
time with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of the effect of food added MSG on closed arm
time revealed a significant main effect of MSG dose (F (3,72) = 17.8, Fig. 3. Effects of food-added monosodium glutamate on grooming. Each bar
p < 0.001), no significant effect of diet (F (1,72) = 2.56, p < 0.114), represents Mean ± S.E.M, *p < 0.05 significantly different from control diet,
and no significant interactions between MSG dose and diet (F #
p < 0.05 significantly different from high fat diet, MSG: monosodium glu-
(3,72) = 0.044, p < 0.988). Pairwise comparisons of the effect of MSG tamate, SD: standard diet, HFD: high fat diet, number of animals/group-10.
on closed arm time revealed a significant increase in the closed arm
time with HFD, and a significant decrease with MSG/SD at 0.1, 0.2,
3.3.5. Spatial working memory
0.4 g/kg, MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared to the mice fed
Fig. 5 shows the effect of food-added MSG on spatial working
standard diet. Compared to HFD, there was a significant decrease in
memory (spatial working memory in the Y maze (upper panel) and
closed arm time with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
radial-arm maze (lower panel). Two-factor ANOVA of the effect of food
added MSG on Y-maze spatial working memory revealed a significant
main effect of MSG dose (F (3,72) = 22.20, p < 0.001), no significant

Fig. 2. Effects of food-added monosodium glutamate on lo-

comotor (upper panel) and rearing (lower panel) activity. Each
bar represents Mean ± S.E.M, *p < 0.05 significantly dif-
ferent from control diet, #p < 0.05 significantly different
from high fat diet, MSG: monosodium glutamate, SD: standard
diet, HFD: high fat diet, number of animals/ group-10.

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A.Y. Onaolapo et al.
effect of diet (F (1,72) = 0.175, p < 0.677), with significant interac-
tions between MSG dose and diet (F (3,72) = 4.03, p < 0.010). Pair-
wise comparisons of the effect of MSG on Y maze tasks revealed a
significant decrease in the % alternation with HFD, and a significant
increase with MSG/SD at 0.2 g/kg and MSG/HFD at 0.2 and 0.4 g/kg
compared to the mice fed standard diet. Compared to HFD, there was a
significant increase in alternation with MSG/HFD at 0.2 and 0.4 g/kg.
Two-factor ANOVA of the effect of food added MSG on radial arm
spatial working memory revealed a significant main effect of MSG dose
(F (3,72) = 13.3, p < 0.001), no significant effect of diet (F
(1,72) = 0.696, p < 0.410), and significant interactions between MSG
dose and diet (F (3,72) = 5.70, p < 0.001). Pairwise comparisons of
the effect of MSG on alternation index in the radial arm maze revealed a
significant decrease in working memory with HFD, and a significant
increase with MSG/HFD at 0.2 and 0.4 g/kg compared to the mice fed
standard diet. Compared to HFD, there was a significant increase in
spatial working memory with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
3.4. Effect of food added MSG on lipid profile and atherogenic index
Table 2 shows the effect of food-added MSG on lipid profile and
atherogenic index. Two-factor ANOVA of total cholesterol levels re-
vealed a significant main effect of MSG dose (F (3,35) = 7.74,
p < 0.007), a significant effect of diet (F (1,35) = 8.29, p < 0.001),
and a significant interaction between MSG dose and diet (F
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Biomedicine & Pharmacotherapy 109 (2019) 417–428
Fig. 4. Effects of food-added monosodium glutamate on time
spent in the open arm (upper panel) and closed arm (lower
panel). Each bar represents Mean ± S.E.M, *p < 0.05 sig-
nificantly different from control diet, #p < 0.05 significantly
different from high fat diet, MSG: monosodium glutamate, SD:
standard diet, HFD: high fat diet, number of animals/ group-
10.
Fig. 5. Effects of food-added monosodium glutamate on Y-
maze (upper panel) and radial-arm maze (lower panel) spatial
working memory. Each bar represents Mean ± S.E.M,
*p < 0.05 significantly different from control diet,
#
p < 0.05 significantly different from high fat diet, MSG:
monosodium glutamate, SD: standard diet, HFD: high fat diet,
number of animals/ group-10.
(3,35) = 21.17, p < 0.001). Pairwise comparisons of the effect of MSG
on total cholesterol (TC) levels revealed a significant increase in TC
with MSG/SD at 0.1 and 0.2 g/kg, HFD, and MSG/HFD at 0.1 and 0.4 g/
kg, compared to the mice fed standard diet. Compared to HFD, there
was a significant decrease in TC with MSG/HFD at 0.1 and 0.4 g/kg.
Two-factor ANOVA of triglyceride levels revealed a significant main
effect of MSG dose (F (3,35) = 5.59, p < 0.002), no significant effect
of diet (F (1,35) = 0.139, p < 0.451), and a significant interaction
between MSG dose and diet (F (3,35) = 3.01, p < 0.031). Pairwise
comparisons of the effect of MSG on triglyceride (TG) levels revealed a
significant increase in TG with MSG/SD at 0.1, 0.2 and 0.4 g/kg, HFD
and MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared to mice fed standard
diet. Compared to HFD, there was a significant decrease in TG with
MSG/HFD at 0.4 g/kg.
Two-factor ANOVA of low density lipoprotein (LDL) levels revealed
a significant main effect of MSG dose (F (3,35) = 8.46, p < 0.003),
significant effect of diet (F (1,35) = 4.24, p < 0.041), and a significant
interaction between MSG dose and diet (F (3,35) = 4.11, p < 0.004).
Pairwise comparisons of the effect of MSG on LDL levels revealed a
significant increase in LDL levels with MSG/SD at 0.4 g/kg, HFD and
MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared to mice fed standard diet.
Compared to HFD, there was a significant decrease in LDL with MSG/
HFD at 0.2 and 0.4 g/kg.
Two-factor ANOVA of high density lipoprotein (HDL) levels re-
vealed a significant main effect of MSG dose (F (3,35) = 2.39,
A.Y. Onaolapo et al. Biomedicine & Pharmacotherapy 109 (2019) 417–428

