Introduction: Obesity is associated with impaired learning, but the mechanisms underlying this cognitive dysfunction are poorly understood. Moreover, whether obesity-induced learning deficits show sexual dimorphism remains controversial. Females are believed to be protected from cognitive decline by oestrogens. These hormones enhance the expression of tryptophan hydroxylase 2, the rate-limiting enzyme in the transformation of tryptophan (Trp) into serotonin which plays a significant role in learning and memory. However, several learning-regulating compounds also arise from Trp metabolism through the kynurenine pathway (KP), including kynurenic acid (KA), xanthurenic acid (XA), and NAD+. The present study aimed to determine the involvement of the KP of Trp metabolism in the regulation of learning in control and obese female rats. Methods: The learning capabilities of control and obese rats were evaluated using the novel object recognition test. Trp and Trp-derived metabolites were quantified in the hippocampus and frontal cortex by ultra-performance liquid chromatography-tandem mass spectrometry. Results: Control rats in proestrus/oestrous performed better than their control mates in metestrus/dioestrus. Likewise, while control and obese rats in dioestrus/metestrus did not show differences in learning, obese rats in proestrus/oestrous displayed decreased memory capacity along with decreased Trp concentration and reduced KA, XA, and NAD+ production in the hippocampus. These neurochemical alterations were associated with impaired expression of mRNAs coding for key enzymes of the KP. Conclusion: The results presented here indicate that the deleterious effects of obesity on learning are closely related to the oestrous cycle and associated with an impairment of the KP of Trp metabolism.

1.
Yau
PL
,
Castro
MG
,
Tagani
A
,
Tsui
WH
,
Convit
A
.
Obesity and metabolic syndrome and functional and structural brain impairments in adolescence
.
Pediatrics
.
2012 Oct
;
130
(
4
):
e856
864
.
2.
Liang
J
,
Matheson
BE
,
Kaye
WH
,
Boutelle
KN
.
Neurocognitive correlates of obesity and obesity-related behaviors in children and adolescents
.
Int J Obes
.
2014 Apr
;
38
(
4
):
494
506
.
3.
Buie
JJ
,
Watson
LS
,
Smith
CJ
,
Sims-Robinson
C
.
Obesity-related cognitive impairment: the role of endothelial dysfunction
.
Neurobiol Dis
.
2019 Dec
;
132
:
104580
.
4.
Abbott
KN
,
Arnott
CK
,
Westbrook
RF
,
Tran
DMD
.
The effect of high fat, high sugar, and combined high fat-high sugar diets on spatial learning and memory in rodents: a meta-analysis
.
Neurosci Biobehav Rev
.
2019 Dec
;
107
:
399
421
.
5.
Leigh
S-J
,
Morris
MJ
.
Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment
.
Biochim Biophys Acta Mol Basis Dis
.
2020 Jun
;
1866
(
6
):
165767
.
6.
Mrak
RE
.
Alzheimer-type neuropathological changes in morbidly obese elderly individuals
.
Clin Neuropathol
.
2009 Feb
;
28
(
1
):
40
5
.
7.
Anstey
KJ
,
Cherbuin
N
,
Budge
M
,
Young
J
.
Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies
.
Obes Rev
.
2011 May
;
12
(
5
):
e426
437
.
8.
Qizilbash
N
,
Gregson
J
,
Johnson
ME
,
Pearce
N
,
Douglas
I
,
Wing
K
,
.
BMI and risk of dementia in two million people over two decades: a retrospective cohort study
.
Lancet Diabetes Endocrinol
.
2015 Jun
;
3
(
6
):
431
6
.
9.
Noh
H-M
,
Han
J
,
Kim
YJ
,
Jung
J-H
,
Roh
YK
,
Song
HJ
.
Sex differences in the relationship between cognitive impairment and overweight or obesity in late life: a 3-year prospective study
.
Medicine
.
2019 Mar
;
98
(
9
):
e14736
.
10.
Guo
D
,
Zhang
X
,
Zhan
C
,
Lin
Q
,
Liu
J
,
Yang
Q
,
.
Sex differences in the association between obesity and cognitive impairment in a low-income elderly population in rural China: a population-based cross-sectional study
.
Front Neurol
.
2021
;
12
:
669174
.
11.
Schwartz
DH
,
Leonard
G
,
Perron
M
,
Richer
L
,
Syme
C
,
Veillette
S
,
.
Visceral fat is associated with lower executive functioning in adolescents
.
Int J Obes
.
2013 Oct
;
37
(
10
):
1336
43
.
