Next Article in Journal
Altilix® Supplement Containing Chlorogenic Acid and Luteolin Improved Hepatic and Cardiometabolic Parameters in Subjects with Metabolic Syndrome: A 6 Month Randomized, Double-Blind, Placebo-Controlled Study
Next Article in Special Issue
Centella asiatica L. Phytosome Improves Cognitive Performance by Promoting Bdnf Expression in Rat Prefrontal Cortex
Previous Article in Journal
Selection of Target Nutrients for the Nutritional Standards of School Lunches in Korea
Previous Article in Special Issue
Acute Impact of Dietary Pattern and Walking on Postprandial Attention, Mood, and Satiety in Older Adults: A Randomized Crossover Trial
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function

Bee Ling Tan
1 and
Mohd Esa Norhaizan
Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
Research Centre of Excellent, Nutrition and Non-Communicable Diseases (NNCD), Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia
Author to whom correspondence should be addressed.
Nutrients 2019, 11(11), 2579;
Submission received: 7 September 2019 / Revised: 16 October 2019 / Accepted: 21 October 2019 / Published: 25 October 2019
(This article belongs to the Special Issue Nutrition, Cognition and Brain Integrity)


Cognitive dysfunction is linked to chronic low-grade inflammatory stress that contributes to cell-mediated immunity in creating an oxidative environment. Food is a vitally important energy source; it affects brain function and provides direct energy. Several studies have indicated that high-fat consumption causes overproduction of circulating free fatty acids and systemic inflammation. Immune cells, free fatty acids, and circulating cytokines reach the hypothalamus and initiate local inflammation through processes such as microglial proliferation. Therefore, the role of high-fat diet (HFD) in promoting oxidative stress and neurodegeneration is worthy of further discussion. Of particular interest in this article, we highlight the associations and molecular mechanisms of HFD in the modulation of inflammation and cognitive deficits. Taken together, a better understanding of the role of oxidative stress in cognitive impairment following HFD consumption would provide a useful approach for the prevention of cognitive dysfunction.

1. Introduction

The prevalence of obesity worldwide has doubled from 1980 to 2008 [1]. Individuals who are overweight or obese are at risk of developing metabolic syndrome (hyperlipidemia, type 2 diabetes, hypertension, and hypercholesterolemia) [2] and psychiatric conditions, for instance depression [3] and anxiety disorders [4]. Dietary intake of fat has markedly increased from 1991 to 2008 [5]. Substantial evidence highlights the detrimental impact of diets high in saturated fat [6], and extensive research has shown that diet-induced obesity potentially leads to memory impairment in rodents [7]. Mice fed a long-term high-fat diet (HFD) show reduced learning and memory performance [8], as well as depressive- [9,10] and anxiety-like behaviors [11,12].
Oxidative stress plays a crucial role in the development of numerous diseases [13]. Reactive nitrogen species (RNS) and reactive oxygen species (ROS) are continuously produced in the body via mitochondrial bioenergetics and oxidative metabolism [14]. Compelling evidence reveals that overproduction of ROS causes cumulative oxidative damage to macromolecules, including DNA, proteins, and membrane lipids [15], leading to neuronal death and affecting the healthspan of several organ systems [16]. High consumption of dietary fat contributes to obesity, which induces a permanent state of inflammation via the generation of white adipose tissue that secretes proinflammatory factors [17]. A previous study demonstrated that activated immune cells produce high levels of ROS, primarily mediated by nuclear factor kappa B (NF-κB) and proinflammatory cytokines [18].
Oxidative stress plays a prominent role in the development of neurodegenerative diseases [19]. The brain is highly sensitive and vulnerable to oxidation due to the presence of large amounts of unsaturated fatty acids and oxygen that serve as a substrate for lipid peroxidation [20]. Peroxidation products of fatty acids are among the biomarkers of oxidative stress in neurodegenerative diseases, along with protein nitration and carbonylation, and RNA and DNA oxidative damages [21]. Neurodegenerative diseases are often linked to abnormal protein aggregation. Such abnormal protein aggregation is able to induce oxidative stress through ROS production and mitochondria dysfunction [22,23]. Food is a vitally important energy source; it provides direct energy and affects brain function. Therefore, the role of high-fat diet (HFD) modulating neurodegeneration and oxidative stress is worthy of further discussion. This review aims to explore the associations and molecular mechanisms of HFD in modulating cognitive impairment and inflammation.

2. HFD-Mediated Oxidative Stress

Diets high in nutrient-dense foods, monounsaturated fatty acids (MUFAs), and dietary fibers have recently been replaced by diets high in saturated fats and refined sugars [24]. Fatty acids interact with various transcriptional factors to trigger downstream signaling pathways [25]. Among all transcription molecules, peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor that acts as a sensor for lipid-regulating proteins [26]. Polyunsaturated fatty acids (PUFAs) interact with sterol regulatory element binding proteins (SREBP) and transcription factors in the liver may modulate genes associated with their synthesis and facilitate phospholipid, fatty acid, and cholesterol uptake [27]. Studies have revealed a positive association between body adiposity and HFD (r = 0.57, p = 0.0002), particularly saturated fat [28]. High body adiposity may induce the production of ROS, accompanied by elevated adipokine and tumor necrosis factor alpha (TNF-α) secretion, which promotes chronic inflammation [29].
Fatty acids are involved in catabolism through peroxisomal β-oxidative and mitochondrial pathways [30]. Mitochondrial β-oxidation is primarily responsible for the degradation of long, medium, and short chain fatty acids (≤18 C), whereas peroxisomal β-oxidation participates in the catabolism of branch chain fatty acids, unsaturated fatty acids, dicarboxylic acids, and very long chain fatty acids (≥20 C) [31,32]. Additionally, peroxisomal β-oxidation is also involved in the synthesis of certain fatty acids, for instance, docosahexaenoic acid (DHA) [33]. Abnormalities in the peroxisomal β-oxidation pathway have been characterized by an accumulation of very long chain fatty acids and progressive neurological dysfunction, including dementia [31]. In particular, PPARα plays a crucial role in regulating fatty acid β-oxidation gene expression for factors such as catalase, acyl-CoA oxidase 1 (ACOX1), and carnitine-palmitoyl transferase-I (CPT-I) [34].
Indeed, the liver is the predominant organ for fatty acid oxidation in the body [35]. A previous study demonstrated that peroxisomal function was inversely correlated with aging [36]. Reduced ACOX1 expression and peroxisomal fatty acid β-oxidation activity have been observed in the liver of old rats [37]. In another study, Sanguino et al. [38] revealed that aging strongly decreases the activity and expression of PPARα in rat liver. These findings imply that fatty acid β-oxidation activity is reduced with age, subsequently resulting in reduced levels of hepatic PPARα [39].
In addition, several studies reported by O’Brien et al. [40] and Okereke et al. [41] have shown an association (p for linear trend = 0.008, odds ratio (OR) with 95% confidence interval (CI) = 1.64) between excessive fat consumption and neurological dysfunction. Data indicated that excessive fat consumption results in a net energy overload, which in turn leads to the expansion of adipose tissue. Sustained chronic fat intake may contribute to adipose tissue dysfunction and metabolic inflammation. When circulating free fatty acids increase, they can induce lipotoxicity to peripheral tissues, such as liver and β-cell dysfunction [40]. The high influx of free fatty acids into the liver triggers very low-density lipoprotein (VLDL) triglycerides production and contributes to the development of dyslipidemia. Subsequently, these impairments can lead to metabolic syndromes. The central nervous system is also adversely affected by elevated levels of circulating free fatty acids and the lipotoxic effects of dyslipidemia [40]. Ultimately, these dysfunctions contribute to neurological disorders, such as mild cognitive impairment and Alzheimer’s disease [40].
Furthermore, HFD increases levels of chylomicrons in the intestine. These chylomicrons enter circulation and cause the generation of free fatty acids, which are taken up by the liver. These hepatic free fatty acids may either enter the mitochondria for β-oxidation or be esterified into triglycerides. Triglycerides either accumulate in hepatocytes as small droplets or produce VLDL, which is then converted into low-density lipoprotein (LDL) [42]. Excessive LDL burden in the blood may form oxidized-LDL (Ox-LDL) due to its excessive accumulation or lack of LDL-receptors in hepatocytes, which in turn is engulfed by macrophages and becomes foam cells. Subsequently, foam cells accumulate in the arterial endothelium to form plaques. Ultimately, these plaques lead to cardiovascular and circulatory disorders and increase blood-brain barrier permeability [43].
Additionally, mitochondrial β-oxidation of free fatty acids is linked to the conversion of oxidized cofactors (FAD and NAD+) into reduced cofactors, FADH2 and NADH and is thereby reoxidized and restored back into FAD and NAD+ by the mitochondrial respiratory chain. During reoxidation, NADH and FADH2 transfer electrons to the first complexes of the respiratory chain. These electrons then migrate up to cytochrome c oxidase and combine with oxygen and protons to form water. These intermediates may interact with oxygen to produce increasing levels of ROS and superoxide anion radicals [44,45]. Therefore, overconsumption of fat triggers mitochondrial β-oxidation of free fatty acids, subsequently leading to excess electron flow using cytochrome c oxidase, which increases ROS accumulation. Mitochondria are a crucial cellular source of ROS; they oxidize unsaturated lipids of fat deposits to cause lipid peroxidation. HFD-induced ROS may trigger proinflammatory signaling and activate NF-κB transcriptional factor, and thus inducing NF-κB-dependent proinflammatory molecules, such as interferon-γ (IFN-γ), TNF-α, and inducible nitric oxide synthase (iNOS) [46]. In addition to ROS production, overproduction of nitric oxide (NO) via the activation of iNOS also causes accumulation of RNS [47].

3. Association of a High-Fat Diet with Cognitive Function

3.1. Animal Study

A previous study has demonstrated that rodents fed a diet high in saturated fatty acids (SFAs) show increased brain inflammatory markers [48]. Increased body weight and adiposity can cause neurological perturbations. These data imply that excess adipose tissue is highly metabolically active and susceptible to the release of proinflammatory mediators [49]. Further, data from a previous study also demonstrated that triglyceride administration impairs hippocampal long-term potentiation [50]. Interestingly, the mice treated with HFD for only one day is sufficient to induce a rapid drop in the performance of episodic memory task [51]. This study further revealed that memory deficits are rapidly reversed when switching mice to a low-fat diet from a HFD [51]. In another study, Duffy et al. [52] found that orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration, fed with HFD accelerate two-way active avoidance (TWAA) hippocampus-dependent memory task and the onset of neuroinflammation. In a study by Woodie and Blythe [53] focusing on hypercaloric diet (high in fat and fructose) and its effects on cognitive health, the rats fed with a HFD exhibited a relatively high fat pad weight compared to the high-fructose group. This study further demonstrated that high-fructose diet promotes insulin dysregulation, development of hyperlipidemia, and impairs cognitive performance. However, no apparent cognitive deficits were observed in rats fed with a HFD [53]. These observations indicate that an individual part of the hypercaloric diet may cause negative impacts on metabolic syndrome and cognitive function, suggesting the combination of high-fructose and high-fat components may further aggravate physiological issues and be detrimental to human health. In support of this, the animal study has shown that hypercaloric diets altered lipid and energy metabolism similar to clinical diabetes, with elevation of fasting glucose and increased cholesterol levels. This study further revealed that hypercaloric diets can impair spatial learning ability and synaptic plasticity [54]. These adverse effects were also found in rats fed with a HFD, suggesting that insulin resistance is a probable mediator to HFD-induced cognitive deficits [55]. Table 1 shows the effects of a HFD on cognitive function in animal models.