Table 2
Effect of food-added MSG on lipid profile and atherogenic index.
Groups TC mmol/L TG mmol/L LDL mmol/L HDL mmol/L ATI

Control diet 1.47 ± 0.04 0.55 ± 0.02 0.72 ± 0.07 0.37 ± 0.03 3.07 ± 0.27
SD/MSG 0.1 2.25 ± 0.02* 0.80 ± 0.04* 0.97 ± 0.17 0.43 ± 0.13 4.25 ± 0.18*
SD/MSG 0.2 2.35 ± 0.29* 0.67 ± 0.04* 1.40 ± 0.12* 0.45 ± 0.11 4.07 ± 0.22*
SD/MSG 0.4 1.53 ± 0.06 0.65 ± 0.02* 0.80 ± 0.06 0.47 ± 0.13 2.30 ± 0.10*
HFD 2.10 ± 0.11* 1.10 ± 0.13* 1.38 ± 0.06* 0.25 ± 0.04* 6.40 ± 0.77*
HFD/MSG 0.1 1.75 ± 0.07*# 0.97 ± 0.11* 1.43 ± 0.07* 0.40 ± 0.06# 3.44 ± 0.18#
HFD/MSG 0.2 2.05 ± 0.02* 0.88 ± 0.03* 1.13 ± 0.07*# 0.50 ± 0.04*# 3.13 ± 0.14#
HFD/MSG 0.4 1.65 ± 0.02*# 0.85 ± 0.12* 1.00 ± 0.08*# 0.40 ± 0.02# 3.00 ± 0.25#

Values are presented as Mean ± S.E.M, *p < 0.05 significantly different from control diet, #p < 0.05 significantly different from high fat diet, MSG: monosodium
glutamate, SD: standard diet, HFD: high fat diet, number of animals/group-5.