12.
Elias
MF
,
Elias
PK
,
Sullivan
LM
,
Wolf
PA
,
D’Agostino
RB
.
Obesity, diabetes and cognitive deficit: the framingham heart study
.
Neurobiol Aging
.
2005 Dec
;
26
(
Suppl 1
):
11
6
.
13.
Kanaya
AM
,
Lindquist
K
,
Harris
TB
,
Launer
L
,
Rosano
C
,
Satterfield
S
,
.
Total and regional adiposity and cognitive change in older adults: the health, aging and body composition (ABC) study
.
Arch Neurol
.
2009 Mar
;
66
(
3
):
329
35
.
14.
Hwang
L-L
,
Wang
C-H
,
Li
T-L
,
Chang
S-D
,
Lin
L-C
,
Chen
C-P
,
.
Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice
.
Obesity
.
2010 Mar
;
18
(
3
):
463
9
.
15.
Espinosa-García
C
,
Fuentes-Venado
CE
,
Guerra-Araiza
C
,
Segura-Uribe
J
,
Chávez-Gutiérrez
E
,
Farfán-García
ED
,
.
Sex differences in the performance of cognitive tasks in a murine model of metabolic syndrome
.
Eur J Neurosci
.
2020 Jul
;
52
(
1
):
2724
36
.
16.
Lord
MN
,
Heo
J-W
,
Schifino
AG
,
Hoffman
JR
,
Donohue
KN
,
Call
JA
,
.
Sexually dimorphic effects of a western diet on brain mitochondrial bioenergetics and neurocognitive function
.
Nutrients
.
2021 Nov
;
13
(
12
):
4222
.
17.
Underwood
EL
,
Thompson
LT
.
High-fat diet impairs spatial memory and hippocampal intrinsic excitability and sex-dependently alters circulating insulin and hippocampal insulin sensitivity
.
Biol Sex Differ
.
2016
;
7
:
9
.
18.
Zanini
P
,
Arbo
BD
,
Niches
G
,
Czarnabay
D
,
Benetti
F
,
Ribeiro
MF
,
.
Diet-induced obesity alters memory consolidation in female rats
.
Physiol Behav
.
2017 Oct
;
180
:
91
7
.
19.
Duarte-Guterman
P
,
Yagi
S
,
Chow
C
,
Galea
LAM
.
Hippocampal learning, memory, and neurogenesis: effects of sex and estrogens across the lifespan in adults
.
Horm Behav
.
2015 Aug
;
74
:
37
52
.
20.
Paletta
P
,
Sheppard
PAS
,
Matta
R
,
Ervin
KSJ
,
Choleris
E
.
Rapid effects of estrogens on short-term memory: possible mechanisms
.
Horm Behav
.
2018 Aug
;
104
:
88
99
.
21.
Bethea
CL
,
Mirkes
SJ
,
Shively
CA
,
Adams
MR
.
Steroid regulation of tryptophan hydroxylase protein in the dorsal raphe of macaques
.
Biol Psychiatry
.
2000 Mar
;
47
(
6
):
562
76
.
22.
Gundlah
C
,
Alves
SE
,
Clark
JA
,
Pai
L-Y
,
Schaeffer
JM
,
Rohrer
SP
.
Estrogen receptor-beta regulates tryptophan hydroxylase-1 expression in the murine midbrain raphe
.
Biol Psychiatry
.
2005 Apr
;
57
(
8
):
938
42
.
23.
Wang
J
,
Chen
Z
,
Xiao
Z
,
Weng
Y
,
Yang
M
,
Yang
L
,
.
Estrogen induces Ido expression via TGF-β in chorionic villi and decidua during early stages of pregnancy
.
Int J Mol Med
.
2020 Sep
;
46
(
3
):
1186
96
.
24.
Zhu
W-H
,
Lu
C-Z
,
Huang
Y-M
,
Link
H
,
Xiao
B-G
.
A putative mechanism on remission of multiple sclerosis during pregnancy: estrogen-induced indoleamine 2, 3-dioxygenase by dendritic cells
.
Mult Scler
.
2007 Jan
;
13
(
1
):
33
40
.
25.
Slomp
M
,
Belegri
E
,
Blancas-Velazquez
AS
,
Diepenbroek
C
,
Eggels
L
,
Gumbs
MCR
,
.
Stressing the importance of choice: validity of a preclinical free-choice high-caloric diet paradigm to model behavioural, physiological and molecular adaptations during human diet-induced obesity and metabolic dysfunction
.
J Neuroendocrinol
.