3.2. Human Study

A recent study stated that Western-style diets, which are high in refined sugars and saturated fats, have a greater likelihood of inducing memory impairment in healthy subjects [56]. Data from human studies investigating the impact of HFD on cognitive function (Table 2) are limited, but evidence from an intervention study indicates an association between HFD consumption and cognitive disorder. Holloway et al. [57] found that HFD administration (nearly 75% of energy) for five days is sufficient to induce depression and impair retrieval speed and attention. Consistent with a study reported by Holloway et al. [57], Edwards et al. [58] demonstrated that HFD consumption for seven days reduced attention and reaction time in sedentary adult males with fewer than 2 h/week physical activity. Similarly, HFD was also found to induce neuroinflammation. A study reported by Mittal and Katare [59] also demonstrated that high triglyceride levels convey poor cognitive performance in type 2 diabetes patients. Moreover, a study by Okereke et al. [41] also found that increased intake of saturated fats in young adults impairs prospective memory, cognitive function, and memory speed and flexibility, leading to neurological diseases, such as dementia and Alzheimer’s disease in mid and later life. Although many studies have demonstrated that HFD increased the risk of cognitive disorders; not all data demonstrated such a link [60]. Several studies reported by Solfrizzi et al. [61], Cherbuin and Anstey [62], and Roberts et al. [63] did not identify an association between high SFA intake and mild cognitive impairment. Variability in study designs may partly explain the inconsistency in findings. For instance, the variation in means of reporting composition and type of dietary fats and its association with cognitive problems shows a barrier in combining the findings of studies. The investigators used different methods for defining fat types (for example, PUFA from spreads or total PUFA) may address different subgroups (for instance, those with diabetes). Furthermore, the small sample size may increase the likelihood of inconsistent findings between the studies. In fact, the small sample size of study makes it difficult to detect significant associations. The nonsignificant findings could be attributed to the lack of statistical power. In addition, by comparing different study groups with diverse populations and its relationship with cognition may also explain inconsistency in findings. Individuals from different human populations have different proportions of genetic. Genetic variation in a population is derived from a wide assortment of alleles and genes. The persistence of certain populations over time via changing environments is highly dependent on their ability to shift or adapt external conditions.
In addition, data from a Rotterdam cohort study involving 197 cases of dementia, including 29 with vascular dementia, 146 with Alzheimer’s disease, and 22 with other types failed to show adverse outcome of high SFA intake and dementia risk after 6 years of follow-up [72]. Furthermore, data from Washington Heights-Inwood Columbia Aging Project (WHICAP) involving 980 New Yorkers aged 65 years and above, in which 28% of them carried APOE ε4 allele, showed that high SFA intake was not associated with the increased risk of Alzheimer’s disease [73]. Specifically, data demonstrate that compared to an omega-6 PUFA diet, Alzheimer’s disease risk was reduced in subjects consuming an omega-3 PUFA diet [74,75]. In contrast, high omega-3 PUFA intake is not associated with long-term dementia risk [76] (p for linear trend = 0.7, hazard ratio (HR) = 0.95; 95% CI = 0.76, 1.19). Taken together, these findings demonstrate an association between HFD and cognitive loss, suggesting potentially causal roles of HFD and brain inflammation in driving cognitive disruption. Figure 1 shows the effects of HFD on cognitive function.
The studies included in Table 1 and Table 2 had to meet the following criteria: exposure to HFD (PUFA, total, saturated, trans fat, or cholesterol) in rodents (rats or mice) or at any adult age in human; endpoints included cognitive function, incident mild cognitive impairment, Alzheimer’s disease, or dementia; or cognitive decline; in studies assessing dietary assessment and determination of cognitive function or outcome (mild cognitive impairment, Alzheimer’s disease, or dementia) or in studies assessing cognitive decline. There was no restriction pertaining to the publication date, sample size or the number of animals, animal strains, ethnicity of participants or on language, race, or gender. Exclusions criteria in animal study should also be considered. First, HFD was not administered. Second, other types of animals (dogs, cats, or sheep) were used. Third, duplicate publications. Moreover, case reports and studies limited to individuals with medical conditions (dyslipidemia or CVD) that are likely to affect intervention trials and cognitive status were excluded because of the confounding or bias in their study designs.
Data from the animal experiments have shown a greater likelihood of inflammation after the administration of HFD (Table 1). Importantly, some research has emerged to suggest the detrimental impact of HFD on gene expression in hypothalamus [66,67,68]. In particular, a HFD led to an upregulation of genes such as toll-like receptor 4 (TLR4), NF-κB, Cd68, Emr1, IL-6, indoleamine 2,3-dioxygenase (IDO), TNF-α, and interferon gamma (IFN-γ) in rodents, suggesting that these changes were related to diet-induced changes rather than obesity. In line with this, human studies also showed an association between HFD and Alzheimer’s disease, mild cognitive impairment, or dementia (Table 2). These relationships could be partly due to the type or composition of dietary fatty acids that may influence the cognitive function. In fact, the methodological quality of human studies may fail to assess precision outcomes. Most of the human studies using semiquantitative food-frequency questionnaire (FFQ) to measure the habitual intake during the study period and do not account for long-term periods or for day-to-day variation of intake. The measures obtained from the FFQ may not have enough precision to make inferences on the absolute amounts of nutrient intake that linked to the occurrence of cognitive outcomes. Although several limitations and potential publication bias may undermine the validity of the findings, HFD may play a potential role in neurodegenerative disease. Overall, these data imply that HFD consumption, particularly SFA may serve as a stimulus to elevate the inflammatory markers and augmented the inflammatory response, and ultimately lead to brain dysfunction and neurodegenerative disease.

4. Mechanisms Responsible for High-Fat Diet-Induced Cognitive Deficits

Substantial evidence suggests that increased oxidative stress and altered apoptosis contribute to the pathogenesis of neurodegenerative diseases [77]. Free radicals are implicated in the progression and development of cognitive deficits by interrupting synaptic transmission, mitochondrial function, neuroinflammation, and axonal transport; all of these factors contribute to neuronal loss in Alzheimer’s and other dementia diseases [78]. In fact, mitochondria are involved in the pathogenesis of numerous neurodegenerative diseases. Mitochondria are the predominant organelles that supply ATP to cells via oxidative phosphorylation, respond to oxidative stress, and synthesize additional key molecules. Mitochondria produce redox enzymes that are required for transferring electrons from one substrate to another, and inefficiencies in this process may lead to ROS production. The central nervous system is highly dependent on mitochondrial function due to its high energy demands. Mutation and ROS production that occurs in the mitochondrial DNA can lead to neurodegenerative disease and brain dysfunction. Indeed, many neurodegenerative diseases have been linked to mitochondrial dysfunction [77].
Accumulation of mitochondria DNA mutations during aging may cause malfunctioning oxidative phosphorylation and an imbalance in antioxidant enzymes. Mitochondrial dysfunction produces the ROS axis and forms a vicious cycle, which is regarded as the basis of the mitochondrial free radical theory of aging. A previous study revealed that ROS plays a critical role in the regulation of several cellular metabolic processes, including antioxidant defense mechanisms and posttranslational modification of proteins. However, oxidative stress in normal homeostasis is disturbed during aging and subsequently increases intracellular ROS levels [79]. Production of oxidative stress affects the mitochondrial defense system and membrane permeability, influences Ca2+ homeostasis, deranges the mitochondrial respiratory chain, and causes DNA mutations in mitochondria. This phenomenon triggers neurodegeneration and amplifies neuronal dysfunction [80].

4.1. Animal Study

Hippocampal injury is found in HFD-fed animals in response to increased blood-brain barrier permeability [71] due to circulating proinflammatory adipokines and reactive glial cytokine production [81]. Increased blood-brain barrier permeability that allows proinflammatory proteins into the hippocampus can initiate neuroinflammation and stimulate neurodegeneration [82]. A previous study further revealed that feeding mice a HFD increases both the permeability of the blood-brain barrier and markers of hippocampal inflammation, such as microglial activation [65]. The animal study further demonstrated that HFD-induced alterations of hippocampal structure and function [83]. For example, HFD impairs the hippocampus [70], a major region in the brain that plays an important role in memory and learning. Emerging evidence suggests that hypothalamic inflammation represents an initial stage of a vicious feed-forward cycle of central nervous system dysfunction, which in turn causes cognitive decline [84]. In addition to inflammation, alteration of free fatty acid metabolism might contribute to changes in the central nervous system [85].

4.2. Human Study

Individuals with obesity or who are overweight are at risk of developing cognitive disorders, metabolic syndrome, and depression. Furthermore, data from a previous study demonstrated that cerebral uptake of free fatty acids is higher in obese individuals compared to healthy individuals [86]. Increased dietary fat not only contributes to hypothalamic injury, but other factors, such as metabolic dysfunction in combination with alteration of triglycerides and free fatty acids, may also affect certain brain regions, particularly the hippocampus [87]. The role of the inflammatory pathway on cognitive impairment will be described in the following section.

5. Modulation of Inflammatory Pathways

Inflammation is a critical pathophysiological mechanism underlying dementia and cognitive dysfunction that results in the formation of neurofibrillary tangles and amyloid plaques [88]. Thus, brain function is highly susceptible to inflammatory mediators. Obesity is characterized as an alteration and elevation of the peripheral inflammatory response [89] and peripheral inflammation, which can promote neuroinflammation [90]. Chronic low-grade systemic inflammation has been suggested as a major pathophysiology underlying obesity [91]. Fatty acids stimulate TLR4, lipopolysaccharide (LPS) receptor, and free fatty acids in immune cells, initiating the inflammatory cascade [92].