p < 0.038), significant effect of diet (F (1,35) = 6.10, p < 0.001),
with no significant interaction between MSG dose and diet (F
(3,35) = 0.22, p < 0.734). Pairwise comparisons of the effect of MSG
on HDL levels revealed a significant decrease in HDL levels with HFD
and an increase with MSG/HFD at 0.2 g/kg compared to mice fed
standard diet. Compared to HFD, there was a significant increase in
HDL with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of atherogenic index (ATI) revealed a significant
main effect of MSG dose (F (3,35) = 11.6, p < 0.001), significant ef-
fect of diet (F (1,35) = 5.15, p < 0.028), with no significant interac-
tion between MSG dose and diet (F (3,35) = 15.62, p < 0.001).
Pairwise comparisons of the effect of MSG on ATI levels revealed a
significant increase in ATI with MSG/SD at 0.1 and 0.2 g/kg, HFD and a
decrease with MSG/SD at 0.4 g/kg compared to mice fed standard diet.
Compared to HFD, there was a significant decrease in ATI with MSG/
HFD at 0.1, 0.2 and 0.4 g/kg
3.5. Effect of food–added MSG on glucose, lipid peroxidation, plasma/brain
glutamate and acetylcholinesterase activity
Table 3 shows the effect of food–added MSG on blood glucose, lipid
peroxidation, plasma/brain glutamate, and brain acetylcholinesterase
activity. Two-factor ANOVA of blood glucose levels revealed a sig-
nificant main effect of MSG dose (F (3,35) = 6.65, p < 0.003), sig-
nificant effect of diet (F (1,35) = 8.29, p < 0.001), and significant
interaction between MSG dose and diet (F (3,35) = 3.22, p < 0.021).
Pairwise comparisons of the effect of MSG on glucose levels revealed a
significant increase in glucose levels with MSG/SD at 0.1 and 0.2 g/kg,
HFD and with MSG/HFD at 0.1 g/kg compared to mice fed standard
diet. Compared to HFD, there was a significant decrease in glucose le-
vels with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of blood lipid peroxidation levels measured as
malondialdehyde (MDA) levels revealed a significant main effect of
MSG dose (F (3,35) = 3.12, p < 0.043), a significant effect of diet (F
(1,35) = 10.11, p < 0.001), and no significant interaction between
MSG dose and diet (F (3,35) = 0.22, p < 0.521). Pairwise comparisons
of the effect of MSG on MDA levels revealed a significant increase in
MDA levels with MSG/SD at 0.4 g/kg, HFD and with MSG/HFD at 0.1,
0.2 and 0.4 g/kg compared to mice fed standard diet. Compared to
HFD, there was a significant decrease in MDA levels with MSG/HFD at
0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of brain MDA levels revealed a significant main
effect of MSG dose (F (3,35) = 9.52, p < 0.002), a significant effect of
diet (F (1,35) = 18.3, p < 0.001), and a significant interaction be-
tween MSG dose and diet (F (3,35) = 7.54, p < 0.001). Pairwise
comparisons of the effect of MSG on MDA levels revealed a significant
increase in brain MDA levels with HFD and with MSG/HFD at 0.1, 0.2
and 0.4 g/kg compared to mice fed standard diet. Compared to HFD,
there was a significant decrease in brain MDA levels with MSG/HFD at
0.1, 0.2 and 0.4 g/kg.
Plasma glutamate decreased significantly (F (7,35) = 10.12,
p < 0.003) with MSG/HFD at 0.2 and 0.4 g/kg compared to mice fed
standard diet. Compared to HFD, there was no significant difference in
plasma glutamate at any of the doses of MSG/HFD. Brain glutamate did
not significantly differ at any of the doses of MSG with standard diet or
high fat diet.
Brain acetylcholinesterase (ACHe) increased significantly (F
(7,35) = 4.01, p < 0.043) with HFD compared to groups fed standard
diet. Compared to high fat diet, there was a significant decrease in brain
ACHe activity with MSG/HFD at 0.1, 0.2 and 0.4 g/kg
3.6. Effect of MSG on liver and kidney function
Table 4 shows the effect of food–added MSG on liver and kidney
function tests. Two-factor ANOVA of aspartate transaminase (AST) le-
vels revealed a significant main effect of MSG dose (F (3,35) = 18.0,
p < 0.001), significant effect of diet (F (1,35) = 3.50, p < 0.008), and
significant interaction between MSG dose and diet (F (3,35) = 11.12,
p < 0.001). Pairwise comparisons of the effect of MSG on AST levels
revealed a significant increase in AST with MSG/SD at 0.1, 0.2 and
0.4 g/kg, HFD, and with MSG/HFD at 0.1, 0.2 and 0.4 g/kg compared
to mice fed standard diet. Compared to HFD, there was a significant
decrease in AST levels with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of alanine transaminase (ALT) levels revealed a

Table 3
Effect of food–added MSG on glucose, MDA levels, glutamate and acetylcholinesterase activity.
Groups Blood glucose mg/dl MDA μM Plasma Glu μmmol/L Brain MDA μM Brain GLU μmmol/g Brain ACHe nmol/mg

Control diet 85.17 ± 6.51 1.59 ± 0.06 10.12 ± 1.27 2.32 ± 0.17 1.12 ± 0.07 33.22 ± 1.17
SD/MSG 0.1 119.67 ± 6.71* 1.54 ± 0.04 11.90 ± 1.10 2.40 ± 0.14 1.22 ± 0.17 34.12 ± 2.10
SD/MSG 0.2 96.17 ± 4.70* 1.62 ± 0.04 9.98 ± 1.12 2.34 ± 0.12 1.250 ± 0.12 32.40 ± 2.12
SD/MSG 0.4 90.67 ± 2.40 2.15 ± 0.02* 9.80 ± 1.22 2.92 ± 0.14* 1.18 ± 0.06 34.24 ± 2.16
HFD 127.17 ± 2.02* 4.78 ± 0.13* 10.18 ± 0.06 7.10 ± 0.20* 1.22 ± 0.06 37.33 ± 3.06*
HFD/MSG 0.1 122.67 ± 84*# 2.27 ± 0.11*# 9.13 ± 2.07 5.24 ± 0.31*# 1.43 ± 0.07 32.43 ± 3.17#
HFD/MSG 0.2 89.67 ± 4.48# 2.18 ± 0.03*# 8.10 ± 2.07* 5.33 ± 0.43*# 1.13 ± 0.07 33.10 ± 4.12#
HFD/MSG 0.4 90.22 ± 6.26# 1.85 ± 0.12# 9.20 ± 2.58* 5.15 ± 0.50## 1.10 ± 0.08 32.20 ± 3.22#

Values are presented as Mean ± S.E.M, *p < 0.05 significantly different from control diet, #p < 0.05 significantly different from high fat diet, MSG: monosodium
glutamate, SD: standard diet, HFD: high fat diet, number of animals/group-5.

