Physiology & Behavior 240 (2021) 113528

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Physiology & Behavior

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

High fat diet and its effects on cognitive health: alterations of neuronal and
vascular components of brain
Sorabh Sharma *
Division of Medical Sciences, University of Victoria, PO Box 1700 STN CSC, Victoria, BC, V8W2Y2, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: It has been well recognized that intake of diets rich in saturated fats could result in development of metabolic
Blood brain barrier disorders such as type 2 diabetes mellitus, obesity and cardiovascular diseases. Recent studies have suggested
Cerebral blood flow that intake of high fat diet (HFD) is also associated with cognitive dysfunction. Various preclinical studies have
Cognitive decline
demonstrated the impact of short and long term HFD feeding on the biochemical and behavioural alterations.
Insulin resistance
Neurotrophic factor
This review summarizes studies and the protocols used to assess the impacts of HFD feeding on cognitive per­
formance in rodents. Further, it discuss the key mechanisms that are altered by HFD feeding, such as, insulin
resistance, oxidative stress, neuro-inflammation, transcriptional dysregulation and loss of synaptic plasticity.
Along with these, HFD feeding also alters the vascular components of brain such as loss of BBB integrity and
reduced cerebral blood flow. It is highly possible that these factors are responsible for the development of
cognitive deficits as a result of HFD feeding.

1. Introduction
It is well known that the human brain requires a high amount of
energy to perform a diverse array of actions. However, the brain pos­
sesses minimal energy reserves that can satisfy only a small portion of its
energy demand. Thus, the brain heavily relies on the continuous supply
of nutrients from the blood via the blood-brain barrier (BBB) to meet its
required energy goals. Under physiological conditions, the brain uses
glucose as a main fuel [49]. However, the brain can also utilize some
alternative energy substrates such as ketone bodies, triglycerides and
lactate during development and times when the glucose availability is
scarce [21]. Recent research has provided exciting evidence that
adequate dietary intake and nutritional status can have a profound
impact on cognitive capabilities, neuronal function, neuronal signaling,
and synaptic plasticity [70, 126]. For example, both clinical and pre­
clinical studies have consistently shown that intake of diets rich in
saturated fats can cause impaired cognitive performance [72, 132].
Interestingly, studies in the adult human population suggested that even
short-term dietary intake of a high fat diet (HFD) is associated with
impaired attention and visual memory [13, 52]. Notably, intake of
saturated fat rich diet is widely considered as a driving factor for
cognitive impairment and AD development [57, 105]. In contrast, diets
rich in polyunsaturated fatty acids have been reported to promote
cognitive health [57, 105, 127, 223]. Thus, it is conceivable that the
composition, abundance or the lack of specific nutrients in the diet can
differentially affect the functions of the brain. In the present review, we
will focus on this vital issue of fat composition in diet and how it ma­
nipulates the functioning of the brain with respect to cognitive perfor­
mance in both humans and rodents.
Traditionally, consumption of saturated fat rich diet is associated
with the development of metabolic and cardiovascular diseases [39,
103, 182]. A growing body of research indicate that patients with
metabolic syndrome (including diabetes, obesity, hypertension) have an
increased relative risk for development of diverse cognitive impairments
and AD [17, 30, 38, 46, 57, 68, 96, 112, 143, 193, 200]. Thus, consid­
ering the progressive increase in global burden of both metabolic dis­
orders and neurological diseases, it is necessary to dig into the possible
mechanisms of association between these diseases. Availability of a
suitable animal model is very critical to study these mechanisms.
Considering the polygenic nature of metabolic diseases such as diabetes
and obesity, it is not wise to use animal models that are monogenic in
nature for example, ob/ob mouse or the Zucker-(fa/fa) fatty rat for
studying all aspects of these polygenic diseases. Importantly, the HFD
feeding model seems best to study these conditions as it is associated
with a wide range of metabolic disturbances related to body weight,
blood glucose, insulin levels, lipid profile, cholesterol level etc. Thus,

* Corresponding author.
E-mail address: sharmasorabh88@gmail.com.

https://doi.org/10.1016/j.physbeh.2021.113528
Received 3 April 2021; Received in revised form 3 July 2021; Accepted 6 July 2021
Available online 11 July 2021
0031-9384/© 2021 Elsevier Inc. All rights reserved.
S. Sharma
researchers have been using this model to generate the metabolic syn­
drome in rodents.
2. Historical aspects of HFD feeding animal model and its
association with cognitive decline in rodents
Although initially described as an animal model to study the impact
of dietary fats on metabolic health, HFD feeding has now emerged as an
indispensable tool to study the effects of fat-rich diets on neuronal
health. During the 1940s, Samuels and colleagues demonstrated that
feeding rats with HFD (containing 70% energy as fat) result in an
elevation of basal and postprandial blood glucose along with the
development of obesity [171]. However, it was not until the 1990′ s
when the initial connections of HFD feeding in rodents were found to
affect their cognitive health by Greenwood and Winocur [73]. They used
Long Evans rats (1-month-old) and fed them with different dietary
regimens including high saturated fatty acid (SFA) diet, a high poly­
unsaturated fatty acid diet, or a normal rat chow diet, for 3 months. The
rats were then evaluated for the impact of these different dietary regi­
mens on their learning and memory performance using a battery of
behavioral tasks. Interestingly, they found that rats fed with a diet rich
in saturated fat, performed poorly in all behavioral tasks as compared to
other diets, highlighting the detrimental effects of a saturated fat-rich
diet on cognitive performance and brain health [73]. Later, seminal
work by these researchers described a link between HFD feeding and
cognitive dysfunction by highlighting insulin resistance as an important
mechanism [72, 220, 221, 219]. Since then, numerous preclinical
studies showed that feeding the rodents with HFD results in significant
impairment in their cognitive function ([33, 75, 128, 169, 177, 178,
210]).
3. Variants of high fat diet and their effects on metabolic and
cognitive health
Different compositions of HFDs have been used to induce obesity and
metabolic disorders in rodents. Conventionally, for making these diets,
the researchers replace the carbohydrate-derived calories with fat-
derived calories and then compared this diet with a standard chow
diet as a control [106]. However, recently, the researchers have been
modifying the diet composition based on their specific experimental
objectives by altering the fat content or by adding additional stressors
such as streptozotocin or higher cholesterol concentration. In this sec­
tion, we will review some of the most commonly used variations in the
diet composition for inducing metabolic and neurological dysfunctions
in rodents.