5.1. Animal Studies

Systemic inflammation has been associated with cognitive decline or dementia [93,94]. Systemic inflammation triggers acute neuronal dysfunction via neuronal receptors. Data from an animal study showed that expression of CD200 on neuronal dendrites was decreased with age in response to LPS stimulation [95]. Similarly, aged animals also exhibited a primed microglial response to secondary stimulation of LPS [96]. In another study, deletion of the CX3CL1 receptor (CX3CR1), a neuronal cell surface marker, increased susceptibility to LPS-induced central nervous system inflammation and promoted sickness behavioral responses in aged mice [97]. Villaran et al. [98] explored the impact of systemic inflammation on neuronal cells using LPS and dextran sulfate sodium (DSS). Data indicated that ulcerative colitis induced by DSS aggravates dopaminergic neuronal loss [98].
Additionally, feeding genetic mice HFD may increase IL-1β levels in the hippocampus, which in turn decreases hippocampal cognitive function [69,99,100,101]. The arcuate nucleus (ARC) of the hypothalamus exhibits a lack of effective blood-brain barrier response to circulating factors, such as inflammatory mediators and nutrients [88]. Yet this circulating signal is a crucial driving force in generating central inflammation after HFD administration. For example, TLR4 binds LPS and extracellular lipids to trigger inflammation [102].
Peripheral cytokines can act on the brain to trigger cytokine production [103]. An animal study demonstrated that feeding a diet containing high-fat content induces central inflammation in genetic models of obesity, particularly in the hypothalamus [104]. Data from another animal study further revealed that insensitivity of the leptin receptor [105] upregulated the transcriptional activity of interleukin-6 (IL-6), TNF-α, and IL-1β in the hippocampus compared to control [106]. Another study also reported that feeding 60% of HFD for 20 weeks increased TNF-α expression in the hippocampus [65]. Furthermore, chronic intake of HFD aggravates LPS-induced cytokine expression such as interferon-γ and TNF-α in the hippocampus and IL-6 in the hypothalamus [68]. Taken together, these data suggest that administration of HFD produces more free fatty acids to enter ARC and initiates an inflammatory cascade [107].

5.2. Human Studies

Extensive studies have shown that accumulation of white adipose tissue is predominant in sites that produce systemic inflammation [108]. In general, both adipose tissue-resident immune cells and hypertrophied adipocytes contribute to the elevation of circulating levels of proinflammatory cytokines, such as TNF-α, IL-6, IL-1β, and C-reactive protein [109] in obese individuals. Individuals with high waist circumference and waist:hip ratio demonstrated a high IL-6 and C-reactive protein concentrations [110]. In addition, evidence suggests that chronic low-grade inflammation is mediated by T-cells [111]. Data from a cross-sectional study revealed that obese women exhibit high levels of T-cell derived cytokines (IL-17 and IL-23), which are statistically independent of leptin and other inflammatory factors, for instance, macrophage migration inhibitory factor [112]. This observation implies that IL-17 plays a critical role in obesity [112].
Notably, data showed that adipose tissue secretes TNF-α [113]. Cytokines, for instance, IL-6 and IL-1β, were found to disrupt neural circuits involved in memory and cognitive function [114]. Increased plasma IL-12 and IL-6 decline cognitive function and processing speed in the elderly population [99]. Another study conducted by Harrison et al. [115] also demonstrated that induction of systemic inflammation in response to Salmonella typhi vaccination in humans reduced spatial memory, suggesting that the medial temporal lobe is involved in modulating systemic inflammation.
HFD promotes cognitive decline via multiple mechanisms, such as increased expression of proinflammatory adipokines (TNF-α and IL-6), upregulated chemotactic adipokines (monocyte chemoattractant protein-1 (MCP-1)), and increased reactive microgliosis and astrocytosis [48]. In this regard, interleukin-1 beta (IL-1β) may modulate neurophysiological mechanisms involved in memory and cognition [116]. Moreover, the detrimental impact of triglycerides was also observed in the brain when pancreatic lipase breaks down triglycerides released from adipocytes into free fatty acids. Additionally, dietary intake of SFAs, such as lauric acid and palmitic acid, was found to trigger inflammatory responses in cultured macrophages [117], as well as microglial and astrocytic signaling pathways [118].
Although proinflammatory cytokines may negatively affect the brain, IL-1β is still required for proper hippocampal memory function [119]. However, elevated IL-1β levels may dampen cognitive processing [120], as shown when the duration of impaired hippocampal-based cognition increased with elevation of hippocampal IL-1β levels [121]. Subsequently, an IL-1 receptor antagonist (IL-1RA) may block IL-1β activity, contributing to inflammation-induced cognitive deficits [122].
Circulating proinflammatory cytokines (due to HFD-induced systemic inflammation) can cross the mediobasal hypothalamus in the brain, activating cytokine receptors [123,124,125]. Cytokines and free fatty acids modulate the perpetuation of this inflammatory signal by producing local proinflammatory cytokines [125]. Additionally, excessive accumulation of free fatty acids may trigger central nervous system inflammation by activating a cascade of prostaglandins in centrally projecting neurons [126]. Therefore, systemic inflammation increases blood-brain barrier permeability, which allows immune cells and peripheral cytokines to enter the circulation [127]. A meta-analysis involving 5,717 participants and 1,311 cases suggested that increased inflammatory markers, such as C-reactive protein (HR = 1.45; 95% CI = 1.10, 1.91) and IL-6 expression (HR = 1.32; 95% CI = 1.06, 1.64) were associated with a modest increase in dementia risk [128].

6. Cognitive Impairment and Hypothalamic Inflammation

The hypothalamus is vital in the modulation of energy homeostasis by regulating energy expenditure and food intake [129]. The hypothalamus is responsible for a broad spectrum of physiological functions, such as reproduction, water balance, regulation, metabolism and feeding, and cardiovascular function. Furthermore, the hypothalamus is also involved in the memory aspects of cognition, learning, and attention [130]. For example, dysregulation of the hypothalamic pituitary adrenal (HPA) axis may impair the cognitive function [131]. Depressive patients have impaired executive function and memory recall, which is related to morning cortisol levels [132].

Animal Study

Hypothalamic inflammation is an early acute response to high concentrations of free fatty acids [133]. Thaler et al. [66] reported that hypothalamic inflammation was observed within 1–3 days after HFD administration prior to body weight gain. Data further revealed that microgliosis, astrogliosis, and neuronal injury are initiated within the first week of HFD administration [66]. Glial cell activation is an essential step in HFD-induced hypothalamic inflammation through astrocyte and microglial reactivity [134]. Microglial activation and early markers of inflammation, such as TNF-α are often present in the ARC of the hypothalamus [64]. Microglia have been suggested as sensors of diet-induced hypothalamic inflammation because they express TLR4 to recognize long-chain fatty acids [135].
Astrocytes are the most predominant glial cell population within the central nervous system that responds to reactive astrogliosis [136]. Astrocytes produce cytokines and trigger inflammatory responses within the hypothalamus [137]. Astrocytes also control central nervous system infiltration and regulate oligodendrocyte and microglial activity [138]. A previous study suggested that central inflammation extends beyond the hypothalamus after feeding with a HFD, subsequently affecting areas related to cognition [111]. Moreover, an animal study demonstrated that administration of cultured primary microglia with sera derived from aged obese mice significantly enhanced oxidative stress and triggered microglia activation [139]. Upon activation, microglia undergo significant morphological changes. After one week administration of a HFD, microglial show reactive gliosis with significant proliferation [66], and subsequently may impact neuronal and synaptic plasticity [104]. Notably, the microglial-related inflammation in diabetic rat hippocampus can lead to the elevation of β-amyloid protein and tau pathology characteristic of Alzheimer’s disease [140]. Furthermore, oxidative stress is reported to be closely associated with cognitive impairment, brain proinflammatory cytokine production, and astrocyte activation following HFD feeding [48,141]. This finding implies that inflammation may influence neuronal function during HFD by promoting oxidative stress [104]. Data from another animal study further demonstrated that HFD triggers TLR4 and endoplasmic reticulum stress signaling pathways [142], activating the c-Jun N-terminal kinase (JNK) [64] and inhibitor of κB kinase β/nuclear factor-κB (IKKβ/NF-κB) [143,144] pathways in the hypothalamus [66].
Furthermore, increased inflammatory responses in the hypothalamus may produce leptin resistance, leading to defective food intake in dietary fat-induced obesity [64]. Data from an animal study revealed that HFD-induced alterations of hypothalamic metabolites and energy metabolism, suggesting an extension of the inflammation pathology to a localized metabolic imbalance produced by HFD [145].
Chronic stress can cause an elevation of hypothalamic proinflammatory cytokine expression, as well as recruitment of peripherally-derived monocytes into the brain such as anxiety-related brain regions for example amygdala [146,147]. This effect is associated with anxiety-related behavior and potentially to anxiety-associated mood disorders, with a stress-sensitized monocyte response that may lead to excessive anxiety in mice [147,148]. TLR4 is a major molecular target for SFAs in the hypothalamus that stimulates intracellular signaling pathways to induce an inflammatory response and contributes to obesity [133]. A previous study reported that HFD upregulates the hypothalamic inhibitor of nuclear factor kappa B kinase subunit beta (IKKB)/NF-κB, which in turn reduces hypothalamic leptin signal transduction [144]. Likewise, data from a genetic study further demonstrated that blocking hypothalamic NF-κB signaling reverses hypothalamic leptin resistance and promotes weight loss and reduced food intake in HFD-induced obesity [142]. Evidence indicates that obesity-derived neuroinflammation affects brain structures, such as the cortex and hippocampus [149]. Furthermore, high-fat consumption also significantly upregulates hypothalamic IL-6, NF-κB, and TLR4 expression in HFD-induced rats [67]. Collectively, these data suggest that stimulation of hypothalamic inflammation is sufficient to control food intake and is more likely involved in the mechanism underlying the pathogenesis of HFD-induced obesity.

7. Cognitive Impairment and Neurotrophic Factors

Brain-derived neurotrophic factor (BDNF) is abundantly expressed in the cerebral cortex, hippocampus, and hypothalamus. It plays a central role in the maintenance and growth of neurons [150]. BDNF causes alteration of neuronal plasticity via modulation of growth-associated protein 43 (GAP-43), cAMP response element-binding protein (CREB), and synapsin 1. BDNF also facilitates the release of neurotransmitters, axonal formation and growth, and maintenance of presynaptic structures by phosphorylating synapsin 1 [151].

Animal Study

Most studies indicate that HFD decreases BDNF levels, and this phenomenon may increase the risk of memory deficits. Data from an animal study demonstrated that HFD decreased hippocampal BDNF protein and mRNA expression [152]. The study also reported downstream effectors, such as CREB, hippocampal synapsin 1, and GAP-43 mRNA levels were diminished when BDNF level was reduced. Nevertheless, the mechanisms underlying reduced BDNF levels in HFD are not fully understood, but it is hypothesized that oxidative stress, augmented by ROS formation [153], contributes to these phenomena, and leading to cognitive dysfunction [154]. Most studies have addressed HFD-induced changes in BDNF level via activation of inflammatory cytokines [155]. Research suggests that chronic HFD exposure is required for reduced neurotrophic factors, such as GAP-43, synapsin 1, BDNF, and CREB [156]. Similar dietary intake was also found to induce brain inflammation and obesity-induced metabolic dysfunction [157].