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A.Y. Onaolapo et al.
Table 4
Effect of food-added MSG on liver and kidney function.
Groups AST (mmol/L) ALT (mmol/L)
Control diet 87.60 ± 6.71 26.17
SD/MSG 0.1 206.33 ± 1.55* 38.67
SD/MSG 0.2 179.17 ± 6.94* 54.20
SD/MSG 0.4 121.13 ± 2.36* 61.67
HFD 205.10 ± 1.6* 57.33
HFD/MSG 0.1 132.15 ± 3.36*# 41.17
HFD/MSG 0.2 149.65 ± 5.21* 43.67
HFD/MSG 0.4 149.17 ± 2.33*# 31.17
Values are presented as Mean ± S.E.M, *p < 0.05 significantly different from control diet, #p < 0.05 significantly different from high fat diet, MSG: monosodium
glutamate, SD: standard diet, HFD: high fat diet, number of animals/group-5.
significant main effect of MSG dose (F (3,35) = 56.9, p < 0.001),
significant effect of diet (F (1,35) = 12.10, p < 0.001), and significant
interaction between MSG dose and diet (F (3,35) = 10.22, p < 0.001).
Pairwise comparisons of the effect of MSG on ALT levels revealed a
significant increase in AST with MSG/SD at 0.1, 0.2 and 0.4 g/kg, HFD
and with MSG/HFD at 0.1 and 0.2 g/kg compared to mice fed standard
diet. Compared to HFD, there was a significant decrease in ALT levels
with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of Urea levels revealed a significant main effect
of MSG dose (F (3,35) = 7.11, p < 0.002), significant effect of diet (F
(1,35) = 3.34, p < 0.011), and significant interaction between MSG
dose and diet (F (3,35) = 13.56, p < 0.001). Pairwise comparisons of
the effect of MSG on urea levels revealed a significant increase in urea
with MSG/SD at 0.1, 0.2 and 0.4 g/kg, HFD and with MSG/HFD at 0.1,
0.2 and 0.4 g/kg compared to mice fed standard diet. Compared to
HFD, there was a significant decrease in urea levels with MSG/HFD at
0.1, 0.2 and 0.4 g/kg.
Two-factor ANOVA of creatinine levels revealed a significant main
effect of MSG dose (F (3,35) = 9.91, p < 0.001), significant effect of
diet (F (1,35) = 5.15, p < 0.001), and significant interaction between
MSG dose and diet (F (3,35) = 17.16, p < 0.001). Pairwise compar-
isons of the effect of MSG on creatinine levels revealed a significant
increase in creatinine with MSGSD at 0.1, 0.2 and 0.4 g/kg, HFD and
with MSG/HFD at 0.2 g/kg compared to mice fed standard diet.
Compared to HFD, there was a significant decrease in creatinine levels
with MSG/HFD at 0.1, 0.2 and 0.4 g/kg.
3.7. Effect of food-added MSG on cerebral cortex morphology
Histological examination of hematoxylin and eosin-stained sections
of the cerebral cortex of animals fed standard diet (Fig. 6A) showed the
characteristic architecture of the mouse cerebral cortex with numerous
pyramidal cells (multipolar shape with rounded vesicular nucleus),
granule cells (round neurons with large open-face nuclei, prominent
nucleoli and scanty cytoplasm) and glial neurons (small round-vesicular
shaped cell).interspersed within a pink-staining background (neuropil).
Examination of the cerebral cortex slides of groups fed MSG at 0.1
(Fig. 6B) and 0.2 (Fig. 6C) and 0.4 g/kg (Fig. 6D) with revealed normal-
looking pyramidal cells, with deeply staining nuclei and slight increase
in glial cell density. Features are generally in keeping with normal
histology.
In the group administered HFD (Fig. 6E) revealed degenerating
pyramidal cells with pale edges and shrunken nuclei, numerous glia
neurons scattered throughout the neuropil. Examination of slides from
groups fed MSG at 0.1 (figure 6 F), 0.2 (Fig. 6G) and 0.4 g/kg (Fig. 6H)
with HFD, revealed a protection against the development of the effects
observed with HFD alone. This is evidenced by the presence of few
degenerating pyramidal cells (with pale edges and poorly staining nu-
clei) interspersed with normal looking pyramidal cell (with deeply
staining nuclei), granule cells and few glia neurons.
Biomedicine & Pharmacotherapy 109 (2019) 417–428
Urea (mmol/L) Creatinine (mmol/L)
± 0.70 2.82 ± 0.11 67.67 ± 3.58