(i) Type of fat: Saturated vs Unsaturated
Numerous factors such as carbon chain length, degree of unsatura­
tion, the position and configuration of double bonds can affect the
metabolic fate of dietary fatty acids [48]. Classically, the HFDs fed to
rodents contains a high fraction of saturated fatty acids and a very low
fraction of monounsaturated and polyunsaturated fatty acids. In addi­
tion, recent studies also showed that diets rich in saturated fats are more
obesogenic compared to diets containing unsaturated fatty acids [39,
77]. A growing body of evidence suggests that excessive intake of a
saturated fat rich diet can result in an increased body weight gain, hy­
perglycemia, impaired glucose tolerance, and obesity [3, 153]. Alter­
natively, a recent prospective study demonstrates that increasing the
intake of unsaturated fatty acids at the expense of saturated fatty acids
may exert beneficial effects on body weight and obesity [15]. Even
short-term feeding of a saturated fat-rich diet is associated with signif­
icant effects on the metabolic profile. For example, oral ingestion of a
high-fat emulsion in Wistar rats for 10 days has been reported to induce
insulin resistance, along with larger adipocyte and pancreatic islets,
increased GLUT2 and α-glucosidase mRNA expression [1]. Similar
2
Physiology & Behavior 240 (2021) 113528
reports demonstrate that lard-based saturated fat-rich diet feeding for 4
weeks results in mild hyperglycemia, hyperinsulinemia, glucose intol­
erance, hypertriglyceridemia, hypercholesterolemia, and hypertension
[148, 208]. Importantly, excessive intake of these saturated fatty
acids-rich diets is strongly associated as a risk factor for the development
of cognitive decline in humans [27, 95, 211]. Although most researchers
use only a HFD, which is rich in saturated fatty acids to induce metabolic
alterations and study the effects on learning and memory tasks [128,
242]. However, others have opted some additional stressors along with
HFD to better mimic the human disease conditions in rodents.
(ii) Additional Stressors: Streptozotocin with HFD
One of the prime examples of an added stressor to HFD feeding is the
use of pancreatic β-cell toxin, streptozotocin (STZ) at a low dose [120,
121, 238]. Administering high doses of STZ alone can severely impair
insulin secretion and mimic the T1DM condition in rodents. However,
when combined with HFD feeding protocol, a low-dose STZ has been
shown to induce a mild impairment of insulin secretion which is a
hallmark feature of later stages of T2DM [165, 186]. Reed and col­
leagues first described this animal model and demonstrated that the
animals fed with HFD alone exhibited high blood insulin levels but
normal blood glucose levels [165]. They suggested that administration
of STZ after HFD feeding can reduce the functional capacity of β-cells of
the pancreas without completely compromising insulin secretion. They
fed the male Sprague-Dawley rats with either normal chow (12% fat), or
a HFD (40% fat) for 2 weeks followed by STZ injections (50 mg/kg
intravenously) and found that the rats fed with HFD and injected with
STZ have hyperglycemia, elevated insulin, free fatty acids (FFAs), and
triglycerides (TGs) level as compared with chow-fed STZ-injected rats
[165]. Later, this model was further modified by Zhang and colleagues,
who used low dose STZ (15 mg/kg) after HFD feeding (30% of calories as
fat) for two months [237]. Further, Srinivasan and colleagues modified
this protocol by feeding male Sprague–Dawley rats with either a normal
pellet diet (NPD) (12% fat) or HFD (58% fat), respectively for 2 weeks.
Following 2 weeks of dietary regimen, they injected the rats with a lower
dose of STZ (35 mg/kg, i.p.) [186]. They reported that following STZ
injection, the HFD fed rats developed frank hyperglycemia, however, the
NPD-fed rats showed just mild elevation in glucose levels. They also
showed that the HFD fed STZ injected rats had an insulin deficit as
compared to normal rats [186]. These studies highlight the importance
of adding STZ as an additional stressor to develop a model which better
mimics the human T2DM condition instead of just using HFD alone.
Since these interesting studies have published, many research groups
have taken advantage of this excellent model and screened a number of
potential drug candidates.
(iii) Addition of higher concentration of carbohydrates
In addition to using STZ as an additional stressor along with HFD,
researchers have also utilized other approaches to modify the HFD
model. Some researchers even replace the fat content with higher
fructose concentrations in their diet composition. However, the effec­
tiveness of such diets in inducing metabolic syndrome is still question­
able. Zaman and colleagues compared the effects of a HFD and a high-
fructose diet on body weight, plasma lipid profiles, and insulin sensi­
tivity in rats in their longitudinal study [236]. They fed the rats with
either a HFD (65% calories from fat) or a high-fructose diet (65% cal­
ories from fructose) for a period of 10-weeks and demonstrated that rats
fed with HFD showed the development of obesity along with low insulin
sensitivity. On the contrary, rats fed with a high-fructose diet showed no
change in insulin sensitivity and lipid profile. This study suggests that
HFD feeding has more deleterious effects on lipid profile and insulin
sensitivity as compared to a high fructose diet [236].
Recent studies suggest that feeding a diet that is composed of a
combination of high fat and high sugar content possesses a higher risk
S. Sharma
Table. 1
Preclinical studies evaluating the effects of HFD feeding on brain health and cognitive functioning of rodents. (Arranged in ascending order of the duration of
diet feeding).
Diet composition and duration of
feeding
HFD containing 45% fat by kcal
for 72 h
High fat high fructose diet
(HFFD) containing 10% lard in
chow and 60% fructose in
drinking water for 7 days
Low-fat diet (10% energy from
fat) and HFD (60% energy from
fat) for 1 or 2 weeks
HFD 60% of kilocalories for 7
days
HFD (Coconut oil 5%;
Cholesterol 2%; Cholic acid
1%) for 28 days
HFD containing 60% calories
from fat for 1, 3 or 6 weeks
HFD 58% fat kcal for 5 weeks
High-fat high-carbohydrate diet
containing mainly 25% total
fat; 44% carbohydrates for 6
weeks
HFD containing 0.236 g fat/g of
diet for 4days or 4 weeks
HFD (21.2% fat) for 4 or 7 weeks
HFD (45% energy from fat) for 7
weeks
HFD (45% energy from fat) for 7
weeks
HFD containing 60 kcal% fat for
8 weeks
HFD containing 60 kcal% fat for
8 weeks
HFD (primarily from lard plus a
small amount of corn oil,
approximately 39% energy) for
2 months
HFD (containing 60% kcal fat for
17days and 45% kcal fat for 8
weeks)
Physiology & Behavior 240 (2021) 113528
Compound tested Behavioral task performed References Animals (sex, strain, Effect of High fat diet feeding on brain health
species, age) and behavioural tasks
– – [66] Male Long-Evans rats HFD fed rats showed increase in BDNF and
(8–10 week-old) HDAC2 in the dorsal hippocampus and
significant increase in HDAC4 in the ventral
hippocampus.
– – [26] Male Sprague Dawley HFD leads to decreased insulin signaling;
Rats weighing 250 to decreased hippocampal weight; reduction in
270 g dendritic arborization in CA1 and MAP-2 levels;
decreased dendritic spine number in CA1 and
synaptophysin content, an increase in tau
phosphorylation; and an increase in reactive
astrocyte associated with microglial changes.