8. Conclusions

Oxidative stress produces excessive ROS, primarily due to imbalances in oxidative to reducing species. It has been suggested that the overproduction of ROS is linked to a high level of inflammation and leads to impaired cognitive function. In fact, the brain is prone to oxidative stress due to its harnessing of chemically diverse reactive species to modulate heterogeneous signaling pathways. Excessive energy, particularly from HFD, impairs cognitive function. The rapid onset of HFD-induced hippocampal deficits may induce high levels of inflammation in the central nervous system. Although the adverse effect of HFD on cognitive function has been demonstrated in both in vitro and in vivo studies, there are still some controversies that need to be elucidated by long-term clinical trials with large cohorts of the general population. Therefore, future studies are needed to delineate the precise mechanism of action to better elucidate the role of HFD on cognition. Based on the evidence of this review, there are several limitations including (1) small sample size [58], (2) short duration of the study [58]; (3) different amount of fat [70]; and (4) lack of evidence from clinical studies showing changes in cognitive functions and fat [57]. It would be useful to have a dose-response relationship of fat in neurodegenerative diseases or cognitive functions compared in the same study, by taking into consideration of other aspects such as genetic, lifestyle, and social context.

Author Contributions

B.L.T. conceived and designed the review and wrote the manuscript. M.E.N. edited the manuscript. All authors read and approved the final manuscript.


This research was funded by Putra Grant (UPM/700-2/1/GPB/2017/9549900).

Conflicts of Interest

The authors declare no conflict of interest.