± 1.65* 5.31 ± 0.85* 98.17 ± 5.40*
± 0.37* 4.97 ± 0.49* 90.67 ± 2.25*
± 1.65* 4.17 ± 0.25* 93.17 ± 1.31*
± 1.45* 5.22 ± 0.40* 100.67 ± 5.34*
± 0.31*# 2.92 ± 0.17*# 70.17 ± 2.61#
± 1.50*# 3.97 ± 0.40*# 83.67 ± 2.25*#
± 1.58# 3.27 ± 0.18*# 73.67 ± 6.55#
3.8. Effect of food-added MSG on liver morphology
Examination of haematoxylin and eosin-stained sections of the
mouse liver in the group fed standard diet (SD) (Fig. 7A) revealed he-
patocyte with deeply staining nuclei radially-arranged around the
central vein, with the hepatocyte cords demarcated by sinusoidal
spaces. The nuclei of a few Kupffer cells scattered around the central
vein are also observed. These features are in keeping with normal liver
histology. Examination of liver slides from groups fed MSG with SD
(Fig. 7B–D) revealed features in keeping with normal histology, with a
few hepatocytes with pale staining nuclei in the group fed MSG at
0.1 g/kg with SD (Fig. 7B). Slides from sections of the liver of the group
fed HFD (Fig. 7E) revealed marked disruption of hepatocyte par-
enchyma, with loss of intervening sinusoidal spaces and numerous va-
cuoles all over the hepatic parenchyma. Pale-staining hepatocyte nuclei
are also observed. Also obvious is a contracted central vein, hepatic
changes are in keeping with fatty liver. Examination of liver slides from
the groups fed MSG with HFD (Fig. 7F–H) reveal sheets of radially-
arranged hepatocytes with deeply-staining nuclei, a few swollen he-
patocytes with pale-staining nuclei around an the central vein, and a
few sinusoidal spaces seen demarcating cords of healthy-looking he-
patocytes. A reduction in the degree of vacuolations is observed with
increasing doses of MSG. Features are in keeping with a protection
against the development of fatty liver change.
3.9. Effect of food-added MSG on kidney morphology
Examination of slides taken from sections of the right kidney of
animals fed SD (Fig. 8A) showed demarcation of the cortex and me-
dulla. In the medulla the Bowman’s capsule glomeruli, Bowman’s space,
proximal and distal renal tubules and blood vessels all appear within
normal limits. The nuclei of the glomeruli and tubular epithelium were
deeply staining. Features are in keeping with normal renal morphology.
Examination of the kidney slides of animals fed increasing doses of MSG
with SD (Fig. 8B–D) revealed well demarcated cortex and medulla with
normal looking Bowman’s capsule and space. The medulla contained a
mixture of normal looking glomeruli with deeply staining nuclei in-
terspersed with a few contracted glomeruli with pale staining nuclei.
Proximal and distal tubules of groups fed MSG at 0.1 (Fig. 8B) and
0.2 g/kg (Fig. 8C) appear within normal limits normal. While in groups
fed MSG at 0.4 g/kg (Fig. 8D) a few enlarged tubules are observed. In
the group fed HFD (Fig. 8E) there was slight disruption of normal
kidney architecture with markedly dilated renal glomeruli, a reduction
in the size of the Bowman’s space and contraction of the renal tubules.
Nuclei of the glomeruli and renal tubular epithelial cells were a mixture
of deeply staining and pale-staining. In animals administered MSG/HFD
at 0.1 and 0.2 g/kg (Fig. 8F and G), a few contracted and necrosed renal
glomeruli are observed interspersed with normal looking glomeruli
with deeply staining nuclei. In the group fed MSG with HFD at 0.4 g/kg
(Fig. 8H), there was preservation of the renal architecture.
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Fig. 6. (A–H): Effect food-added MSG on cerebral cortex morphology. 6 A) Standard diet, 6B) 0.1 g/kg MSG + SD, 6C) 0.2 g/kg MSG + SD, 6D) 0.4 g/kg MSG + SD,
6E) High fat diet 6 F) 0.1 g/kg MSG + HFD, 6 G) 0.2 g/kg MSG + HFD, 6H) 0.4 g/kg MSG + HFD. Representative photomicrographs of hematoxylin and eosin (H&E)
stained sections of the mouse cerebral cortex showing granule cells (Gc), pyramidal cells (Pc), neuroglia (Ng) and H&E x160.