2019 May
;
31
(
5
):
e12718
.
26.
Ennaceur
A
,
Delacour
J
.
A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data
.
Behav Brain Res
.
1988 Nov
;
31
(
1
):
47
59
.
27.
Spijker
S
.
Dissection of rodent brain regions
. In:
Li
KW
, editor.
Neuroproteomics
.
Totowa (NJ)
:
Humana Press
;
2011
. p.
13
26
.
28.
Honório de Melo Martimiano
P
,
de Sa Braga Oliveira
A
,
Ferchaud-Roucher
V
,
Croyal
M
,
Aguesse
A
,
Grit
I
,
.
Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring
.
J Neurochem
.
2017
;
140
(
1
):
68
81
.
29.
Daher-Abdi
A
,
Olvera Hernández
S
,
Reyes Castro
LA
,
Mezo-González
CE
,
Croyal
M
,
García-Santillán
JA
,
.
Maternal DHA supplementation during pregnancy and lactation in the rat protects the offspring against high-calorie diet-induced hepatic steatosis
.
Nutrients
.
2021 Aug
;
13
(
9
):
3075
.
30.
Dahl
A
,
Hassing
LB
,
Fransson
E
,
Berg
S
,
Gatz
M
,
Reynolds
CA
,
.
Being overweight in midlife is associated with lower cognitive ability and steeper cognitive decline in late life
.
J Gerontol A Biol Sci Med Sci
.
2010 Jan
;
65
(
1
):
57
62
.
31.
Coppin
G
,
Nolan-Poupart
S
,
Jones-Gotman
M
,
Small
DM
.
Working memory and reward association learning impairments in obesity
.
Neuropsychologia
.
2014 Dec
;
65
:
146
55
.
32.
Walf
AA
,
Rhodes
ME
,
Frye
CA
.
Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats
.
Neurobiol Learn Mem
.
2006 Jul
;
86
(
1
):
35
46
.
33.
Paris
JJ
,
Frye
CA
.
Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks
.
Reproduction
.
2008 Jul
;
136
(
1
):
105
15
.
34.
van Goethem
NP
,
Rutten
K
,
van der Staay
FJ
,
Jans
LAW
,
Akkerman
S
,
Steinbusch
HWM
,
.
Object recognition testing: rodent species, strains, housing conditions, and estrous cycle
.
Behav Brain Res
.
2012 Jul
;
232
(
2
):
323
34
.
35.
Cordeira
J
,
Kolluru
SS
,
Rosenblatt
H
,
Kry
J
,
Strecker
RE
,
McCarley
RW
.
Learning and memory are impaired in the object recognition task during metestrus/diestrus and after sleep deprivation
.
Behav Brain Res
.
2018 Feb
;
339
:
124
9
.
36.
Frick
KM
,
Gresack
JE
.
Sex differences in the behavioral response to spatial and object novelty in adult C57BL/6 mice
.
Behav Neurosci
.
2003 Dec
;
117
(
6
):
1283
91
.
37.
Ghi
P
,
Orsetti
M
,
Gamalero
SR
,
Ferretti
C
.
Sex differences in memory performance in the object recognition test. Possible role of histamine receptors
.
Pharmacol Biochem Behav
.
1999 Dec
;
64
(
4
):
761
6
.
38.
Sutcliffe
JS
,
Marshall
KM
,
Neill
JC
.
Influence of gender on working and spatial memory in the novel object recognition task in the rat
.
Behav Brain Res
.
2007 Feb
;
177
(
1
):
117
25
.
39.
Benice
TS
,
Rizk
A
,
Kohama
S
,
Pfankuch
T
,
Raber
J
.
Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein 2 and synaptophysin immunoreactivity
.
Neuroscience
.
2006
;
137
(
2
):
413
23
.
40.
Frye
CA
,
Walf
AA
.
Progesterone enhances performance of aged mice in cortical or hippocampal tasks
.
Neurosci Lett
.
2008 May
;
437
(
2
):
116
20
.
41.
Jenkins
TA
,
Nguyen
JCD
,
Polglaze
KE
,
Bertrand
PP
.
Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain Axis
.
Nutrients
.
2016 Jan
;
8
(
1
):
E56
.
42.
Schmitt
Ja. J
,
Wingen
M
,
Ramaekers
JG
,
Evers
Ea. T
,
Riedel
WJ
.
Serotonin and human cognitive performance
.
Curr Pharm Des
.
2006
;
12
(
20
):
2473
86
.
43.