  1. World Health Organization. Obesity and Overweight. 2015. Available online: (accessed on 26 November 2018).
  2. Furukawa, S.; Fujita, T.; Shimabukuro, M.; Iwaki, M.; Yamada, Y.; Nakajima, Y.; Nakayama, O.; Makishima, M.; Matsuda, M.; Shimomura, I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Investig. 2017, 114, 1752–1761. [Google Scholar] [CrossRef]
  3. Milaneschi, Y.; Lamers, F.; Bot, M.; Drent, M.L.; Penninx, B.W.J.H. Leptin Dysregulation is specifically associated with major depression with atypical features: Evidence for a mechanism connecting obesity and depression. Biol. Psychiatry 2017, 81, 807–814. [Google Scholar] [CrossRef]
  4. De Noronha, S.R.; Campos, G.V.; Abreu, A.R.; de Souza, A.A.; Chianca, D.A.; de Menezes, R.C. High fat diet induced-obesity facilitates anxiety-like behaviors due to GABAergic impairment within the dorsomedial hypothalamus in rats. Behav. Brain Res. 2017, 316, 38–46. [Google Scholar] [CrossRef]
  5. Vadiveloo, M.; Scott, M.; Quatromoni, P.; Jacques, P.; Parekh, N. Trends in dietary fat and high-fat food intakes from 1991 to 2008 in the Framingham heart study participants. Br. J. Nutr. 2014, 111, 724–734. [Google Scholar] [CrossRef]
  6. DiNicolantonio, C.J.; Lucan, S.C.; O’Keefe, J.H. The evidence for saturated fat and sugar related to coronary heart disease. Prog. Cardiovasc. Dis. 2016, 58, 464–472. [Google Scholar] [CrossRef]
  7. Alzoubi, K.H.; Mayyas, F.A.; Mahafzah, R.; Khabour, O.F. Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. Behav. Brain Res. 2018, 336, 93–98. [Google Scholar] [CrossRef]
  8. Cordner, Z.A.; Tamashiro, K.L. Effects of high-fat diet exposure on learning and memory. Physiol. Behav. 2015, 152, 363–371. [Google Scholar] [CrossRef]
  9. Kurhe, Y.; Mahesh, R.; Gupta, D. Effect of a selective cyclooxygenase type 2 inhibitor celecoxib on depression associated with obesity in mice: An approach using behavioral tests. Neurochem. Res. 2014, 39, 1395–1402. [Google Scholar] [CrossRef]
  10. Kurhe, Y.; Mahesh, R. Ondansetron attenuates co-morbid depression and anxiety associated with obesity by inhibiting the biochemical alterations and improving serotonergic neurotransmission. Pharm. Biochem. Behav. 2015, 136, 107–116. [Google Scholar] [CrossRef]
  11. Sivanathan, S.; Thavartnam, K.; Arif, S.; Elegino, T.; McGowan, P.O. Chronic high fat feeding increases anxiety-like behaviour and reduces transcript abundance of glucocorticoid signaling genes in the hippocampus of female rats. Behav. Brain Res. 2015, 286, 265–270. [Google Scholar] [CrossRef]
  12. Zemdegs, J.; Quesseveur, G.; Jarriault, D.; Pénicaud, L.; Fioramonti, X.; Guiard, B.P. High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice. Br. J. Pharm. 2016, 173, 2095–2110. [Google Scholar] [CrossRef]
  13. Tan, B.L.; Norhaizan, M.E.; Liew, W.-P.-P. Nutrients and oxidative stress: Friend or foe? Oxid. Med. Cell. Longev. 2018, 2018. [Google Scholar] [CrossRef]
  14. Sies, H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol. 2017, 11, 613–619. [Google Scholar] [CrossRef]
  15. Wang, L.; Chen, X.; Du, Z.; Li, G.; Chen, M.; Chen, X.; Liang, G.; Chen, T. Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics. J. Exp. Clin. Cancer Res. 2017, 36, 47. [Google Scholar] [CrossRef]
  16. Mazon, J.N.; de Mello, A.H.; Ferreira, G.K.; Rezin, G.T. The impact of obesity on neurodegenerative diseases. Life Sci. 2017, 182, 22–28. [Google Scholar] [CrossRef]
  17. Muñoz, A.; Costa, M. Nutritionally mediated oxidative stress and inflammation. Oxidat. Med. Cell. Longev. 2013, 2013. [Google Scholar] [CrossRef]
  18. Knight, J.A. Review: Free radicals, antioxidants, and the immune system. Ann. Clin. Lab. Sci. 2000, 30, 145–158. [Google Scholar]
  19. Angelova, P.R.; Abramov, A.Y. Role of mitochondrial ROS in the brain: From physiology to neurodegeneration. Febs Lett. 2018, 592, 692–702. [Google Scholar] [CrossRef]
  20. Cobley, J.N.; Fiorello, M.L.; Bailey, D.M. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018, 15, 490–503. [Google Scholar] [CrossRef]
  21. Butterfield, D.A.; Reed, T.; Newman, S.F.; Sultana, R. Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic. Biol. Med. 2007, 43, 658–677. [Google Scholar] [CrossRef]
  22. Selfridge, J.E.; Lezi, E.; Lu, J.; Swerdlow, R.H. Role of mitochondrial homeostasis and dynamics in Alzheimer’s disease. Neurobiol. Dis. 2013, 51, 3–12. [Google Scholar] [CrossRef]
  23. Zhao, Y.; Zhao, B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid. Med. Cell. Longev. 2013, 2013, 316523. [Google Scholar] [CrossRef]
  24. Marventano, S.; Godos, J.; Platania, A.; Galvano, F.; Mistretta, A.; Grosso, G. Mediterranean diet adherence in the Mediterranean healthy eating, aging and lifestyle (MEAL) study cohort. Int. J. Food Sci. Nutr. 2018, 69, 100–107. [Google Scholar] [CrossRef]
  25. Du, X.; Zhu, Y.; Peng, Z.; Cui, Y.; Zhang, Q.; Shi, Z.; Guan, Y.; Sha, X.; Shen, T.; Yang, Y.; et al. High concentrations of fatty acids and β-hydroxybutyrate impair the growth hormone-mediated hepatic JAK2-STAT5 pathway in clinically ketotic cows. J. Dairy Sci. 2018, 101, 3476–3487. [Google Scholar] [CrossRef]
  26. Derosa, G.; Sahebkar, A.; Maffioli, P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J. Cell. Physiol. 2018, 233, 153–161. [Google Scholar] [CrossRef]
  27. Dong, X.; Tan, P.; Cai, Z.; Xu, H.; Li, J.; Ren, W.; Xu, H.; Zuo, R.; Zhou, J.; Mai, K.; et al. Regulation of FADS2 transcription by SREBP-1 and PPAR-α influences LC-PUFA biosynthesis in fish. Sci. Rep. 2017, 7. [Google Scholar] [CrossRef]
  28. Norris, G.H.; Porter, C.M.; Jiang, C.; Millar, C.L.; Blesso, C.N. Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice. J. Nutr. Biochem. 2017, 40, 36–43. [Google Scholar] [CrossRef]
  29. Maurizi, G.; Della Guardia, L.; Maurizi, A.; Poloni, A. Adipocytes properties and crosstalk with immune system in obesity-related inflammation. J. Cell. Physiol. 2018, 233, 88–97. [Google Scholar] [CrossRef]
  30. Shi, Y.; Sun, X.; Sun, Y.; Hou, L.; Yao, M.; Lian, K.; Li, J.; Lu, X.; Jiang, L. Elevation of cortical C26:0 due to the decline of peroxisomal β-oxidation potentiates amyloid β generation and spatial memory deficits via oxidative stress in diabetic rats. Neuroscience 2016, 315, 125–135. [Google Scholar] [CrossRef]
  31. Van Veldhoven, P.P. Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. J. Lipid Res. 2010, 51, 2863–2895. [Google Scholar] [CrossRef] [Green Version]
  32. Yagita, Y.; Shinohara, K.; Abe, Y.; Nakagawa, K.; Al-Owain, M.; Alkuraya, F.S.; Fujiki, Y. Deficiency of a retinal dystrophy protein, acyl-CoA binding domain-containing 5 (ACBD5), impairs peroxisomal β-oxidation of very-long-chain fatty acids. J. Biol. Chem. 2017, 292, 691–705. [Google Scholar] [CrossRef]
  33. Kanamori, S.; Ishida, H.; Yamamoto, K.; Itoh, T. Construction of a series of intermediates in the β-oxidation pathway from THA to EPA via DHA in free acid form. Bioorg. Med. Chem. 2018, 26, 4390–4401. [Google Scholar] [CrossRef]
  34. Zheng, F.; Cai, Y. Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis. 2019, 18, 6. [Google Scholar] [CrossRef]
  35. Le Cras, T.D.; Mobberley-Schuman, P.S.; Broering, M.; Fei, L.; Trenor, C.C., 3rd; Adams, D.M. Angiopoietins as serum biomarkers for lymphatic anomalies. Angiogenesis 2017, 20, 163–173. [Google Scholar] [CrossRef]
  36. Périchon, R.; Bourre, J.M. Peroxisomal b-oxidation activity and catalase activity during development and aging in mouse liver. Biochimie 1995, 77, 288–293. [Google Scholar] [CrossRef]
  37. An, H.J.; Lee, B.; Kim, S.M.; Kim, D.H.; Chung, K.W.; Ha, S.G.; Park, K.C.; Park, Y.J.; Kim, S.J.; Yun, H.Y.; et al. A PPAR pan agonist, MHY2013 alleviates age-related hepatic lipid accumulation by promoting fatty acid oxidation and suppressing inflammation. Biol. Pharm. Bull. 2018, 41, 29–35. [Google Scholar] [CrossRef]
  38. Sanguino, E.; Roglans, N.; Alegret, M.; Sánchez, R.M.; Vázquez-Carrera, M.; Laguna, J.C. Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br. J. Pharm. 2005, 145, 853–861. [Google Scholar] [CrossRef]
  39. Chee, C.; Shannon, C.E.; Burns, A.; Selby, A.L.; Wilkinson, D.; Smith, K.; Greenhaff, P.L.; Stephens, F.B. Relative contribution of intramyocellular lipid to whole body fat oxidation is reduced with age, but subsarcolemmal lipid accumulation and insulin resistance are only associated with overweight individuals. Diabetes 2016, 65, 840–850. [Google Scholar] [CrossRef]
  40. O’Brien, P.D.; Hinder, L.M.; Callaghan, B.C.; Feldman, E.L. Neurological consequences of obesity. Lancet Neurol. 2017, 16, 465–477. [Google Scholar] [CrossRef]
  41. Okereke, O.I.; Rosner, B.A.; Kim, D.H.; Kang, J.H.; Cook, N.R.; Manson, J.E.; Buring, J.E.; Willett, W.C.; Grodstein, F. Dietary fat types and 4-year cognitive change in community-dwelling older women. Ann. Neurol. 2012, 72, 124–134. [Google Scholar] [CrossRef]
  42. Pessayre, D.; Berson, A.; Fromenty, B.; Mansouri, A. Mitochondria in steatohepatitis. Semin. Liver Dis. 2001, 21, 57–69. [Google Scholar] [CrossRef]
  43. Ference, B.A.; Ginsberg, H.N.; Graham, I.; Ray, K.K.; Packard, C.J.; Bruckert, E.; Hegele, R.A.; Krauss, R.M.; Raal, F.J.; Schunkert, H.; et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 2017, 38, 2459–2472. [Google Scholar] [CrossRef] [Green Version]
  44. Pessayre, D.; Mansouri, A.; Fromenty, B. Nonalcoholic steatosis and steatohepatitis. Mitochondrial dysfunction in steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282, G193–G199. [Google Scholar] [CrossRef]
  45. Matsuzawa-Nagata, N.; Takamura, T.; Ando, H.; Nakamura, S.; Kurita, S.; Misu, H.; Ota, T.; Yokoyama, M.; Honda, M.; Miyamoto, K.; et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 2008, 57, 1071–1077. [Google Scholar] [CrossRef]
  46. Dalvi, P.S.; Chalmers, J.A.; Luo, V.; Han, D.-Y.D.; Wellhauser, L.; Liu, Y.; Tran, D.Q.; Castel, J.; Luquet, S.; Wheeler, M.B.; et al. High fat induces acute and chronic inflammation in the hypothalamus: Effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. Int. J. Obes. 2017, 41, 149–158. [Google Scholar] [CrossRef]
  47. Tapias, V.; Hu, X.; Luk, K.C.; Sanders, L.H.; Lee, V.M.; Timothy Greenamyre, J. Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production. Cell. Mol. Life Sci. 2017, 74, 2851–2874. [Google Scholar] [CrossRef]
  48. Pistell, P.J.; Morrison, C.D.; Gupta, S.; Knight, A.G.; Keller, J.N.; Ingram, D.K.; Bruce-Keller, A.J. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J. Neuroimmunol. 2010, 219, 25–32. [Google Scholar] [CrossRef] [Green Version]
  49. Ferreira, M.R.; Alvarez, S.M.; Illesca, P.; Giménez, M.S.; Lombardo, Y.B. Dietary Salba (Salvia hispanica L.) ameliorates the adipose tissue dysfunction of dyslipemic insulin-resistant rats through mechanisms involving oxidative stress, inflammatory cytokines and peroxisome proliferator-activated receptor γ. Eur. J. Nutr. 2018, 57, 83–94. [Google Scholar] [CrossRef]