Fig. 7. (A–H): Effect of food-added MSG on liver morphology. 7 A) Standard diet, 7B) 0.1 g/kg MSG + SD, 7C) 0.2 g/kg MSG + SD, 7D) 0.4 g/kg MSG + SD, 7E)
High fat diet 7 F) 0.1 g/kg MSG + HFD, 7 G) 0.2 g/kg MSG + HFD, 7H) 0.4 g/kg MSG + HFD. Representative photomicrographs of hematoxylin and eosin (H&E)
stained sections of the mouse liver showing sinusoidal spaces (S) demarcating hepatocytes (H), with hepatocyte nucleus (Hn) and Kupffer cell nucleus (K), Central
vein (CV) and vacuoles (V). H&E x160.

4. Discussion food intake across the doses b) a dose-dependent increase in locomotor

This study examined the effects of food-added MSG on metabolic
indices (body weight, food intake, glucose levels and lipid profile),
biochemical indices (blood levels of urea/creatinine, alanine transa-
minase and aspartate transaminase), alterations in brain behaviour/
neurochemistry, and changes in morphology (of the brain, liver and
kidneys) in mice that were fed standard rodent chow, or high fat diet.
The results showed that incorporation of MSG into SD was associated
with a) a decrease in weight gain at the highest dose, and an increase in
activity as well as a decrease in rearing and grooming behaviours, c) a
dose-dependent decrease in anxiety-related behaviours and increase in
spatial working memory, d) derangements in lipid profile, liver/kidney
biochemistry and lipid peroxidation, e) mild renal injury at the highest
dose, with no injury to the liver or brain, f) no significant difference in
brain glutamate levels or acetylcholinesterase activity,
Incorporation of MSG into HFD (when compared with effects ob-
served with HFD alone) was associated with; a) a decrease in
HFD–induced increase in body weight and food intake, b) a reversal of