– Object-place-context [128] Male C57Bl/6 J mice Performance deficits were seen after only one
(OPC) memory task; Object (12 week old) day of HFD. Switching from a high-fat diet back
exploration; Novel object to a low-fat diet reverses cognitive deficits
recognition (NOR) task
Tyr-Leu-Gly (YLG), Object recognition test [136] Eleven-week-old HFD intake reduced cognitive function in
a tripeptide derived (ORT) and object location male ddY mice behavioural tasks; decreased the number of
from αS1-casein test (OLT). 5‑bromo-2′ -deoxyuridine (BrdU)–positive cells;
decreased nerve growth factor (NGF) and glial
cell line–derived neurotrophic factor (GDNF)
Atorvastatin Y maze; Hebb-William’s [18] Swiss albino mice HFD fed animals showed impaired performance
Maze; elevated plus; either sex (22–28 g) in all behavioural tasks
Passive Avoidance
Glyburide NOR and Object Location [65] C57BL/6 J male mice HFD fed mice showed impaired performance in
Recognition (OLR) (3–4 weeks old) NOR task after 1 week. After 3 weeks, HFD-mice
had impaired NOR and OLR. These mice also
displayed anxiety-like behavior. After 6 weeks,
HFD-mice were comparable to LFD-mice in
NOR, open-field and elevated zero maze
performance, but they remained impaired
during OLR testing
Rosiglitazone MWM [148] Adult male SD rats HFD feeding results in severe deficit in learning
weighing 150–190 g and memory
Vitamin E RAM [4] Adult male Wistar HFD feeding results in impaired memory;
rats weighing Elevated oxidative stress; Reduced antioxidant
200–250 g defense.
– – [114] Male and female After 4 weeks, HFD fed male rats showed
Long-Evans rats reduction in BDNF expression in the VMN of the
hypothalamus, but no change in females.
– Object-place recognition; [216] Male C57BL/6 J mice HFD animals had increased oxidative stress and
Open-field test; fear (6–8 weeks old, biochemical alterations in the hippocampus
conditioning task 18–22 g) after 4 weeks and were aggravated by a longer
exposure time; HFD-fed mice displayed long-
term memory impairments, abnormal
expression of proteins associated with synaptic
function.
Salvianolic acid B MWM [228] Male C57BL/6 mice HFD feeding resulted in higher food intake,
(4–6 weeks old dyslipidemia, cognitive impairment and
increasing hippocampal and frontal cortex
oxidative stress.
– – [146] Male C57BL/6 mice HFD feeding decreased the numbers of newly
(5 week-old) generated cells in the dentate gyrus; increased
MDA and decreased the level of BDNF in the
hippocampus
Pyridoxine – [233] Male C57BL/6 J mice In the HFD-fed group, Ki67-positive nuclei and
DCX-ir neuroblasts were significantly decreased
in the DG compared with those in the LFD-fed
mice. HFD also reduced the levels of GAD67,
pCREB, BDNF.
Metformin and – [232] Male C57BL/6 mice Ki67-immunoreactive (+) nuclei, DCX+
Glimepiride (6 weeks age) neuroblasts and BDNF protein levels were
markedly decreased in the DG of the HFD mice
Exercise MWM [133] Female Fisher 344 HFD feeding results in an increased reactive
rats; 2 months old oxygen species; reduced BDNF and altered CREB
activity; impaired spatial learning in MWM
– T-maze [7] C57BL/6 J male mice HFD mouse showed insulin resistance in
(9 week old) cerebral cortex; their hippocampus exhibited
increased expression (IRS1-pS616), as well as
decreased expression of PSD-95, and
(continued on next page)
3
S. Sharma
Table. 1 (continued )
Diet composition and duration of
feeding
Diet high in monounsaturated fat
(≈ 38% energy) and refined
sugar (≈ 38% energy) for 8
weeks
HFD lard based 39% fat for 2
months
HFD containing 32% fat for 8
weeks
HFD containing 60% of energy as
lipids for 8 weeks
HFFD containing 45% fructose,
20% fat for 60 days
HFHC (21% fat and 1.25%
cholesterol) for 2 months
HFD containing 45% of fat for 11
weeks
HFD containing 20 g lard/100 g
diet for 3 months
HFD containing 59.28% fat
mostly from lard for 12 weeks
HFD (60% of calorie from fat) for
12 weeks
HFD 59.3% fat for 12 weeks
HFD 59.3% fat for 12 weeks
HFD (containing 45% of calories
as crude fat) for 12 weeks
HFHF (46% fructose and 20%
lard) for 12 weeks
HFD containing 42% of calories
from fat for 12 weeks
HFD contains Lard 310 g/1000 g
for 90 days
HFD 310 g/1000 g for 90 days
HFD containing 21.2% fat and
1% cholesterol) for 13 weeks
HFD 32% kcal from fat for 13
weeks
Physiology & Behavior 240 (2021) 113528
Compound tested Behavioral task performed References Animals (sex, strain, Effect of High fat diet feeding on brain health
species, age) and behavioural tasks
synaptopodin; Spatial working memory was
impaired.
– NOR; MWM; Operant [63] Male Sprague Dawley Rats fed with high fat and refined sugar diet
Lever Press (OLP) and rats showed impaired performance in NOR and
Extinction Task MWM tasks.
Vitamin E MWM [224] Male Sprague Dawley Reduced CREB; Synapsin 1; BDNF; increased
rats 200–240 g oxidative stress; impaired learning and memory
performance
β-Alanyl-L-Histidine Fear conditioning [80] B6C3-Tg (APP swe/ Significant decline in the contextual memory in
PSEN1dE9)85Dbo/J transgenic mice fed with HFD; an increase e in
AD mice both sexes (4 the expression of RAGE in blood vessels as well
month old) as increased microglial activation in the
hippocampus of animals fed with HFD
Lipoic acid NOR [166] Male Wistar rats (6 HFD rats showed alterations in central insulin
week old) signaling; Significantly decreased VGlut1
expression, and memory impairments.
Indirubin-3- – [173] Male Swiss albino HFFD fed-mice had significant amyloid deposits
monoxime mice (7 weeks old) in cerebral cortex and hippocampus, and protein
expression analyses showed activation of GSK-
3β, nuclear translocation of NF-κB p65 and
upregulation of inflammatory (TNF-α, IL-6,
COX-2), astrocytic (GFAP), glial surface (CD-68)
and pro-apoptotic markers (Bax and caspase-3).
– – [16] 4 month old C57BL/6 Presence of hyperphosphorylated tau correlated
mice with activated GSK3
BDNF – [69] Male SD rats Chronic VMN administration of BDNF reduced
(225–250 g) 10-week insulin elevation and/or reversed
old hyperleptinemia
– RAM; Variable-interval [73] Male Long-Evans Among different diets, the rats fed with lard-rich
delayed alternation task, hooded rats; 1 month diet showed impaired performance in all tests.
Hebb-Williams maze of age and weighing
60–80 g
Vildagliptin MWM and Open field test [157] Male Wistar rats HFD results in neuronal insulin resistance and
180–200 g brain mitochondrial dysfunction with impaired
learning and memory.
– [116] 3 month old C57BL/ Decreased IRS-1/ ERK/CREB and GLUT4 in the
6 J mice brain of HFD fed mice.
Metformin MWM [156] male Wistar rats 180 Increased peripheral and brain oxidative stress
to 200 g (5 weeks old) levels, brain mitochondrial dysfunction;
impaired learning behavior
Vildagliptin and MWM and Open field task [155] male Wistar rats HFD feeding results in increased circulating and
Sitagliptin 180–200 g (6–7 brain oxidative stress levels; brain and
weeks old) hippocampal mitochondrial dysfunction;
impaired learning behavior.