  50. Ana, C.; Danila, D.R.; Ana, M.; Carmen, G.; Lidia, M.; Mariano, R.-G.; Nuria, D.O. Inhibition of hippocampal long-term potentiation by high-fat diets: Is it related to an effect of palmitic acid involving glycogen synthase kinase-3? Neuroreport 2017, 28, 354–359. [Google Scholar] [CrossRef]
  51. McLean, F.H.; Grant, C.; Morris, A.C.; Horgan, G.W.; Polanski, A.J.; Allan, K.; Campbell, F.M.; Langston, R.F.; Williams, L.M. Rapid and reversible impairment of episodic memory by a high-fat diet in mice. Sci. Rep. 2018, 8, 11976. [Google Scholar] [CrossRef]
  52. Duffy, C.M.; Hofmeister, J.J.; Nixon, J.P.; Butterick, T.A. High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss. Neurobiol. Learn. Mem. 2019, 157, 41–47. [Google Scholar] [CrossRef]
  53. Woodie, L.; Blythe, S. The differential effects of high-fat and high-fructose diets on physiology and behavior in male rats. Nutr. Neurosci. 2018, 21, 328–336. [Google Scholar] [CrossRef]
  54. Stranahan, A.M.; Norman, E.D.; Lee, K.; Cutler, R.G.; Telljohann, R.S.; Egan, J.M.; Mattson, M.P. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 2008, 18, 1085–1088. [Google Scholar] [CrossRef] [Green Version]
  55. Greenwood, C.E.; Winocur, G. High-fat diets, insulin resistance and declining cognitive function. Neurobiol. Aging 2005, 26, 42–45. [Google Scholar] [CrossRef]
  56. Jena, P.K.; Sheng, L.; Di Lucente, J.; Jin, L.-W.; Maezawa, I.; Yvonne Wan, Y.-J. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity. FASEB J. 2018, 32, 2866–2877. [Google Scholar] [CrossRef]
  57. Holloway, C.J.; Cochlin, L.E.; Emmanuel, Y.; Murray, A.; Codreanu, I.; Edwards, L.M.; Szmigielski, C.; Tyler, D.J.; Knight, N.S.; Saxby, B.K.; et al. A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. Am. J. Clin. Nutr. 2011, 93, 748–755. [Google Scholar] [CrossRef] [Green Version]
  58. Edwards, L.M.; Murray, A.J.; Holloway, C.J.; Carter, E.E.; Kemp, G.J.; Codreanu, I.; Brooker, H.; Tyler, D.J.; Robbins, P.A.; Clarke, K. Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. FASEB J. 2011, 25, 1088–1096. [Google Scholar] [CrossRef]
  59. Mittal, K.; Katare, D.P. Shared links between type 2 diabetes mellitus and Alzheimer’s disease: A review. Diabetes Metab. Syndr. Clin. Res. Rev. 2016, 10, S144–S149. [Google Scholar] [CrossRef]
  60. Bernard, N.D.; Bunner, A.E.; Agarwal, U. Saturated and trans fats and dementia: A systematic review. Neurobiol. Aging 2014, 35, S65–S73. [Google Scholar] [CrossRef]
  61. Solfrizzi, V.; Colacicco, A.M.; D’Introno, A.; Capurso, C.; Del Parigi, A.; Capurso, S.A.; Argentieri, G.; Capurso, A.; Panza, F. Dietary fatty acids intakes and rate of mild cognitive impairment. The Italian Longitudinal Study on Aging. Exp. Gerontol. 2006, 41, 619–627. [Google Scholar] [CrossRef]
  62. Cherbuin, N.; Anstey, K.J. The Mediterranean diet is not related to cognitive change in a large prospective investigation: The PATH through life study. Am. J. Geriatr. Psychiatry 2012, 20, 635–639. [Google Scholar] [CrossRef]
  63. Roberts, R.O.; Roberts, L.A.; Geda, Y.E.; Cha, R.H.; Pankratz, V.S.; O’Connor, H.M.; Knopman, D.S.; Petersen, R.C. Relative intake of macronutrients impacts risk of mild cognitive impairment or dementia. J. Alzheimer’s Dis. 2012, 32, 329–339. [Google Scholar] [CrossRef]
  64. De Souza, C.T.; Araujo, E.P.; Bordin, S.; Ashimine, R.; Zollner, R.L.; Boschero, A.C.; Saad, M.J.; Velloso, L.A. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 2005, 146, 4192–4199. [Google Scholar] [CrossRef]
  65. Jeon, B.T.; Jeong, E.A.; Shin, H.J.; Lee, Y.; Lee, D.H.; Kim, H.J.; Kang, S.S.; Cho, G.J.; Choi, W.S.; Roh, G.S. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes 2012, 61, 1444–1454. [Google Scholar] [CrossRef]
  66. Thaler, J.P.; Yi, C.X.; Schur, E.A.; Guyenet, S.J.; Hwang, B.H.; Dietrich, M.O.; Zhao, X.; Sarruf, D.A.; Izqur, V.; Maravilla, K.R.; et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 2012, 122, 153–162. [Google Scholar] [CrossRef] [Green Version]
  67. Wang, X.; Ge, A.; Cheng, M.; Guo, F.; Zhao, M.; Zhou, X.; Liu, L.; Yang, N. Increased hypothalamic inflammation associated with the susceptibility to obesity in rats exposed to high-fat diet. Exp. Diabetes Res. 2012, 2012. [Google Scholar] [CrossRef]
  68. Andre, C.; Dinel, A.L.; Ferreira, G.; Laye, S.; Castanon, N. Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behaviour: Focus on brain indoleamine 2,3-dioxygenase activation. Brain Behav. Immunol. 2014, 41, 10–21. [Google Scholar] [CrossRef]
  69. Boitard, C.; Cavaroc, A.; Sauvant, J.; Aubert, A.; Castanon, N.; Laye, S.; Ferreira, G. Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats. Brain Behav. Immun. 2014, 40, 9–17. [Google Scholar] [CrossRef]
  70. Tsai, S.-F.; Wu, H.-T.; Chen, P.-C.; Chen, Y.-W.; Yu, M.; Wang, T.-F.; Wu, S.Y.; Tzeng, S.F.; Kuo, Y.M. High-fat diet suppresses the astrocytic process arborization and downregulates the glial glutamate transporters in the hippocampus of mice. Brain Res. 2018, 1700, 66–77. [Google Scholar] [CrossRef]
  71. Schuster, F.; Huber, G.; Stölting, I.; Wing, E.E.; Saar, K.; Hübner, N.; Banks, W.A.; Raasch, W. Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice. Pflügers Arch. Eur. J. Physiol. 2018, 470, 1673–1689. [Google Scholar] [CrossRef]
  72. Engelhart, M.J.; Geerlings, M.I.; Ruitenberg, A.; Van Swieten, J.C.; Hofman, A.; Witteman, J.C.; Breteler, M.M. Diet and risk of dementia: Does fat matter? the Rotterdam Study. Neurology 2002, 59, 1915–1921. [Google Scholar] [CrossRef]
  73. Luchsinger, J.A.; Tang, M.X.; Shea, S.; Mayeux, R. Caloric intake and the risk of Alzheimer disease. Arch. Neurol. 2002, 59, 1258–1263. [Google Scholar] [CrossRef]
  74. Swanson, D.; Block, R.; Mousa, S.A. Omega-3 fatty acids EPA and DHA: Health benefits throughout life. Adv. Nutr. 2012, 3, 1–7. [Google Scholar] [CrossRef]
  75. Luchtman, D.W.; Song, C. Cognitive enhancement by omega-3 fatty acids from childhood to old age: Findings from animal and clinical studies. Neuropharmacol. 2013, 64, 550–565. [Google Scholar] [CrossRef]
  76. Devore, E.E.; Grodstein, F.; van Rooij, F.J.; Hofman, A.; Rosner, B.; Stampfer, M.J.; Witteman, J.C.; Breteler, M.M. Dietary intake of fish and omega-3 fatty acids in relation to long-term dementia risk. Am. J. Clin. Nutr. 2009, 90, 170–176. [Google Scholar] [CrossRef] [Green Version]
  77. Bhat, A.H.; Dar, K.B.; Anees, S.; Zargar, M.A.; Masood, A.; Sofi, M.A.; Ganie, S.A. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharm. 2015, 74, 101–110. [Google Scholar] [CrossRef]
  78. Swerdlow, R.H.; Burns, J.M.; Khan, S.M. The Alzheimer’s disease mitochondrial cascade hypothesis: Progress and perspectives. Biochim. Biophys. Acta 2014, 1842, 1219–1231. [Google Scholar] [CrossRef]
  79. Wang, C.H.; Wu, S.B.; Wu, Y.T.; Wei, Y.H. Oxidative stress response elicited by mitochondrial dysfunction: Implication in the pathophysiology of aging. Exp. Biol. Med. 2013, 238, 450–460. [Google Scholar] [CrossRef]
  80. Guo, C.Y.; Sun, L.; Chen, X.P.; Zhang, D.S. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen. Res. 2013, 8, 2003–2014. [Google Scholar] [CrossRef]
  81. Unamuno, X.; Gómez-Ambrosi, J.; Rodríguez, A.; Becerril, S.; Frühbeck, G.; Catalán, V. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur. J. Clin. Investig. 2018, 48, e12997. [Google Scholar] [CrossRef] [Green Version]
  82. Danielski, L.G.; Giustina, A.D.; Badawy, M.; Barichello, T.; Quevedo, J.; Dal-Pizzol, F.; Petronilho, F. Brain barrier breakdown as a cause and consequence of neuroinflammation in sepsis. Mol. Neurobiol. 2018, 55, 1045–1053. [Google Scholar] [CrossRef]
  83. Jagan, K.; Priya, C.S.; Kalpana, K.; Vidhya, R.; Anuradha, C.V. Apigenin attenuates hippocampal oxidative events, inflammation and pathological alterations in rats fed high fat, fructose diet. Biomed. Pharm. 2017, 89, 323–331. [Google Scholar] [CrossRef]
  84. Feng, X.; Valdearcos, M.; Uchida, Y.; Lutrin, D.; Maze, M.; Koliwad, S.K. Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2017, 2, e91229. [Google Scholar] [CrossRef] [Green Version]
  85. Romano, A.; Koczwara, J.B.; Gallelli, C.A.; Vergara, D.; Di Bonaventura, M.V.M.; Gaetani, S.; Giudetti, A.M. Fats for thoughts: An update on brain fatty acid metabolism. Int. J. Biochem. Cell Biol. 2017, 84, 40–45. [Google Scholar] [CrossRef]
  86. Karmi, A.; Iozzo, P.; Viljanen, A.; Hirvonen, J.; Fielding, B.A.; Virtanen, K.; Oikonen, V.; Kemppainen, J.; Viljanen, T.; Guiducci, L.; et al. Increased brain fatty acid uptake in metabolic syndrome. Diabetes 2010, 59, 2171–2177. [Google Scholar] [CrossRef]
  87. Williams, L.M. Hypothalamic dysfunction in obesity. Proc. Nutr. Soc. 2012, 71, 521–533. [Google Scholar] [CrossRef] [Green Version]
  88. Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer’s Dement. 2016, 12, 719–732. [Google Scholar] [CrossRef]
  89. Pugazhenthi, S.; Qin, L.; Reddy, H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 1037–1045. [Google Scholar] [CrossRef]
  90. Lai, K.S.; Liu, C.S.; Rau, A.; Lanctôt, K.L.; Köhler, C.A.; Pakosh, M.; Carvalho, A.F.; Herrmann, N. Peripheral inflammatory markers in Alzheimer’s disease: A systematic review and meta-analysis of 175 studies. J. Neurol. Neurosurg. Psychiatry 2017, 88, 876–882. [Google Scholar] [CrossRef]
  91. Asghar, A.; Sheikh, N. Role of immune cells in obesity induced low grade inflammation and insulin resistance. Cell. Immunol. 2017, 315, 18–26. [Google Scholar] [CrossRef]
  92. Shu, C.J.; Benoist, C.; Mathis, D. The immune system’s involvement in obesity-driven type 2 diabetes. Semin. Immunol. 2012, 24, 436–442. [Google Scholar] [CrossRef] [PubMed]
  93. Schram, M.T.; Euser, S.M.; De Craen, A.J.M.; Witteman, J.C.; Frölich, M.; Hofman, A.; Jolles, J.; Breteler, M.M.; Westendorp, R.G. Systemic markers of inflammation and cognitive decline in old age. J. Am. Geriatr. Soc. 2007, 55, 708–716. [Google Scholar] [CrossRef]
  94. Dziedzic, T. Systemic inflammatory markers and risk of dementia. Am. J. Alzheimers Dis Other Demen. 2006, 21, 258–262. [Google Scholar] [CrossRef] [PubMed]
  95. Ojo, B.; Rezaie, P.; Gabbott, P.L.; Davies, H.; Colyer, F.; Cowley, T.R.; Lynch, M.; Stewart, M.G. Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL. Brain Behav. Immun. 2012, 26, 778–788. [Google Scholar] [CrossRef] [PubMed]
  96. Godbout, J.P.; Chen, J.; Abraham, J.; Richwine, A.F.; Berg, B.M.; Kelley, K.W.; Johnson, R.W. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J. 2005, 19, 1329–1331. [Google Scholar] [CrossRef]
  97. Wynne, A.M.; Henry, C.J.; Huang, Y.; Cleland, A.; Godbout, J.P. Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge. Brain Behav. Immun. 2010, 24, 1190–1201. [Google Scholar] [CrossRef] [Green Version]