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A.Y. Onaolapo et al.
Fig. 8. (A–H): Effect of food-added MSG on kidney morphology. 8 A) Standard diet, 8B) 0.1 g/kg MSG + SD, 8C) 0.2 g/kg MSG + SD, 8D) 0.4 g/kg MSG + SD, 8E)
High fat diet 8 F) 0.1 g/kg MSG + HFD, 8 G) 0.2 g/kg MSG + HFD, 8H) 0.4 g/kg MSG + HFD Representative photomicrographs of hematoxylin and eosin (H&E)
stained sections of the mouse kidney showing the glomerulus (G), Bowman’s capsule (BC) Bowman’s space (BS), proximal tubule (PT), and distal tubule (DT). H&E
x160.
HFD-induced decrease in locomotor and rearing activity at the lower
doses, c) a potentiation of HFD-induced decrease in grooming at 0.1
and 0.4 g/kg, and a dose related anxiolytic response, d) a reversal of
HFD–induced impairment of spatial working memory, e) a protection
against the development of HFD-induced alterations in lipid profile,
liver/kidney functions, and lipid peroxidation, f) a decrease in brain
acetylcholinesterase activity, and a protection against the development
of HFD–induced hepatic, renal and brain injury.
In this study, the changes observed following ingestion of HFD are
consistent with the results of previous studies [24–26]. Effects of HFD
on metabolism and energy balance have been attributed to the palat-
ability of HFD, inhibitory effect on satiety [27], enhancement of fat
utilisation, and suppression of lipid biosynthesis [28]. Increased oxi-
dation of fatty acid increases the production of reactive oxygen species
and prevents glucose oxidation, culminating in the development of
hyperglycaemia and insulin resistance [28,29]. A reduction in lipo-
protein lipase levels [30] and derangement of the hypothalamo-pitui-
tary-adrenal (HPA) axis [31] have also been reported.
As observed in the present study, incorporation of MSG (with SD or
HFD) resulted in a general reduction in weight gain (despite an increase
in food intake in SD fed mice). This finding corroborates previous re-
sults from our laboratory [11,12] and those of studies by Diniz et al.
[32], Collison et al. [33] and Tordoff et al. [34] which demonstrated
that administration of MSG was not associated with an increase in
weight gain. Results from studies in humans and laboratory animals
(dating back to decades) continue to raise concerns regarding MSG’s
importance as a risk factor in the development of obesity [35–40]
especially when administered in the neonatal period. Also, there have
been suggestions that a complex relationship exists between MSG and
the regulation of body weight; a relationship that is modulated by age
at exposure (neonates or adults), and environmental factors like phy-
sical exercise and diet [11,12,40,41].
In the study, incorporation of MSG into HFD was associated with
decreased food intake (compared to HFD alone) which might suggest
induction of satiety. The results of the effects of food-added MSG on
weight gain and food intake suggest that while MSG may increase food-
palatability and quantitatively affect food intake, its effects on body
weight may be independent of the mode of administration or dietary
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Biomedicine & Pharmacotherapy 109 (2019) 417–428
composition. These effects may be mediated by a stimulatory effect of
MSG on the release of neuromodulators that are present in the arcuate
nucleus [42], and peripheral hormones including insulin, leptin and
ghrelin which are important in the signalling of adiposity and satiety
[43]. In this study, incorporation of MSG into SD was associated with
derangements of lipid homeostasis/glucose levels, and increased lipid
peroxidation; however, its incorporation into HFD was associated with
protection against HFD-induced deleterious changes in these para-
meters. MSG’s association with the development of metabolic syndrome
has been reported in experimental animals [32,44,33,45] and human
subjects [46], especially following administration of MSG to neonatal
animals or pregnant dams ([32,33,45]). The results of the present study
are corroborated by a number of other studies ([32,44,33,45]). Collison
et al. [33] reported evidence of dyslipidaemia in animals administered
MSG alone, and a mitigation of Trans fat acid (TFA) diet-induced
changes in metabolic indices in mice that were fed MSG plus TFA. This
is similar to our observations in the present study. The results from this
study suggest that while MSG interacts with HFD to modulate (or re-
duce significantly at higher doses) the ability of HFD to cause dyslipi-
daemia and hyperglycaemia, its addition to SD was associated with
derangements in the lipid profile. However, the mechanism(s) that may
be involved need to be evaluated.
The hepatotoxic and nephrotoxic effects of orally-administered MSG
has been reported [47–50,7,51]). In this study, a derangement of bio-
chemical parameters of hepatic and renal function was observed with
MSG/SD, while the incorporation of MSG into HFD reduced the extent
of HFD-induced alteration of liver and kidney function. MSG’s ability to
protect against the biochemical derangements induced by HFD may be
related to the reduction of food intake in the MSG/HFD groups. Es-
sentially, a reduced consumption of the HFD possibly led to a reduction
in extent of cellular injury. MSG’s ability to stimulate release of hor-
mones/neuromediators, interact with the different dietary components,
and modulate physiological or biochemical responses may be im-
plicated in this. Again, studies have reported that MSG-induced gas-
trointestinal changes are dependent on the dietary composition of the
meal [52–54]. Although, a 2014 study examining the effect of MSG/
HFD on amino acid metabolism in pigs, reported that little or no in-
teractions occurred between dietary fat and MSG in the regulation of
A.Y. Onaolapo et al.
amino acid concentration [55].
In this study, (despite the presence of biochemical derangements)
no morphologic evidence of liver or kidney injury was observed in
groups of animals fed with MSG/SD. This is contrary to the results of
previous studies from our laboratory where we reported that oral ad-
ministration of MSG was associated with liver and kidney injuries
[7,11]. There have been reports of the development of hepatic micro-
steatosis in offspring of pregnant dams fed with MSG [33], and evidence
showing that neonatal MSG administration altered lipid metabolism
enough to cause fat redistribution, thermogenesis, and features con-
sistent with non-alcoholic fatty liver disease (NAFLD) in adulthood
[56,33,57]. The results of these studies differ from that of our study.
The differences could be attributed to differences in the age of mice,
route of administration or effective dose of MSG consumed. In groups of
mice fed with HFD alone, hepatic steatosis as well as renal glomerular
and tubular injury was observed. This supports the results of studies
that have demonstrated that high dietary fat can lead to organ changes
that are consistent with cellular damage [33,58]. The incorporation of
MSG into HFD was associated with a protection of the liver and kidneys
against the development of the changes observed with HFD. Effects of
HFD on the liver have been attributed to the efflux of non-esterified
fatty acids, and the release of proinflammatory cytokines and adipo-
kines (which ultimately result in excessive deposition of fat in the liver)
[58]. However, the effects observed with MSG/HFD would suggest that
addition of MSG to HFD could have limited the deleterious effects of
HFD by 1) reducing the quantity of HFD consumed, 2) reducing the
ability of HFD to trigger biochemical pathways that may mediate organ
injury, 3) reducing the degree of lipid peroxidation, and possibly in-
hibiting pathways that are likely to cause fat accumulation or, 4) pos-
sibly altering the expression of genes that control lipid and nitrogen
metabolism [59]. In summary, while the exact mechanisms responsible