– Open field; MWM; Operant [129] Male Wistar rats HFD animals were consistently poorer in all
task (150–175 g) aspects of an operant based delayed matching to
position task, no significant difference in open
field and MWM.
Cinnamon Y maze; Elevated plus [5] Male Wistar rats 5 Higher anxiety in an elevated plus maze test;
maze weeks down regulation of the mRNA coding for GLUT1
and GLUT3; increases in mRNA associated with
AD including PTEN, Tau and amyloid precursor
protein (App)
– [99] Tg2576 female mice Elevated level of Aβ40 and Aβ42 in HFD-fed Tg
(4-week old) brain; decrease in the expression of the
anorexigenic neuropeptide, brain-derived
neurotrophic factor,
Liver X receptor MWM [183] Swiss albino mice HFD produced a significant decline in MWM
agonist T0901317 (20–25 g) of either performance of the animals, reflecting
sex impairment of learning and memory; Increased
oxidative stress; reduced anti-oxidant defense
Silymarin MWM [139] Swiss albino mice HFD significantly impaired the cognitive
(20–25 g) of either abilities, along with increasing brain AchE,
sex TBARS, MPO, nitrate/nitrite, and serum
cholesterol levels. Marked reduction of brain
GSH levels was observed.
Quercetin MWM [226] Male Chinese Escape latency was increased and percent time
Kunming (KM) mice spent in the target quadrant was decreased, with
increased reactive carbonyls, malondialdehyde
(MDA) and declined expression of pi3k, akt,
nrf2, creb and bdnf in the hippocampus of HFD
calorie restriction MWM [94] Male Sprague- HFD results in reduced BDNF expression in the
Dawley rats (350 to hippocampus and reduced cognitive
425 g) performance in MWM
(continued on next page)
4
S. Sharma
Table. 1 (continued )
Diet composition and duration of
feeding
HFD containing 42% kcal from
fat, for 4 months
HFD of 2 types: Western diet
(41% fat), very high fat lard
diet (60% fat for 16 weeks)
HFD containing 60 kcal% fat; for
4 months then switched to
normal diet till 22 months of
age
HFD 45% fat for 20 weeks
HFD (60%) fat for 20 weeks.
High cholesterol 5% for 20 weeks
HFD 60% fat for 20 week
HFD containing 60% fat for 5
months
HFD containing 60 kcal% fat; for
6 Months
High-fat, high-glucose
supplemented with 20% high-
fructose corn syrup for 8
months
HFD containing 60% kcal fat for
9 months
HFD for 9–12 months
HFD (45% kcal fat) for 10 months
HFD containing 45 kcal% fat for
approximately 10–11 months
HFD containing 60% energy from
fat, for varying intervals and
age upto 3–16months
AD: Alzheimer’s disease; HFD: High fat diet; HFHF: High fat-high fructose; HFHC: high fat high cholesterol; Aβ: Amyloid-β; MWM: Morris Water Maze; GLUT: Glucose
transporter; NOR: Novel Object Recognition task; TNF-α: Tumour Necrosis factor-α; CREB: cAMP Responsive element binding protein; GSK-3β: Glycogen synthase
kinase-3β; BDNF: Brain-derived neurotrophic factor; T2DM: Type 2 diabetes mellitus; PKB: Protein Kinase B; ROS: Reactive Oxygen Species; MDA: Malondialdehyde;
AGEs: Advanced glycation end products; LTP: Long term potentiation; HDAC: Histone deacetylases;MMP-9: matrix metalloproteinase-9: MPO: Myeloperoxidase;
TBARS: Thiobarbituric acid reactive substances; GSH: Reduced glutathione; AchE: Acetyl cholinesterase; ERK: Extracellular signal–regulated kinases; IRS: Insulin
Receptor Substrate; VMN: Ventromedial nucleus of the hypothalamus; RAGE: Receptor for Advanced Glycation End Products; OLP: Operant Lever Press; OLR: Object
Location Recognition; GDNF: glial cell line–derived neurotrophic factor; NGF: nerve growth factor.
Physiology & Behavior 240 (2021) 113528
Compound tested Behavioral task performed References Animals (sex, strain, Effect of High fat diet feeding on brain health
species, age) and behavioural tasks
– T-water maze; New object [201] APPswe/PS1 mice (3 HFD accelerates age-associated cognitive
recognition and 12 month old) decline without affecting parenchymal Aβ; HFD
decreases MMP-9 enzymatic activity and brain-
derived neurotrophic factor mRNA and protein
levels; altering BBB functionality
– 14-Unit T-maze [135] Male C57Bl/6 mice Only the HF Lard diet increased age-related
(20-month old) oxidative damage (protein carbonyls); impaired
retention in the behavioral test; a decline in Nrf2
levels and Nrf2 activity
– MWM; contextual fear [213] Female C57BL6/J HFD fed mice displayed severe deficits in
conditioning test mice 2 months of age learning and long-term memory consolidation.
HFD mice also showed increased expression of
HDAC 5, accompanied by reduced expression of
BDNF in the brains 61 weeks after the mice had
been off the high-fat diet.
Liraglutide ORT [159] Young Male Swiss TO LTP was completely abolished in high fat saline-
mice (6–8 weeks old) treated mice. HFD fed mice also performed
poorly in object recognition task.
Resveratrol MWM [89] Male C57BL/6 J mice HFD induces hepatic steatosis, macrophage
(3 weeks old) infiltration, and insulin resistance. HFD mice
also showed increased expression of TNF-α and
Iba-1, tau phosphorylation in hippocampus and
memory deficits.
Troxerutin, a MWM; step-through [119] Male C57BL/6 mice Cholesterol rich diet feeding results in an
naturally occurring passive avoidance task (4-week-old) increased ROS, AGEs; endoplasmic reticulum
flavonoid stress and impaired PI3K/Akt/CREB pathway.
These mice also showed impaired performance
in behavioural tasks.
Treadmill Exercise MWM; step-down [147] Four-week-old HFD fed mice showed a decrease in insulin
C57BL/6 male mice signaling, neuroplasticity in the hippocampus
and the dentate gyrus along with cognitive
impairment.
– MWM; Locomotor activity [82] Female 3xTg-AD HFD feeding result in an elevation in
mice amyloidogenic Aβ1–42 and Aβ1–42 peptide;
altered insulin signaling and Impaired learning
in behavioural tasks.
HDAC II inhibitor – [214] Female C57BL6/J T2DM mice showed increased expression of
MC1568 mice 2 months of age HDAC5 and 9 in the brain, and increased
susceptibility to oligomeric Aβ-induced synaptic
impairments in the hippocampal formation and
synaptic dysfunction.
– MWM [191] Rats HFD fed rats exhibited impaired spatial learning
ability, reduced hippocampal dendritic spine
density, and reduced long-term potentiation at
Schaffer collateral—CA1 synapses; Reduced
BDNF in hippocampus.