Latif-Hernandez
A
,
Shah
D
,
Ahmed
T
,
Lo
AC
,
Callaerts-Vegh
Z
,
Van der Linden
A
,
.
Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity
.
Sci Rep
.
2016 Nov
;
6
:
36489
.
44.
Vohra
M
,
Lemieux
GA
,
Lin
L
,
Ashrafi
K
.
Kynurenic acid accumulation underlies learning and memory impairment associated with aging
.
Genes Dev
.
2018 Jan
;
32
(
1
):
14
9
.
45.
Hou
Y
,
Lautrup
S
,
Cordonnier
S
,
Wang
Y
,
Croteau
DL
,
Zavala
E
,
.
NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency
.
Proc Natl Acad Sci U S A
.
2018 Feb
;
115
(
8
):
E1876
85
.
46.
Chandrasekaran
K
,
Choi
J
,
Arvas
MI
,
Salimian
M
,
Singh
S
,
Xu
S
,
.
Nicotinamide mononucleotide administration prevents experimental diabetes-induced cognitive impairment and loss of hippocampal neurons
.
Int J Mol Sci
.
2020 May
;
21
(
11
):
3756
.
47.
Robinson
CM
,
Hale
PT
,
Carlin
JM
.
The role of IFN-gamma and TNF-alpha-responsive regulatory elements in the synergistic induction of indoleamine dioxygenase
.
J Interferon Cytokine Res
.
2005 Jan
;
25
(
1
):
20
30
.
48.
Urata
Y
,
Koga
K
,
Hirota
Y
,
Akiyama
I
,
Izumi
G
,
Takamura
M
,
.
IL-1β increases expression of tryptophan 2, 3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells
.
Am J Reprod Immunol
.
2014 Nov
;
72
(
5
):
496
503
.
49.
Xiao
B-G
,
Liu
X
,
Link
H
.
Antigen-specific T cell functions are suppressed over the estrogen-dendritic cell-indoleamine 2, 3-dioxygenase axis
.
Steroids
.
2004 Sep
;
69
(
10
):
653
9
.
50.
Saadati
H
,
Sadegzadeh
F
,
Sakhaie
N
,
Panahpour
H
,
Sagha
M
.
Serotonin depletion during the postnatal developmental period causes behavioral and cognitive alterations and decreases BDNF level in the brain of rats
.
Int J Dev Neurosci
.
2021 Apr
;
81
(
2
):
179
90
.
51.
Covarrubias
AJ
,
Perrone
R
,
Grozio
A
,
Verdin
E
.
NAD+ metabolism and its roles in cellular processes during ageing
.
Nat Rev Mol Cell Biol
.
2021 Feb
;
22
(
2
):
119
41
.
52.
Lautrup
S
,
Sinclair
DA
,
Mattson
MP
,
Fang
EF
.
NAD+ in brain aging and neurodegenerative disorders
.
Cell Metab
.
2019 Oct
;
30
(
4
):
630
55
.
53.
Hosseini
L
,
Mahmoudi
J
,
Pashazadeh
F
,
Salehi-Pourmehr
H
,
Sadigh-Eteghad
S
.
Protective effects of nicotinamide adenine dinucleotide and related precursors in alzheimer’s disease: a systematic review of preclinical studies
.
J Mol Neurosci
.
2021 Jul
;
71
(
7
):
1425
35
.
54.
Giil
LM
,
Midttun
Ø
,
Refsum
H
,
Ulvik
A
,
Advani
R
,
Smith
AD
.
Kynurenine pathway metabolites in alzheimer’s disease
.
J Alzheimers Dis
.
2017
;
60
(
2
):
495
504
.
55.
Whiley
L
,
Chappell
KE
,
D’Hondt
E
,
Lewis
MR
,
Jiménez
B
,
Snowden
SG
,
.
Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease
.
Alzheimers Res Ther
.
2021 Jan
;
13
(
1
):
20
.
56.
Bakker
L
,
Ramakers
IHGB
,
van Boxtel
MPJ
,
Schram
MT
,
Stehouwer
CDA
,
van der Kallen
CJH
,
.
Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study
.
Diabetologia
.
2021 Nov
;
64
(
11
):
2445
57
.
57.
Porter
GA
,
O’Connor
JC
.
Chronic unpredictable stress alters brain tryptophan metabolism and impairs working memory in mice without causing depression-like behaviour
.
Neurol Neurobiol
.
2021
;
4
(
3
). Epub ahead of print. https://doi.org/10.31487/j.nnb.2021.03.03.
You do not currently have access to this content.