for the modulation of lipid parameters, liver and kidney function and
organ morphology are still being evaluated, the results suggest a pos-
sible interaction between dietary fat and MSG resulting in changes in
fat metabolism.
In this study, ingestion of HFD was associated with decrease in lo-
comotor activity, rearing, grooming, and spatial working memory;
while increase in anxiety-related behaviours, lipid peroxidation levels
and acetylcholinesterase activity were also observed. These results
corroborate those of previous studies [60–64]. The behavioural effects
of HFD have been linked to its ability to alter the function of circadian
clock genes and the circadian system [65], as well as alter the expres-
sion of nuclear factor kappa beta gene and the function of the hippo-
campal stress-related glucocorticoid and mineralocorticoid receptor
genes [62]. Also, effects of HFD on memory have been associated with
impairment of peripheral and central insulin signalling [66] as well as
increase in oxidative stress and inflammation which has also been
shown to negatively impact cognition [67].
The behavioural effects of MSG administration have been well-
documented [12,68–70]. Studies have also suggested that these effects
could be modulated by age [68], environmental enrichment [70], and
duration of administration [12,68,69]. In this study, food-added MSG
was generally associated with a dose-related increase in locomotor
activity, and this was not dependent on dietary composition. Also, the
addition of MSG to HFD was observed to protect against HFD-induced
suppression of locomotion and rearing. While studies in which MSG was
administered systemically or by oral gavage have reported excitatory
and inhibitory responses that was dependent on dose, duration of ad-
ministration and arena enrichment [69–71], the results of the present
study show that mode of administration may not directly influence the
direction of the central response to MSG. Results from previous studies
in which MSG was administered systemically (or by oral gavage) have
reported increased or reduced grooming response, which is modulated
by duration of administration and dose of MSG. However, what is ob-
vious from the present study is that MSG/HFD was associated with a
decrease in grooming activity across all the groups, when compared to
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Biomedicine & Pharmacotherapy 109 (2019) 417–428
MSG/SD.
There are reports of the anxiogenic effects of MSG, following either
systemic administration or oral gavage [12,72–74]). In this study, food-
added MSG was associated with an anxiolytic response in both MSG/SD
and MSG/HFD mice, and the magnitude of the anxiolytic response
observed was dependent on dose. The involvement of glutamatergic
transmission in anxiety-related disorders has been studied extensively
[75,76]. There have also been reports suggesting that the diversity of
glutamate receptors enables it to modulate both brain excitation and
inhibition [77].The anxiogenic response of drugs or different agents
have been linked to an imbalance between gamma amino butyric acid
(GABA) and glutamate, neurotransmitters that are very important in the
inhibitory or excitatory response of these agents. Also, there are reports
suggesting that anxiolytic response could be linked to the stimulation of
metabotropic glutamate (m-GLU) receptors in the brain [75]. Vitor-de-
Lima et al. [74] examined the role of route of administration on the
response of rats to MSG and concluded that two distinct mechanisms of
action were responsible for the response of MSG following oral gavage
or subcutaneous administration. In essence, it is possible that the ad-
dition of MSG to food may result in the stimulation of m-Glu receptors,
while systemic or oral administration may result in the stimulation of
other receptors that elicit an anxiogenic response. However, these as-
sumptions would require further evaluation.
In this study, food-added MSG was associated with a dose-related
improvement in Y-maze working memory in both SD and HFD fed mice.
Also, in the radial arm maze, MSG protected against the memory loss
associated with HFD. While studies have observed that MSG adminis-
tration can cause changes in memory in rodents [12,78–80], there are
differences in the specific types of responses elicited by MSG adminis-
tration. A few studies have shown that neonatal exposure to MSG could
impair acquisition and retention in discrimination learning [78] or
place-learning ability in adult rats [80] following the administration of
high doses of MSG. Park et al. [79] also reported evidence of memory
impairment following the subcutaneous administration of MSG to adult
rats. In another study conducted by our team, we reported a dose-re-
lated memory response which was also dependent on duration of ad-
ministration [12]. Overall, the results from the present study would
suggest that mode of administration, as well as dietary composition
may also play important roles in the memory response of MSG, at least
in rodents. The behavioural effects of MSG/HFD (especially as it relates
to memory) could be linked to the combined effects of a reduction in
brain levels of lipid peroxidation and acetylcholinesterase activity.
Other possible mechanisms would include the effects of MSG at dopa-
mine [81] and/or glutamate [82] receptors.
In the brain, studies have linked the administration of MSG with
neurotoxic injury, especially when administered at very high doses in
the neonatal period, or following repeated oral administration.
However, in this study, MSG/SD was not associated with morphological
evidence of brain injury, although there was an increase in lipid per-
oxidation at the highest dose. On the other hand, HFD was associated
with morphological evidences of brain injury and lipid peroxidation.
Previous studies have reported that HFD causes deleterious changes in
the brain of experimental animals, leading to increased lipid perox-
idation and a decrease in the level of brain-derived neurotrophic factor
[83,84]. The incorporation of MSG into HFD appeared to protect
against brain morphological changes and changes in brain lipid per-
oxidation levels observed with HFD. While we do not consider MSG to
have any therapeutic potential, this observation may suggest that the
addition of MSG to foods that are high in dietary fat may be protective,
simply by possibly increasing satiety and reducing the quantity of HFD
that is consumed.
5. Conclusion
In conclusion, we can deduce from this study that food-added MSG
has effects on behaviour, biochemical indices, oxidative status, and
A.Y. Onaolapo et al.
morphology of several body organs in mice. Also, these effects may be
distinct from those resulting from direct administration of MSG.
However, the effects can be significantly modulated by dietary com-
position, as demonstrated by the differential impacts of MSG/SD or
MSG/HFD in this study. The implication of this is that in debating the
possible effects of MSG consumption in humans, it is important to
consider the likelihood that food-added MSG may elicit effects that may
be different from those seen after direct administration of MSG in an-
imals; and that significant variations in these effects may be due to the
modulatory effects of dietary composition.
Ethical approval
All procedures performed in studies involving animals were in ac-
cordance with the ethical standards of the Ladoke Akintola University
of Technology Ogbomosho, Nigeria, where the studies were conducted.
Source of funding
This research did not receive any specific grant from agencies in the
public, commercial, or not-for-profit sectors.
Conflict of interest
All authors of this paper declare that there is no conflict of interest
related to the content of this manuscript.
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