Insulin object-recognition task [206] Female 3xTg-AD HFD enhanced glucose intolerance, brain
mice (at 6months of soluble Aβ, and memory impairment in 3xTg-AD
age) mice
– Contextual fear [85] C57BL/6 J mice both The obese male, but not female, mice showed
conditioning and step- sexes poorer learning performance than their normal
down passive avoidance counterpart in behavioural tasks.
tasks
– Morris water maze; [130] Male C57BL/6 mice No effect in MWM; Impaired performance in an
Operant-learning task (17–20 g) operant bar-pressing task.
Melatonin MWM [229] Female Sprague- HFD feeding increases Aβ accumulation, Tau
Dawley rats (8- phosphorylation in the hippocampus along with
month-old) activated microglia and astrocytes. Cognitive
decline was observed in these rats in MWM task
along with reduced CREB activity and BDNF
levels in the hippocampus.
– Y-maze spontaneous [98] Male 3xTgAD mice HFD impairs learning and memory in different
alternation, smell (8 week old) tasks.
recognition, NOR; MWM
5
S. Sharma
Fig. 1. Pathways leading to hippocampal neuronal damage and cognitive impairment as a result of HFD feeding Note: DAG: Diacyl glycerol; IL-1β: Inter­
leukin-1β; PKC: Protein Kinase C; ROS: Reactive oxygen species; TNF- α: Tumour Necrosis factor- α.
for the development of metabolic syndrome as compared to diets rich in
either fat or sugar [11, 117]. Lozano and colleagues showed that 2
months of feeding of either a high-fat high fructose diet (HFHF) or HFD
results in an increased body weight, leptin, and HOMA-IR in rats.
However, the rats fed with alone high fructose diet had only a transient
increase of leptin and c-peptide [117]. Some studies even reported
better outcomes of this combination of a high-fat, high- carbohydrate
diet compared to HFD alone. For example, in their interesting study,
Kohli and colleagues randomly assign C57BL/6 mice to different dietary
regimens, including, a chow diet, a HFD (58 kcal% fat), or a high-fat,
high-carbohydrate (HFHC) diet and drinking water enriched with
high-fructose corn syrup equivalent. They demonstrated similar effects
of HFD and HFHC on weight gain, insulin resistance, body fat, and liver
steatosis. Interestingly, the mice fed with the HFHC diet had increased
hepatic oxidative stress, fibrogenesis and collagen deposition as
compared to the HFD fed group. Thus, it is proposed that the addition of
fructose to HFD promotes liver fibrogenesis [100]. Based upon these
findings, several preclinical studies have used this diet composition to
reveal its effect on learning and memory in rodents [5, 26, 173].
(iv) Addition of higher cholesterol in HFD
Cholesterol is essential for the normal functioning of the brain and
plays an important role in signaling pathways, synaptic plasticity,
learning, and memory. Previous research has suggested that the brain
contains the remarkably highest level of cholesterol in the body, which
is approximately 20% of whole-body cholesterol [19]. A growing body
of evidence suggests that higher than normal cholesterol levels can be
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Physiology & Behavior 240 (2021) 113528
detrimental to brain health and could even account for mild cognitive
impairment and dementia [62, 184, 185, 218]. Thus, not surprisingly,
researchers have used this idea and studied how the addition of
cholesterol to HFD can affect the metabolic and neurological functions
in rodents. Recently, a comparative study demonstrated that
cholesterol-rich HFD induces more severe liver damage, inflammation,
fibrosis, and insulin resistance than HFD without cholesterol [79].
Moreover, there is increasing evidence that a high-cholesterol diet can
induce neuroinflammation and neuronal apoptosis, ultimately resulting
in neurodegeneration and cognitive deficits [28, 161]. Interesting
studies by Thirumangalakudi and colleagues demonstrated that feeding
a high fat/high cholesterol diet to C57BL/6 for 8 weeks results in a loss
of working memory in mice, which was correlated with
neuro-inflammatory changes and increased AβPP processing [202].
Thus, these authors suggested that cognitive deficit associated with
hypercholesterolemia is mediated by increased neuro-inflammation and
APP processing in a non-transgenic mouse model. Moreover, recently
these authors also demonstrated that feeding the cholesterol-rich diet
can also result in hyperphosphorylated tau and increased GSK-3 activity
in the hippocampus of mice. These changes were attributed to insulin
resistance conditions in the hippocampus [16]. Some other groups have
also observed significant deficits in working memory of mice fed with a
high fat/high cholesterol diet [71]. Alternatively, some studies have also
shown that decreasing cholesterol levels in the brain could improve
learning and memory performance in different behavioral tasks [93,
231].
In summary, it is plausible that the composition of the diet is a vital
factor that affects the development of cognitive and metabolic
S. Sharma
alterations. It is advisable that along with the composition of the diet,
many other important factors should also be kept in the mind while
studying the effects of HFD on cognitive functions such as duration of
the HFD feeding, age, sex, and strain of the animal. Perhaps all these
factors make it difficult to compare studies among each other. For
example, most of the studies have shown that cognitive deficits can be
observed in HFD fed rodents within 4 to 12 weeks period. However, a
recent study by McLean and colleagues exhibited that HFD-mediated
cognitive deficits can be observed within a week of diet feeding [128].
This study provided evidence that HFD mediated cognitive decline starts
much earlier than anticipated based on previous literature [37, 90].
Another study reported that the biochemical alterations in the brain
associated with HFD feeding could be observed as early as 72 h after the
initiation of diet feeding [66]. These researchers observed that levels of
enzyme histone deacetylases (HDACs) were significantly higher in the
hippocampus of HFD-fed rats after 72 h of feeding [66]. Moreover,
recent studies have demonstrated that the underlying insulin resistance
in the brain can occur after only 3 days of a HFD feeding initiation [35,
142].
Some other factors such as the strain of rats/mice can affect the
development of metabolic and neurological alterations. For example,
some strains such as C57BL/6 J mice or Wistar rats develop obesity and
insulin resistance as a result of HFD feeding but 129S6 mice [2] or A/J
mice do not [194]. Thus, in this review, we have distilled hundreds of
papers and provided a summary of various factors such as diet compo­
sition (% of fat), diet duration, animal variables (strain, age, and sex),
behavioral task performed that can affect the metabolic and neurolog­
ical functioning (Table. 1). As discussing each of this factor is beyond the
scope of this review, the readers are directed to very good papers that
focus on how these differences among strains, sex, age, and diet
composition can affect the development of pathological conditions [25,
39, 81, 140].
4. Potential mechanisms of HFD mediated neuronal dysfunction
and cognitive deficits
4.1. HFD and oxidative stress
The brain is considered as the most vulnerable organ to damage by
oxidative stress [67]. This is attributed to the higher lipid content, high
demand for oxygen, and the limited availability of antioxidant enzymes
[21]. Continuous over-nutrition, as a result of HFD feeding, might lead
to the generation of excessive reactive oxygen species (ROS) and reac­
tive nitrogen species (RNS) [207]. Overproduction of these species
damages the macromolecules such as DNA, membrane lipids, and pro­
tein structures [198]. Physiologically, these free radicals are quenched
by endogenous antioxidant enzymes including reduced glutathione,
catalase, and superoxide dismutase. However, with HFD feeding, ROS
levels overwhelm the antioxidant enzyme capacity and lead to excessive
ROS accumulation [199].
Numerous studies have shown that HFD feeding results in an
elevated level of oxidative stress markers in the brain [115, 119, 139,
155, 156, 183, 198, 216, 224, 226]. The hippocampus and neocortex are
among the most vulnerable parts of the brain that undergo selective
damage by oxidative stress. Moreover, hippocampal oxidative stress is
strongly linked to cognition dysfunction [47, 58, 59, 190]. To support
the hypothesis that oxidative stress might be a possible mechanism
involved in HFD feeding associated cognitive decline, several re­
searchers have used antioxidant therapies and showed that cognitive
deficits can be rescued by using this approach in HFD fed animals [4,
139, 228].
Briefly, the mechanism by which HFD feeding can cause elevated
oxidative stress is stated here (Fig. 1). HFD feeding results in an
increased generation of free fatty acids [151]. Under normal diet
feeding, the mitochondrial β-oxidation of free fatty acids is associated
with the transfer of electrons from cofactors (NADH and FADH2) to the
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Physiology & Behavior 240 (2021) 113528
complex I of the mitochondrial respiratory chain, where most of these
electrons safely combine with oxygen and protons to form water.
However, a portion of these electrons reacts with oxygen to form su­
peroxide radicals. In contrast, during HFD feeding, elevated mitochon­
drial β-oxidation of FFAs leads to an excess electron flow and increased
production of ROS, and eventually, elevated superoxide anion level
[125, 152]. Importantly, the ROS can also consume the endogenous
antioxidant enzymes and put the brain at higher risk from oxidative
damage [109, 152]. A growing body of evidence suggests a possible
relationship between increased oxidative stress and the development of
cognitive decline [78, 134, 149, 192]. Considering these evidences, it is
highly likely that HFD mediated cognitive deficits are mediated by
increased oxidative stress.
4.2. HFD and neuro-inflammation
Chronic unchecked inflammation has been found to be deleterious
that could result in the pathology of metabolic and neurodegenerative
diseases [60, 164]. Literature has suggested that HFD feeding is not only
associated with the development of inflammation in the peripheral or­
gans such as the liver, adipose tissue, skeletal muscle, but it can also lead
to the development of neuro-inflammation. Several possible mecha­
nisms by which this happens include, generation of peripherally derived
pro-inflammatory cytokines that cross BBB and could eventually lead to
damage of neuronal function in the brain [9, 42]. Several studies have
shown that HFD feeding increased the expression of various cytokines
including TNF-α, interleukin-6 (IL-6), IL-1β, interferon-γ in the hippo­
campus, neocortex, and hypothalamus [6, 20, 29, 55, 89, 115, 131, 173,
229]. These cytokines bind to their respective receptors in the brain and
lead to neurodegeneration (Fig. 1). By using anti-inflammatory com­
pounds in the HFD model, researchers have repeatedly shown that these
compounds can ameliorate cognitive deficits and prevent neuronal
death [215, 230]. Not surprisingly, increased levels of these
pro-inflammatory cytokines have been well reported in AD brains [83,
167] and blood samples [196]. Interestingly, studies have shown that
prolonged use of anti-inflammatory drugs such as nonsteroidal
anti-inflammatory drugs (NSAIDs) can reduce the risk of development of
AD by 50% [86].
Several studies have also shown that HFD fed mice exhibit activated
microglial and astrocytic activity in the hippocampus along with an
elevated level of pro-inflammatory cytokines [158, 202]. An interesting
study by Baufeld and colleagues showed that HFD feeding results in an
increased number of microglia cells (using Iba1 + cells count) and
increased activity of astrocytes (using GFAP) specifically in the hypo­
thalamus region of HFD fed mice. They also suggested that these
microglial and astrocytic responses increase with the duration of diet
feeding [12].
Additionally, recent studies have also suggested that cognitive
decline as a result of HFD feeding could be associated with alteration of
richness, diversity, and composition of gut microbiota [217, 230, 239].
As such this alteration of microbiota has been found to be associated
with neuro-inflammation and resulting cognitive impairment [56, 180].
Thus, it is likely that inflammation resulting from HFD feeding could be
responsible for neuronal dysfunction and cognitive decline through
various possible mechanisms.
4.3. HFD and insulin resistance
For many decades after its discovery, insulin was considered just a
peripheral hormone that performs important functions including regu­
lation of glucose metabolism, food intake, and body weight but does not
affect the brain. However, later it was discovered that insulin is also vital
for brain health as it performs an array of functions ranging from
enhancing hippocampal long-term potentiation [88], modulation of
synaptic plasticity [205, 241] and plays an important role in learning
and memory [240]. In addition, insulin has also been reported to
S. Sharma
regulate structural plasticity in the brain [32], along with inducing the
expression of PSD95, (a scaffold protein required for the formation of the
postsynaptic junction) [111]. Thus, keeping in mind the vast majority of
functions mediated by insulin in the brain, it can be assumed that any
alteration in insulin signaling, especially during insulin resistance can
severely impact neuronal activity and possibly results in
neurodegeneration.
Insulin resistance has been well reported to play a critical role in the
pathogenesis of T2DM and metabolic syndrome. Moreover, the litera­
ture is rich with reports highlighting the role of insulin resistance in HFD
induced cognitive deficits [7, 37, 89, 118, 156]. Insulin resistance is
usually denoted by the increased homeostasis model assessment
(HOMA) index in most of the preclinical studies [8]. Despite much work,
the mechanisms by which HFD feeding results in development of insulin
resistance are still not completely understood. According to recent
literature, it has been proposed that HFD contributes to free fatty acid
(FFA) elevation which induces insulin resistance in skeletal muscle.
Increased plasma FFA results in the accumulation of intramuscular
lipids, in particular: diacylglycerols (DAG), ceramide and long-chain
acyl-CoAs, which are proposed to be involved in the induction of insu­
lin resistance [31, 54, 174, 188]. DAG has been well reported to impair
insulin action via activation of novel PKCs (nPKCs), including PKCε in
the liver and both PKCθ and PKCε in skeletal muscle [122]. Activation of
PKC subsequently impairs tyrosine phosphorylation of IRS-1/2 [123,
235].
From the insulin signaling standpoint, Glycogen synthase kinase-3 β
(GSK-3β) is a plausible candidate for mediating HFD induced compli­
cations such as insulin resistance and cognitive decline. GSK-3β regu­
lates a plethora of biological processes and downstream signaling of
insulin primarily through insulin receptor activation. Feeding HFD to
experimental animals has been shown to increase the expression of
GSK3β and its association with cognitive decline [16, 82]. Alternatively,
several researchers have highlighted that GSK3β inhibitors could reverse
cognitive decline as a result of HFD feeding [43, 173, 178, 179].