  98. Villaran, R.F.; Espinosa-Oliva, A.M.; Sarmiento, M.; De Pablos, R.M.; Arguelles, S.; Delgado-Cortes, M.J.; Sobrino, V.; Van Rooijen, N.; Venero, J.L.; Herrera, A.J.; et al. Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: Potential risk factor in Parkinson’s disease. J. Neurochem. 2010, 114, 1687–1700. [Google Scholar] [CrossRef]
  99. Trollor, J.N.; Smith, E.; Agars, E.; Kuan, S.A.; Baune, B.T.; Campbell, L.; Samaras, K.; Crawford, J.; Lux, O.; Kochan, N.A.; et al. The association between systemic inflammation and cognitive performance in the elderly: The Sydney Memory and Ageing Study. Age 2012, 34, 1295–1308. [Google Scholar] [CrossRef]
  100. Erion, J.R.; Wosiski-Kuhn, M.; Dey, A.; Hao, S.; Davis, C.L.; Pollock, N.K.; Stranahan, A.M. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J. Neurosci. 2014, 34, 2618–2631. [Google Scholar] [CrossRef]
  101. Hu, J.; Feng, X.; Valdearcos, M.; Lutrin, D.; Uchida, Y.; Koliwad, S.K.; Maze, M. Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice. Br. J. Anaesth. 2018, 120, 537–545. [Google Scholar] [CrossRef] [Green Version]
  102. Calvo-Rodríguez, M.; de la Fuente, C.; García-Durillo, M.; García-Rodríguez, C.; Villalobos, C.; Núñez, L. Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons. J. Neuroinflammation 2017, 14, 24. [Google Scholar] [CrossRef]
  103. Dantzer, R.; O’Connor, J.C.; Freund, G.G.; Johnson, R.W.; Kelley, K.W. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat. Rev. Neurosci. 2008, 9, 46–56. [Google Scholar] [CrossRef]
  104. Miller, A.A.; Spencer, S.J. Obesity and neuroinflammation: A pathway to cognitive impairment. Brain Behav. Immun. 2014, 42, 10–21. [Google Scholar] [CrossRef] [PubMed]
  105. Hummel, K.P.; Dickie, M.M.; Coleman, D.L. Diabetes, a new mutation in the mouse. Science 1966, 153, 1127–1128. [Google Scholar] [CrossRef]
  106. Dinel, A.L.; Andre, C.; Aubert, A.; Ferreira, G.; Laye, S.; Castanon, N. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS ONE 2011, 6, e24325. [Google Scholar] [CrossRef]
  107. Reilly, S.M.; Saltiel, A.R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 2017, 13, 633–643. [Google Scholar] [CrossRef] [PubMed]
  108. Odegaard, J.I.; Chawla, A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Sci. 2013, 339, 172–177. [Google Scholar] [CrossRef] [PubMed]
  109. Ouchi, N.; Parker, J.L.; Lugus, J.J.; Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 2011, 11, 85–97. [Google Scholar] [CrossRef] [PubMed]
  110. Hermsdorff, H.H.; Zulet, M.A.; Puchau, B.; Martinez, J.A. Central adiposity rather than total adiposity measurements are specifically involved in the inflammatory status from healthy young adults. Inflammation 2011, 34, 161–170. [Google Scholar] [CrossRef] [PubMed]
  111. Nguyen, J.C.D.; Killcross, A.S.; Jenkins, T.A. Obesity and cognitive decline: Role of inflammation and vascular changes. Front. Neurosci. 2014, 8, 375. [Google Scholar] [CrossRef]
  112. Sumarac-Dumanovic, M.; Stevanovic, D.; Ljubic, A.; Jorga, J.; Simic, M.; Stamenkovic-Pejkovic, D.; Starcevic, V.; Trajkovic, V.; Micic, D. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int. J. Obes. 2009, 33, 151–156. [Google Scholar] [CrossRef] [PubMed]
  113. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87–91. [Google Scholar] [CrossRef] [PubMed]
  114. Misiak, B.; Stańczykiewicz, B.; Kotowicz, K.; Rybakowski, J.K.; Samochowiec, J.; Frydecka, D. Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: A systematic review. Schizophr. Res. 2018, 192, 16–29. [Google Scholar] [CrossRef]
  115. Harrison, N.A.; Doeller, C.F.; Voon, V.; Burgess, N.; Critchley, H.D. Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism. Biol. Psychiatry 2014, 76, 585–593. [Google Scholar] [CrossRef] [PubMed]
  116. Charlton, R.A.; Lamar, M.; Zhang, A.; Ren, X.; Ajilore, O.; Pandey, G.N.; Kumar, A. Associations between pro-inflammatory cytokines, learning, and memory in late-life depression and healthy aging. Int. J. Geriatr. Psychiatry 2018, 33, 104–112. [Google Scholar] [CrossRef] [PubMed]
  117. Afonso, M.S.; Lavrador, M.S.F.; Koike, M.K.; Cintra, D.E.; Ferreira, F.S.; Nunes, V.S.; Castilho, G.; Gioielli, L.A.; Paula Bombo, R.; Catanozi, S.; et al. Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation. J. Nutr. Biochem. 2016, 32, 91–100. [Google Scholar] [CrossRef]
  118. Nishimura, Y.; Moriyama, M.; Kawabe, K.; Satoh, H.; Takano, K.; Azuma, Y.-T.; Nakamura, Y. Lauric acid alleviates neuroinflammatory responses by activated microglia: Involvement of the GPR40-dependent pathway. Neurochem. Res. 2018, 43, 1723–1735. [Google Scholar] [CrossRef]
  119. Almeida-Suhett, C.P.; Graham, A.; Chen, Y.; Deuster, P. Behavioral changes in male mice fed a high-fat diet are associated with IL-1β expression in specific brain regions. Physiol. Behav. 2017, 169, 130–140. [Google Scholar] [CrossRef]
  120. Yirmiya, R.; Goshen, I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 2011, 25, 181–213. [Google Scholar] [CrossRef]
  121. Barrientos, R.M.; Frank, M.G.; Hein, A.M.; Higgins, E.A.; Watkins, L.R.; Rudy, J.W.; Maier, S.F. Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection. Brain Behav. Immun. 2009, 23, 46–54. [Google Scholar] [CrossRef]
  122. Barrientos, R.M.; Hein, A.M.; Frank, M.G.; Watkins, L.R.; Maier, S.F. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J. Neurosci. 2012, 32, 14641–14648. [Google Scholar] [CrossRef] [PubMed]
  123. Hall, J.R.; Wiechmann, A.R.; Johnson, L.A.; Edwards, M.; Barber, R.C.; Winter, A.S.; Singh, M.; O’Bryant, S.E. Biomarkers of vascular risk, systemic inflammation, and microvascular pathology and neuropsychiatric symptoms in Alzheimer’s disease. J. Alzheimer’s Dis. 2013, 35, 363–371. [Google Scholar] [CrossRef] [PubMed]
  124. Viscogliosi, G.; Andreozzi, P.; Chiriac, I.M.; Cipriani, E.; Servello, A.; Marigliano, B.; Ettorre, E.; Marigliano, V. Depressive symptoms in older people with metabolic syndrome: Is there a relationship with inflammation? Int. J. Geriatr. Psychiatry 2013, 28, 242–247. [Google Scholar] [CrossRef] [PubMed]
  125. de Sousa Rodrigues, M.E.; Bekhbat, M.; Houser, M.C.; Chang, J.; Walker, D.I.; Jones, D.P.; Oller do Nascimento, C.M.P.; Barnum, C.J.; Tansey, M.G. Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice. Brain Behav. Immun. 2017, 59, 158–172. [Google Scholar] [CrossRef]
  126. Hotamisligil, G.S. Inflammation, metaflammation and immunometabolic disorders. Nat. 2017, 542, 177–185. [Google Scholar] [CrossRef]
  127. Lu, P.; Gonzales, C.; Chen, Y.; Adedoyin, A.; Hummel, M.; Kennedy, J.D.; Whiteside, G.T. CNS penetration of small molecules following local inflammation, widespread systemic inflammation or direct injury to the nervous system. Life Sci. 2009, 85, 450–456. [Google Scholar] [CrossRef]
  128. Koyama, A.; O’Brien, J.; Weuve, J.; Blacker, D.; Metti, A.L.; Yaffe, K. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: A meta-analysis. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 433–440. [Google Scholar] [CrossRef]
  129. Najam, S.S.; Zglinicki, B.; Vinnikov, I.A.; Konopka, W. MicroRNAs in the hypothalamic control of energy homeostasis. Cell Tissue Res. 2019, 375, 173–177. [Google Scholar] [CrossRef]
  130. Petrovich, G.D. Lateral hypothalamus as a motivation-cognition interface in the control of feeding behaviour. Front. Syst. Neurosci. 2018, 12, 14. [Google Scholar] [CrossRef]
  131. Reppermund, S.; Zihl, J.; Lucae, S.; Horstmann, S.; Kloiber, S.; Holsboer, F.; Ising, M. Persistent cognitive impairment in depression: The role of psychopathology and altered hypothalamic-pituitary-adrenocortical (HPA) system regulation. Biol. Psychiatry 2007, 62, 400–406. [Google Scholar] [CrossRef]
  132. Young, K.D.; Siegle, G.J.; Zotev, V.; Phillips, R.; Misaki, M.; Yuan, H.; Drevets, W.C.; Bodurka, J. Randomized clinical trial of real-time fMRI amygdala neurofeedback for major depressive disorder: Effects on symptoms and autobiographical memory recall. Am. J. Psychiatry 2017, 174, 748–755. [Google Scholar] [CrossRef] [PubMed]
  133. Jais, A.; Brüning, J.C. Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Investig. 2017, 127, 24–32. [Google Scholar] [CrossRef] [PubMed]
  134. Baufeld, C.; Osterloh, A.; Prokop, S.; Miller, K.R.; Heppner, F.L. High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia. Acta Neuropathol. 2016, 132, 361–375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Chen, Z.; Trapp, B.D. Microglia and neuroprotection. J. Neurochem. 2016, 136, 10–17. [Google Scholar] [CrossRef]
  136. Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2010, 119, 7–35. [Google Scholar] [CrossRef]
  137. Garcia-Caceres, C.; Yi, C.X.; Tschop, M.H. Hypothalamic astrocytes in obesity. Endocrinol. Metab. Clin. N. Am. 2013, 42, 57–66. [Google Scholar] [CrossRef]
  138. Mayo, L.; Quintana, F.J.; Weiner, H.L. The innate immune system in demyelinating disease. Immunol. Rev. 2012, 248, 170–187. [Google Scholar] [CrossRef]
  139. Tucsek, Z.; Toth, P.; Sosnowska, D.; Gautam, T.; Mitschelen, M.; Koller, A.; Szalai, G.; Sonntag, W.E.; Ungvari, Z.; Csiszar, A. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: Effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69, 1212–1226. [Google Scholar] [CrossRef]
  140. Cai, Z.; Yan, Y.; Wang, Y. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder. Clin. Interv. Aging 2013, 8, 1089–1095. [Google Scholar] [CrossRef] [Green Version]
  141. Pepping, J.K.; Freeman, L.R.; Gupta, S.; Keller, J.N.; Bruce-Keller, A.J. NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet. Am. J. Physiol. Endocrinol. Metab. 2013, 304, E392–E404. [Google Scholar] [CrossRef] [Green Version]
  142. Zhang, X.; Zhang, G.; Zhang, H.; Karin, M.; Bai, H.; Cai, D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008, 135, 61–73. [Google Scholar] [CrossRef] [PubMed]
  143. Milanski, M.; Degasperi, G.; Coope, A.; Morari, J.; Denis, R.; Cintra, D.E.; Tsukumo, D.M.; Anhe, G.; Amaral, M.E.; Takahashi, H.K.; et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: Implications for the pathogenesis of obesity. J. Neurosci. 2009, 29, 359–370. [Google Scholar] [CrossRef] [PubMed]
  144. Posey, K.A.; Clegg, D.J.; Printz, R.L.; Byun, J.; Morton, G.J.; Vivekanandan-Giri, A.; Pennathur, S.; Baskin, D.G.; Heinecke, J.W.; Woods, S.C.; et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E1003–E1012. [Google Scholar] [CrossRef] [PubMed]
  145. Lizarbe, B.; Cherix, A.; Duarte, J.M.N.; Cardinaux, J.-R.; Gruetter, R. High-fat diet consumption alters energy metabolism in the mouse hypothalamus. Int. J. Obes. 2019, 43, 1295–1304. [Google Scholar] [CrossRef] [PubMed]
  146. Johnson, J.D.; O’Connor, K.A.; Deak, T.; Stark, M.; Watkins, L.R.; Maier, S.F. Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav. Immun. 2002, 16, 461–476. [Google Scholar] [CrossRef] [PubMed]
  147. Wohleb, E.S.; Powell, N.D.; Godbout, J.P.; Sheridan, J.F. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. 2013, 33, 13820–13833. [Google Scholar] [CrossRef] [PubMed]