4.4. HFD and transcriptional dysregulation
Brain-derived neurotrophic factor (BDNF) is a member of the neu­
rotrophin family of the growth factors that play a vital role in regulating
the survival, growth, and differentiation of peripheral and central ner­
vous systems. BDNF has been reported to be critical for activity-
dependent neuroplasticity [53] and can also induce long-term potenti­
ation (LTP) and thus plays a key role in learning and memory [110]. A
reduction in BDNF expression has been associated with cognitive decline
and reduced mRNA and protein expression of BDNF has been found in
AD brains [36, 154] and serum samples [107]. Moreover, studies have
also demonstrated a reduction in circulating levels of BDNF in diabetes
and obesity [138, 144, 195]. BDNF has also been a focus of extensive
research in relation to HFD feeding. Various studies have highlighted the
deleterious effects of HFD feeding on BNDF profile in different brain
regions. Earlier studies by Molteni and colleagues found that rats fed
with saturated fat and refined sugar diet for 2 months showed impaired
performance in learning and memory tasks (morris water maze), which
was associated with reduced BDNF in the hippocampus [132]. These rats
also showed a decrease in mRNA and protein levels of synapsin I; cyclic
AMP-response element-binding protein (CREB) and growth-associated
protein 43 (mRNA only). Since these initial observations, several other
labs have demonstrated that HFD diet intake is associated with
decreased expression of BDNF in the brain ([224]; [94, 115, 191, 213,
227]). Keeping in mind the important role played by BDNF in memory
formation, it is plausible that the negative effects of HFD diet con­
sumption on learning and memory may also be mediated in part by
alteration of BDNF-related synaptic plasticity.
Although it is still not clear how exactly HFD feeding results in a
reduction of BDNF levels, however, the BDNF receptor signaling can
shed some light on this. BDNF binds to a tyrosine kinase receptor called
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Physiology & Behavior 240 (2021) 113528
tropomyosin-related kinase B (TrkB) and activates different pathways
involving phospholipase C (PLC)-γ, phosphatidylinositol 3-kinase
(PI3K)/ protein kinase B (Akt) and mitogen-activated protein kinase
(MAPK)/ extracellular signal-regulated kinase (ERK) [225]. All of these
converge on the transcription factor cyclic adenosine monophosphate
(cAMP) response element-binding protein (CREB), which can upregulate
genes related to cell survival, growth, and differentiation [101][176]. It
has been demonstrated that BDNF regulates phosphorylation of CREB
[61, 181]. Importantly, CREB is also reported to be regulated by insulin
signaling components [24, 51, 97]. Once activated, CREB is well re­
ported to regulate the expression of proteins associated with learning
and memory [10, 14]. Various studies have demonstrated that HFD diet
intake is associated with reduced CREB activity in the brain [119, 133,
224, 226, 229]. Thus, probably the reduction in BDNF level and
cognitive deficits observed as a result of HFD feeding could in turn be a
result of reduced CREB activity.
4.5. HFD and synaptic plasticity dysfunction
In line with the neurotrophic factor hypothesis, impairment in brain
morphological and structural abnormalities in relation to HFD feeding
has also been suggested by few histological studies. Several animal
studies have demonstrated that HFD feeding is associated with patho­
logical changes in the hippocampus and cortex, including reduced
dendritic spines in CA1 and impaired LTP along with memory impair­
ment [50, 74, 204]. Out of many brain structures, the hippocampus is
extremely sensitive to changes in glucose homeostasis [124, 145, 163].
Stranahan et al. [191] demonstrated that feeding rats with a high-fat,
high-glucose diet for eight months results in significant impairment of
spatial learning ability (assessed by MWM) along with reduced hippo­
campal dendritic spine density, and reduced LTP at Schaffer collater­
al–CA1 synapses. They also observed reduced BDNF level in the
hippocampus of high-fat high glucose fed animals as compared to con­
trols. These authors described the changes could be a result of peripheral
insulin resistance or it may be due to direct effects of some components
of diet on brain health and hippocampal plasticity [191]. In addition,
impairment of stimulus-evoked LTP has been reported in granular cells
of the DG of HFD fed rats [92]. Although many studies have shown that
HFD feeding result in a change of expression of protein-coding genes in
the cortex, however, the alterations of non-coding RNAs of the brain
cortex is relatively less explored. In this direction, a recent study by
Yoon and colleagues showed changes in expression of both coding and
non-coding RNAs in the brain cortex as a result of HFD feeding in mice.
These researchers reported that HFD feeding for 8 weeks results in
decreased expression of genes associated with synaptogenesis and
neurotransmitter release [234]. Arnold and colleagues also demon­
strated decreased expression of PSD-95, in the hippocampus of mice fed
with HFD [7]. Interestingly studies have also reported reduced neuro­
genesis in the dentate gyrus of HFD fed animals [113]. Thus, it is evident
that HFD feeding might severely affect the brain morphology and syn­
aptic plasticity by altering the expression of various genes associated
with these processes.
5. Potential mechanisms of HFD mediated vascular dysfunction
and cognitive deficits
5.1. HFD and blood–brain barrier dysfunction
Many pathophysiological complications associated with HFD feeding
have profound effects on vascular function. The BBB is a complex unit
comprising of endothelial cells joined together by tight junction proteins
(i.e., occludin and claudin), scaffolding proteins (i.e., ZO-1 and ZO-2),
and astrocytes [150]. Continuous tight junctions form the
adhesion-based connections between vascular endothelial cells, forming
a seal around the vessel lumen and restricting the passage of anything
larger than 180 Da [172]. Any damage to the BBB might lead to leakage
S. Sharma
of unwanted substances in the brain, which can result in neuronal
damage and neurodegenerative diseases including AD [22, 212]. For
instance, Wisniewski and Kozlowski initially reported extensive peri­
vascular leakage of IgG and albumin in AD brain samples compared to
controls [222]. Since then, several studies have found histopathological
evidence of BBB abnormalities in AD [34, 76, 203].
Similarly, alterations of BBB integrity have also been reported in
T2DM [84]. In a clinical study, Starr and colleagues showed increased
BBB permeability to gadolinium diethylenetriamine pentaacetic acid in
patients with well-controlled T2DM [187]. Although the clinical studies
are rare, the literature is rich with preclinical studies demonstrating the
damaging effects of hyperglycemia and the advanced glycation
end-products (AGEs) on BBB integrity in T2DM [160, 175]. Stranahan
and colleagues used the db/db mouse model of leptin deficiency (a
widely used mouse model of T2DM) and showed that the BBB break­
down results in cerebral macrophage infiltration in these mice [189].
Another study used AD transgenic APP/PS1 mice crossed with diabetic
db/db mice, and showed that F1 progeny of these mice demonstrate BBB
alterations associated with the onset of T2DM [162].
Most importantly, in the context of this review, the effects of HFD
feeding on BBB integrity and the associated cognitive decline has also
been demonstrated in various studies ([45, 90, 91][64, 197]). Seminal
work from Davidson lab revealed that rats fed with saturated fats and
sugar-rich western diet showed impaired performance on a
hippocampal-dependent serial feature negative discrimination task that
is accompanied by increased BBB permeability as detected by higher
sodium fluorescein density in hippocampus of these rats, as compared to
chow-fed rats [44]. In another study, where they used a lard-based
saturated fat rich diet in rats, Kanoski and colleagues showed
decreased mRNA expression for tight junction proteins (claudin-5 and
claudin-12) as compared to chow fed rats [91]. In a more recent study,
Takechi and colleagues showed that 4 weeks of feeding a diet rich in fats
and fructose (HFF) to C57BL/6 J mice results in a significant BBB
dysfunction along with associated neuro-inflammation in cortex and
hippocampal regions. In addition, they also reported the effects of
long-term diet feeding (24 weeks) and showed that mice fed with HFF
diet showed significant cognitive decline associated with increased BBB
permeability [197]. Another interesting study reveals the long-term ef­
fects (6 months) of a diet rich in saturated fat and cholesterol on the
hippocampus in middle-aged Fischer 344 rats [64]. These researchers
used SMI-71 immunofluorescence to evaluate the integrity of BBB and
showed reduced SMI-71 and occludin protein immunoreactivity on
blood vessels of these rats, indicating a loss in tight junction protein and
a consequent increase in BBB permeability. Surprisingly, they found
increased levels of occludin and ZO-1, along with an increased number
of activated microglia in the hippocampus of HFHC diet-fed rats as
compared with control rats [64]. A recent study by Salameh and col­
leagues showed that HFD feeding in mice results in increased entry of
14C-sucrose (in the hypothalamus and hippocampus), and 99mTc-albu­
min (in the whole brain) as compared to the normal diet fed mice.
Moreover, they demonstrated that treatment with topiramate (an
anti-epileptic drug) significantly attenuate the increased permeability
through BBB, decreased oxidative stress markers, and also increased the
expression of ZO-1 and claudin-12 (tight junction proteins) [170].
Two different studies using the same in vitro model, human cerebral
microvascular endothelial cell line (hCMEC/D3) for assessing human
BBB integrity showed the effects of insulin on tight junction proteins
[87, 104]. They demonstrated that insulin treatment enhances the
integrity of tight junction by increasing the expression of tight junction
transmembrane proteins. In contrast, they showed that inhibiting
insulin/insulin-like growth factor-1 receptor kinase activity using
AG1024, results in blocking of the increase of tight-junction integrity
[87]. Similarly, in a recent study, Ogata and colleagues investigated
changes in BBB and brain parenchymal protein expression as a result of
HFD feeding, where they found reduced expression levels of BBB
transporters as well as tight-junction proteins (claudin-5, occludin) 2
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Physiology & Behavior 240 (2021) 113528
weeks after HFD feeding. Interestingly, these levels recovered to normal
after 10 weeks of diet feeding. These studies highlight the importance of
insulin signaling in BBB integrity and suggesting that changes in the
status of insulin signaling/resistance could influence the expression of
BBB transporters, which in turn may alter the expression of cognitive
function-related proteins. [141].
5.2. HFD and impaired cerebral blood flow
Keeping in mind, the high metabolic demand of brain, a continuous
blood supply is required for its proper functioning. Thus, cerebral blood
flow (CBF) is tightly regulated and any disturbance in blood flow to
brain might result in severe neurological or neurodegenerative condi­
tion. An important review by David Attwell’s group highlighted the role
of decreased CBF in cognitive impairments observed in AD patients
[102]. In addition, the impact of diabetes has also been studied in
relation to CBF and cognitive impairments, and findings across these
limited studies are contradictory. Dandona et al. [41] reported no dif­
ference in age-related perfusion reductions in T2DM patients and control
subjects by measuring global CBF using 133-Xe inhalation method. On
the contrary, other studies employing single photon emission computed
tomography (SPECT) found that diabetic subjects showed reduced CBF
[137, 168, 209]. Moreover, recent studies also demonstrated regional
cerebral hypoperfusion in individuals with diabetes using Arterial spin
labeling (ASL) [40, 108, 226, 244]. Although the effect of HFD feeding
on CBF changes has not been studied extensively but a recent study
explored the effect of HFD induced T2DM on cognitive performance in
mice [243]. These researchers found that vascular cognitive impairment
mice fed a HFD showed higher cognitive deficits in behavioral tasks (fear
conditioning and Morris water maze), increased neuronal loss, glial
activation, and most importantly global decrease in CBF as compared to
control diet-fed vascular cognitive impairment mice. They described
that HFD exacerbates vascular cognitive impairment pathology. In
contrast, a recent study found no significant change in CBF level in
APP/PS1 mice fed a HFD as compared to controls [23]. Schaffer lab used
adult APP/PS1 transgenic mice and fed them with HFD (42% calories
from fat) for a long duration (over 6 months) and then tested their CBF
along with other experimental protocols. Surprisingly, they did not find
a significant difference in CBF in HFD fed or control-fed mice [23]. Thus,
further studies are required to confirm the role of CBF changes in HFD
induced cognitive decline.
6. Conclusion and future directions
In conclusion, the HFD feeding animal model has proven an
invaluable tool not only for studying the pathology of metabolic con­
ditions such as obesity and diabetes, but also for the identification of
molecular pathways involved in co-morbid metabolic and cognitive
dysfunctions. Researchers across the globe have manipulated the diet
composition to study different objectives based upon their research
goals and to better mimic the human disease condition. The fact that
these diets have not been standardized makes it very hard to replicate
the findings of the previous studies. Most of the studies have used lard
based saturated fat diet (60% kcal). The characteristic features of HFD
feeding induced cognitive decline have been reported to be influenced
by several factors such as the sex, strain and age of mice as well as
composition an duration of HFD feeding. Although the detrimental ef­
fects of HFD feeding on neuronal health have been reported as early as
24 h after the initiation of diet feeding. However, the duration can be
decided based on the research questions for particular study. Among
various behavioural tasks used to evaluate the impact of diet feeding on
learning and memory paradigms, the Morris water maze is considered as
a gold standard and has been used extensively by researchers. It is
mostly a hippocampal based task where a mice swims in a water tank
and tries to find the hidden platform by using external clues. Numerous
behavioural studies suggest that the effect of HFD feeding is not just
S. Sharma
Fig. 2. Schematic diagram of possible mechanisms responsible for HFD mediated cognitive decline by affecting neuronal and vascular components of
brain. Note: BBB: Blood Brain Barrier; BDNF: Brain-derived neurotrophic factor; CREB: cAMP Responsive element binding protein; HFD: High fat diet.
confined to one brain area, however, it affects the functioning of
different brain areas, including hippocampus, cortex, hypothalamus etc.
Thus, instead of using just one behavioural task that mostly relies on
functioning of particular brain area, it is advisable to use a battery of
behavioural tasks which rely on different brain areas to study a more
diverse action of HFD feeding on overall brain functioning. Overall, from
these preclinical studies, it has been postulated that oxidative stress,
neuro-inflammation, insulin resistance and BBB disruption are among
the most important factors that underlies the HFD induced cognitive
decline (Fig. 2). However, further studies are still warranted to fully
understand the relationship between fat intake and cognitive
performance.
Declaration of Competing Interest
The authors have declared that no conflict of interest exists.
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