  148. Wohleb, E.S.; McKim, D.B.; Shea, D.T.; Powell, N.D.; Tarr, A.J.; Sheridan, J.F.; Godbout, J.P. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol. Psychiatry 2013, 75, 970–981. [Google Scholar] [CrossRef]
  149. Guillemot-Legris, O.; Muccioli, G.G. Obesity-induced neuroinflammation: Beyond the hypothalamus. Trends Neurosci. 2017, 40, 237–253. [Google Scholar] [CrossRef]
  150. Castrén, E.; Kojima, M. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments. Neurobiol. Dis. 2017, 97, 119–126. [Google Scholar] [CrossRef] [Green Version]
  151. Kowiański, P.; Lietzau, G.; Czuba, E.; Waśkow, M.; Steliga, A.; Moryś, J. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell. Mol. Neurobiol. 2018, 38, 579–593. [Google Scholar] [CrossRef]
  152. Molteni, R.; Barnard, R.J.; Ying, Z.; Roberts, C.K.; Gómez-Pinilla, F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 2002, 112, 803–814. [Google Scholar] [CrossRef] [Green Version]
  153. Jabri, M.-A.; Sakly, M.; Marzouki, L.; Sebai, H. Chamomile (Matricaria recutita L.) decoction extract inhibits in vitro intestinal glucose absorption and attenuates high fat diet-induced lipotoxicity and oxidative stress. Biomed. Pharm 2017, 87, 153–159. [Google Scholar] [CrossRef] [PubMed]
  154. Molteni, R.; Wu, A.; Vaynman, S.; Ying, Z.; Bernard, R.J.; Gómez-Pinilla, F. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience 2004, 123, 429–440. [Google Scholar] [CrossRef] [PubMed]
  155. Mi, Y.; Qi, G.; Fan, R.; Qiao, Q.; Sun, Y.; Gao, Y.; Liu, X. EGCG ameliorates high-fat- and high-fructose-induced cognitive defects by regulating the IRS/AKT and ERK/CREB/BDNF signaling pathways in the CNS. FASEB J. 2017, 31, 4998–5011. [Google Scholar] [CrossRef] [PubMed]
  156. Beilharz, J.E.; Maniam, J.; Morris, M.J. Short exposure to a diet rich in both fat and sugar or sugar alone impairs place, but not object recognition memory in rats. Brain Behav. Immun. 2014, 37, 134–141. [Google Scholar] [CrossRef]
  157. Villapol, S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell. Mol. Neurobiol. 2018, 38, 121–132. [Google Scholar] [CrossRef]
Figure 1. The effect of a high-fat diet (HFD) on cognitive function. Consumption of HFD induces reactive oxygen species (ROS). Accumulation of ROS leads to DNA mutation and protein/lipid oxidation and subsequently reduced the mitochondrial function. Overproduction of reactive species that occur in the mitochondrial DNA can lead to neurodegenerative disease and brain dysfunction. Systemic inflammation and hypothalamic inflammation promotes cognitive decline via secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6).
Figure 1. The effect of a high-fat diet (HFD) on cognitive function. Consumption of HFD induces reactive oxygen species (ROS). Accumulation of ROS leads to DNA mutation and protein/lipid oxidation and subsequently reduced the mitochondrial function. Overproduction of reactive species that occur in the mitochondrial DNA can lead to neurodegenerative disease and brain dysfunction. Systemic inflammation and hypothalamic inflammation promotes cognitive decline via secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6).
Nutrients 11 02579 g001
Table 1. The effects of a HFD on cognitive function in animal models.
Table 1. The effects of a HFD on cognitive function in animal models.
Animal Strains [Number of Animals]The Diet UsedFindingsReferences
Male 4-week-old Wistar rats (n = 10)Hyperlipidic diet
  • ↑ TNF-α, IL-1β, and IL-6 expression at 16 weeks.
  • ↑ Phospho-[Thr183]-c-Jun N-terminal kinase (JNK) and NFκB.
  • ↓ Insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS-2).
  • ↑ Hypothalamic expression of SOCS-3.
Middle-aged (12 months old) male C57BL/6 mice (n = 40 (8–10 mice per group))The initial study [Western diet for 21 weeks] The following study [high-fat lard diet for 16 weeks]
  • ↑ Increase glial fibrillary acidic protein (GFAP) expression.
  • ↑ TNF-α, IL-6, MCP-1, and Iba-1 expression.
  • ↓ Cortical BDNF levels.
Male C57BL/6J mice (3 weeks old) (n = 120)HFD for 20 weeks
  • ↓ The ratio of brain to body weight.
  • The hepatocytes of HFD-fed mice were distended by large cytoplasmic lipid droplets.
  • ↑ Immune densities and TNF-α.
  • Showed activated microglia in the hippocampus.
  • ↑ Hippocampal 4-hydroxynonenal (4-HNE) expression.
  • ↓ p-IR, hippocampal phospho-AMP-activated protein kinase (p-AMPK), and phosphoacetyl-CoA carboxylase (p-ACC).
  • ↑ Escape latencies and swimming distance during training trials.
Weight-matched male Long-Evans rats (300–350 g; Harlan) or male C57BL/6 mice (20–25 g) (n = 16)HFD for 20 weeks
  • ↑ Expression of proinflammatory genes by approximately 50% in both hypothalamus and liver.
  • ↑ Hypothalamic expression of mRNA encoding myeloid cell-specific markers Cd68 and Emr1 (which encodes F4/80).
  • ↑ Microglial number in the rat arcuate nucleus (ARC).
Six-week-old outbred male Sprague-Dawley rats (n = 55)HFD
  • ↑ Hypothalamic expression of genes encoding TLR4 and NF-κB mRNA.
  • ↑ Hypothalamic TNF-α, IL-1β, and IL-6 mRNA expression.
Male C57BL/6J mice (three-week-old) (n = 48)Western diet group
  • ↑ Hypothalamus IL-6, IDO, TNF-α, and IFN-γ mRNA expression induced by LPS.
  • ↑ Brain KYN/TRP ratio.
Wistar naïve male rats (3 weeks old (juvenile groups) or 12 weeks old (adult groups) (n = 143)HFD
  • Long-term memory disturbance.
  • Impaired long-term spatial reference memory in Morris water maze.
  • Showed a higher latency to reach the platform.
  • Spatial reversal learning enhanced interleukin-1β (IL-1β) mRNA level in the hippocampus.
  • TNF-α and IL-6 mRNA expression.
C57BL/6J male mice (5-week-old, 15–20 g) (n = 34)HFD
  • Animals treated with HFD for 48 h presented a partial inhibition of long-term potentiation (LTP).
  • The maintenance of LTP was impaired by HFD treatment.
Male C57BL/6 mice (8-week-old) (n = 10)HFD for 12 weeks
  • HFD did not alter the swimming speed, performance of mice in Morris water maze during learning phase or memory retrieval phase.
  • ↓ Total travel distance.
  • Induced anhedonia and despair in mice.
  • ↑ Immobility in forced swimming test.
  • ↑ GFAP in the whole hippocampi.
  • ↓ The lengths of total process and the numbers of branch point of the GFAP+ astrocytes in the hippocampal CA1 and CA3 regions.
  • ↓ Glutamate-aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), and connexin 43 (Cx-43) in the hippocampi.
Male C57BL/6N mice (aged 6–8 weeks) (n = 297)HFD
  • ↑ Local inflammation such as CD53, leptin, interleukin 1 receptor antagonist, cathepsin S, integrin beta 2, chemokine (C-C motif) ligand 2, interleukin 7 receptor, and chemokine (C-C motif) ligand 8.
Male (C57Bl/6J mice) 12 week old (n = 112)HFD for one day
  • Induce episodic memory, contextual associative, and spatial memory
Male (Orexin/ataxin-3 (O/A3) mice (7–8 month of age) (n = 36)HFD
  • Learning impairment was evident in both 2 and 4 weeks.
  • ↑ Microglial activation marker Iba-1.
  • ↑ CX3 chemokine receptor 1 (CX3CR1), TNF-α, and mitochondria-associated enzyme immune responsive gene-1 (Irg1).
Table 2. The effects of a HFD on cognitive function in human studies.
Table 2. The effects of a HFD on cognitive function in human studies.
Subjects [Sample Size]Study DesignThe Diet UsedFindingsLimitationsReferences
Elderly (n = 5395)At baseline (1990 to 1993), the subjects had normal cognition, were noninstitutionalized, and underwent a complete dietary assessment by a semiquantitative food-frequency questionnaire (FFQ). The cohort was continuously monitored for incident dementia [(1993–1994) and (1997–1999)].HFD (Total, saturated, trans fat, and cholesterol)Not associated with increased risk of dementia or its subtypes.The semiquantitative FFQ may not have enough precision to measure the nutrient intake.[72]
Elderly individuals free of dementia (n = 980)The subjects were followed for a mean of 4 years. Daily consumption of protein, fats, carbohydrates, and calories was recalled using a semiquantitative FFQ administered between the baseline and first follow-up visits.HFDA high intake of SFA was not associated with the increased risk of Alzheimer’s disease.
  • The semiquantitative FFQ may not have enough precision to measure the nutrient intake.
  • Underreport calorie intake.
Nondemented elderly subjects (65–84 years) (n = 704)Participants were followed-up for a median period of 2.6 years. Dietary intakes were assessed at baseline with a 77-item semiquantitative FFQ.High PUFAProtect against the development of mild cognitive impairment.
  • Small sample size.
  • The length of the follow-up time was fairly short.
  • The nonparticipation rate was high.
  • The attrition rate of this longitudinal study is quite high.
Healthy male adults (aged 22 ± 1 year) (n = 16)Subjects were randomly assigned to receive either a high-fat, low-carbohydrate diet or a standard diet for 5 days and then crossed over to the alternate diet after a 2-week washout period. During the diets, cognitive function was measured.High-fat, low-carbohydrate diet for 5 daysImpaired attention, speed, and mood.Small sample size.[57]
Sedentary men with fewer than 2 h/week physical activity (n = 20)The participants were assessed when consuming a standardized, nutritionally balanced diet (control) and after 7 days of consuming a diet comprising 74% kcal from fat.HFDIncreased simple reaction times and decreased power of attention.Small sample size.[58]
Elderly (n = 6183)Serial cognitive testing was conducted over 4 years, began 5 years post-dietary assessment using 131-item semiquantitative FFQ.High SFA↓ Global cognitive and verbal memory trajectories.
  • Repeated diet assessments were not available.
  • Reverse causation is possible.
  • The participants were primarily Caucasian women.
Elderly (median age, 79.5 years) (n = 937)Participants were followed over a median of 3.7 years of follow-up. At baseline and every 15 months, participants were evaluated using the Clinical Dementia Rating Scale, a neurological evaluation, and neuropsychological testing for a diagnosis of dementia, normal cognition, or mild cognitive impairment. The participants were given a 128-item FFQ at baseline.HFD↓ The risk of mild cognitive impairment or dementia.
  • Recall bias in reporting of dietary nutrients.
  • The participants were primarily northern European ancestry.
  • Non-participation bias.
  • FFQ may not have enough precision to measure nutrient intake.

Share and Cite

MDPI and ACS Style

Tan, B.L.; Norhaizan, M.E. Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function. Nutrients 2019, 11, 2579.

AMA Style

Tan BL, Norhaizan ME. Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function. Nutrients. 2019; 11(11):2579.

Chicago/Turabian Style

Tan, Bee Ling, and Mohd Esa Norhaizan. 2019. "Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function" Nutrients 11, no. 11: 2579.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop