aersi

High fat dietHypothalamusInammationObesity

emevie winnit

liferation. This local inammation likely causes synaptic remodeling and neurodegeneration within thehypothalamus, altering internal hypothalamic circuitry and hypothalamic outputs to other brain regions.

s indeepiden repoeightn wer

It is well known that obesity increases the risk for a wide spec-

James, 2005). In addition, relationships between obesity and cogni-tive function, as well as risk of dementias such as Alzheimers dis-ease (AD), have more recently come to attention. For example,clinical and experimental evidence indicates that obesity and/or

implicated in the neuropathological hallmarks of AD (i.e. a10). On thd with low

Hotamisligil, 2011; Spencer, 2013). Moreover, accumulating evi-dence suggests that obesity also results in inammation in thebrain and particularly in the hypothalamus. Thus, whilst severalmechanisms are likely to link obesity and cognitive impairment,it might be hypothesized that systemic and central inammationmay converge into a nal common pathway leading not only toimpairment of hypothalamic regulatory pathways of feeding butalso cognitive dysfunction.

Corresponding author. Address: School of Health Sciences and HIRi, RMITUniversity, Melbourne, Vic. 3083, Australia. Tel.: +61 3 9925 7745.

E-mail address: Sarah.Spencer@rmit.edu.au (S.J. Spencer).

Brain, Behavior, and Immunity 42 (2014) 1021

Contents lists availab

Brain, Behavior,

.erespiratory problems, and many types of cancer (Haslam and inammation in peripheral tissues and the circulation (Gregor andtrum of conditions including type 2 diabetes, hypertension, heartdisease, stroke, musculoskeletal disorders, gastrointestinal and

plaques and neurobrillary tangles) (Gorelick, 20hand, it is well accepted that obesity is associatehttp://dx.doi.org/10.1016/j.bbi.2014.04.0010889-1591/ 2014 Elsevier Inc. All rights reserved.myloide other-gradeThe prevalence of overweight and obese children and adolescentsis also high. For example, during 20092010 the prevalence ofchildhood obesity was 16.9% in the United States of America(Ogden et al., 2012). Alarmingly, evidence shows that childrenwho are overweight are more likely to remain so in adulthood(Biro and Wien, 2010).

In light of the high numbers of overweight and obese individu-als, there is a clear need to better understand the pathophysiolog-ical mechanisms underpinning obesity and its impact on cognitivefunction. Inammation, the bodys defense response to harmfulstimuli, is proposed to be an important pathophysiological mecha-nism underlying cognitive impairment and dementia, and has been1. Introduction

The number of obese (body masweight (BMI >25) people is reachingwide. The World Health Organizatiothan 1.4 billion adults were overwmen and nearly 300 million womeThe result is disruption to cognitive function mediated by regions such as hippocampus, amygdala, andreward-processing centers. Central inammation is also likely to affect these regions directly. Thus, cen-tral inammation in obesity leads not just to disruption of hypothalamic satiety signals and perpetuationof overeating, but also to negative outcomes on cognition.

2014 Elsevier Inc. All rights reserved.

x, BMI >30) and over-mic proportions world-rts that in 2008, moreand over 200 millione obese (WHO, 2013).

high fat feeding are associated with decits in learning, memory,and executive functioning (Elias et al., 2003, 2005; Cournot et al.,2006; Sabia et al., 2009), and potentially brain atrophy (Enzingeret al., 2005; Ward et al., 2005). Moreover, accumulating evidenceindicates obesity during mid-life increases the risk of dementiassuch as AD later in life (Gorospe and Dave, 2007; Beydoun et al.,2008; Anstey et al., 2011).Keywords:Cognition

mation and excess circulating free fatty acids. Circulating cytokines, free fatty acids and immune cellsreach the brain at the level of the hypothalamus and initiate local inammation, including microglial pro-Named Series: Diet, Inammation and the Brain

Obesity and neuroinammation: A pathw

Alyson A. Miller a, Sarah J. Spencer b,a School of Medical Sciences and Health Innovations Research Institute (HIRi), RMIT Univb School of Health Sciences and HIRi, RMIT University, Melbourne, Vic., Australia

a r t i c l e i n f o

Article history:Received 23 January 2014Received in revised form 19 March 2014Accepted 1 April 2014Available online 12 April 2014

a b s t r a c t

Obesity is a growing problnitive dysfunction. In this rto cognitive dysfunction. Wleads to inammation withsible for these negative cog

journal homepage: wwwy to cognitive impairment

ty, Melbourne, Vic., Australia

worldwide and is associated with a range of comorbidities, including cog-ew we will address the evidence that obesity and high fat feeding can leadill also examine the idea that obesity-associated systemic inammation

the brain, particularly the hypothalamus, and that this is partially respon-ive outcomes. Thus, obesity, and high fat feeding, lead to systemic inam-

le at ScienceDirect

and Immunity

lsevier .com/locate /ybrbi

cognitive impairment (West and Haan, 2009). The reasons for thediscrepancies between these studies are unclear, however, it is

avionoteworthy that the battery of cognitive tests used in these studiesvaried considerably in terms of the breadth of domains tested andthe stringency of tests employed. Thus, this may make it difcult tocompare their ndings. Additionally, it is well known that aging isassociated with changes in body composition, including anincrease in fat mass and a decline in muscle mass (sarcopenia).Thus, the mixed ndings may reect the difculties in deningIn this review we will rstly focus on clinical and experimentalevidence that obesity and/or high fat diet feeding, the latter used toinduce obesity in animal models, are associated with cognitive dys-function and also an increased risk of dementias such as AD. Sec-ondly, we will discuss evidence that central inammation may bean important link between obesity and cognitive dysfunction, witha particular focus on inammation within the hypothalamus.

2. Association of obesity with cognitive function and brainstructure

2.1. Clinical studies of adults

The negative effects of obesity on cardiovascular and metabolicphysiology are well known, and it is now apparent that the brain isalso negatively affected by obesity. Several studies have reported alink between obesity and risk of dementias including vascular cog-nitive impairment and AD (see Section 3). Moreover, evidence indi-cates that obesity is linked with cognitive dysfunction long beforethe onset of these conditions. Studies have shown higher BMI isassociated with decits in learning, memory, and executive func-tioning in non-demented middle-aged adults, independent of itsrelationship to cardiovascular and cerebrovascular disease (Eliaset al., 2003, 2005; Cournot et al., 2006; Sabia et al., 2009). Similarly,studies of otherwise healthy (i.e. no abnormalities other than obes-ity) young adults have found BMI to be inversely related to cogni-tive function including memory and executive functioning(Cournot et al., 2006; Gunstad et al., 2007). A relationship betweenobesity and cognitive performance is also evident when otherobesity indices are examined. Gunstad and colleagues recentlyreported that indices of central obesity (waist circumference andwaist-to-hip ratio) show similar associations with poorer cognitivetest performance (Gunstad et al., 2010). Sabia and colleaguesexamined the associations of BMI at early adulthood (25 years)and in early (44 years) and late (61 years) midlife with multipledomains of cognition assessed in late midlife (Sabia et al., 2009).They found that being obese at 23 of these time points was asso-ciated with lower memory and executive function scores, evenafter adjusting for age and education (Sabia et al., 2009). Thusthe impact of obesity on cognition appears to accumulate overthe adult life course. The relationship between obesity and cogni-tive performance in late-life (>65 years) is, however, less clear.For example, The Framingham Heart Study showed that higherBMI is associated with lower cognitive performance (learning,memory, and executive function) in elderly individuals (Eliaset al., 2003). Moreover, in a smaller cohort of elderly patients, Cat-tin et al. reported that cognitive impairment decreases withincreasing BMI (Cattin et al., 1997). In contrast, Kuo et al. foundthat although elderly obese (assessed by BMI) individuals did notdemonstrate compelling superiority in memory compared withnormal-weight individuals, they demonstrated better performancein visuospatial speed of processing (Kuo et al., 2006). Furthermore,West et al. showed an inverse association between BMI and rate of

A.A. Miller, S.J. Spencer / Brain, Behobesity in elderly cohorts based on anthropomorphic measure-ments such as BMI. Indeed, using waist circumference as ameasure of central obesity, West et al. revealed that obesity isassociated with an increased rate of cognitive impairment innon-demented elderly individuals while BMI in the same cohortwas inversely associated (West and Haan, 2009).

In addition to its effect on cognitive performance, growing evi-dence indicates that obesity may inuence brain structure. Indeed,current literature suggests that obesity is associated with brainatrophy (Enzinger et al., 2005; Ward et al., 2005; Taki et al.,2008; Raji et al., 2010; Fotuhi et al., 2012; Brooks et al., 2013).For example, higher BMI and waist circumference are linked withlower total brain volume in non-demented elderly patients(75 years) (Enzinger et al., 2005; Raji et al., 2010; Fotuhi et al.,2012; Brooks et al., 2013). Similarly, in a cohort of younger adults(mean age 54 years) BMI was inversely associated with globalbrain volume, even after adjusting for age and a number of cardio-vascular risk factors such as systolic blood pressure and cholesterollevels (Liang et al., 2014). A negative relationship between regionalbrain atrophy and obesity has also been described (Jagust et al.,2005; Pannacciulli et al., 2006; Taki et al., 2008; Raji et al., 2010).In particular, the temporal (including the hippocampus) and fron-tal lobes appear to be particularly vulnerable to the effects of obes-ity. Indeed, several studies report a negative relationship betweenobesity (BMI or waist-to-hip ratio) and grey matter volumes ofthese brain regions in various age groups in non-demented individ-uals (Jagust et al., 2005; Pannacciulli et al., 2006; Taki et al., 2008;Raji et al., 2010). Greater BMI is also found to correlate withdecreased neuronal viability of grey matter in temporal lobes ofmiddle-aged adults, and neuronal and/or myelin metabolic abnor-malities in grey and white matter (Gazdzinski et al., 2008, 2010;Mueller et al., 2011). Thus, the reduction in regional brain volumesin obese individuals could reect loss of neurons. It is well knownthat large hippocampal size is closely linked with good cognitivefunction and memory (Stewart et al., 2005), and frontal brainregions are necessary for intact executive functions (Alvarez andEmory, 2006). Thus, whilst direct evidence is lacking, it is conceiv-able that atrophy of these brain regions contributes to poor cogni-tive performance in obese individuals.

The majority of studies examining associations between obesityand cognitive health/brain structure either do not include femalesor study males or females in isolation. Furthermore, ndings fromstudies where potential sex-dependent differences have beenexamined are mixed. For example, in the Framingham Heart Studyit was found that higher BMI was associated with poorer cognitiveperformance in middle-aged men but not women, with a signi-cant interaction between obesity and sex (Elias et al., 2003,2005). Similarly, Kanaya et al. reported higher total fat mass,abdominal fat, BMI, and waist circumference, are associated withworsening of cognitive function in elderly men at follow up sevenyears later, whereas women of similar age have a trend towardsinverse associations between these obesity indices and cognitivefunction (Kanaya et al., 2009). In contrast, Cournot et al. foundno sex-dependent differences in the adverse effects of obesity(BMI) on cognitive performance in either young or middle-agedindividuals (Cournot et al., 2006). There is also controversy in theliterature about whether sex inuences the association betweenobesity and alterations in brain structure. For example, a studyfound an association between BMI and cerebral volume loss inmen but not in women (Taki et al., 2008), whereas two separatestudies showed an association between BMI and brain atrophy inwomen (Gustafson et al., 2004; Raji et al., 2010). Gazdzinski et al.found virtually identical relationships between BMI and markersof myelin metabolic abnormalities in males and females(Gazdzinski et al., 2008). In contrast, another study found an asso-

r, and Immunity 42 (2014) 1021 11ciation between BMI and markers of myelin degeneration only inwomen (Mueller et al., 2011). It is clear therefore that more

bral vascular function including neurovascular coupling, blood

2009). A similar association between BMI and VaD risk is found in

avioresearch is required to fully determine whether sex inuencesobesity-related function and structural brain changes.

The hypothalamicpituitary-adrenal (HPA) axis plays an impor-tant role in many brain functions including cognitive function.Moreover, as discussed in Section 6.3, dysregulation of this axisand the subsequent hypersecretion of glucocorticoids (GC) arelinked to impaired cognition dysfunction. For example, hyperactiv-ity of the HPA axis is associated with memory impairments in var-ious conditions, including depression, AD, and Cushings syndrome(Raber, 1998). Evidence also indicates that chronic HPA axis activa-tion and elevation of GC levels can cause hippocampal pathology.Indeed, sustained exposure of the hippocampus to GC is reportedto induce dendritic atrophy in hippocampal neurons, neuronal loss,and alterations in synaptic plasticity (see Section 6.3). Moreover,HPA axis hyperactivity has been linked with hippocampal volumereductions (Starkman et al., 1992; MacQueen and Frodl, 2011).Importantly, evidence indicates that obesity is associated withhyperactivity of the HPA (Spencer and Tilbrook, 2011), raisingthe possibility that HPA axis dysregulation may be an importantcontributor to the structural and cognitive changes during obesity.Consistent with this hypothesis, a recent study of non-demented,obese type 2 diabetics reported an association between impairedHPA negative feedback regulation and poorer cognitive perfor-mance (Bruehl et al., 2009). Importantly, it is well recognized thatthe hippocampus plays an important role in negative feedbackinhibition of the HPA axis (McEwen et al., 1968; Sapolsky et al.,1983). Thus, GC-dependent and/or -independent obesity-relateddamage to the hippocampus might cause a feed-forward cascadeof HPA activation, hippocampal degeneration, and cognitiveimpairment (Raber, 1998).

2.2. Clinical studies of children and adolescents

Given evidence indicates obesity negatively impacts brain func-tion and structure in adulthood, it is clearly important to also eval-uate its impact on the developing brain during childhood andadolescence. In children and adolescents, the majority of ndingson cognition in obesity have been predominately focussed onexecutive functioning. Several studies have reported that youngchildren (35 years) undergo rapid development of executive func-tioning, which continues to mature well into adolescence (Reinertet al., 2013). Thus, this cognitive domain may be particularly vul-nerable to a stressor such as obesity during childhood. Consistentwith this idea, there is ample evidence that several domains ofexecutive functioning are poorer in children or adolescents withobesity than their healthy weight counterparts (reviewed in(Liang et al., 2014)). Studies on the relationship between obesityand other cognitive functions have, however, produced mixedresults. Indeed, some studies report that obese children and ado-lescents perform worse in tests of global cognitive functioning,academic achievement or IQ (Li et al., 2008; Maayan et al., 2011;Yau et al., 2012) and have decits in memory and learning(Holcke et al., 2008; Maayan et al., 2011), whereas other studieseither report no relationship (Cserjesi et al., 2007; Gunstad et al.,2008; Verdejo-Garcia et al., 2010), or positive associations (Veenaet al., 2014). Consistent with the impact of obesity on brain struc-ture in adulthood, there is evidence of differences in global andregional brain volumes between obese and healthy weight childrenand adolescents. For example, in a cohort of adolescent females(mean age 18 years), obese individuals had lower total and regio-nal (temporal lobe) brain volumes than lean (not obese) counter-parts (Yokum et al., 2012). Similarly, Yau and colleagues foundreduced hippocampal volumes and compromised white matter

12 A.A. Miller, S.J. Spencer / Brain, Behmicrostructural integrity in obese adolescents (Yau et al., 2012).Conceivably, these effects of obesity on cognitive function couldyounger individuals (2040 years) (Chen et al., 2010), whereas itremains to be determined whether obesity during childhood andadolescence inuences dementia risk. In the elderly, however, stud-ies exploring the relationship between obesity and dementia areconicting. Some studies show that the obesitydementia relation-ship persists into late life (Gustafson et al., 2003), whereas otherssuggest it plateaus and/or reverses (Stewart et al., 2005; Gustafson,2006, 2009, 2012; Dahl et al., 2008; Fitzpatrick et al., 2009).

Generally, risk factors for VaD are the same as for traditionalstroke (e.g. type 2 diabetes, hypertension, and dyslipidemia)(Gorelick et al., 2011). Moreover, emerging evidence indicatesbrain barrier (BBB) permeability, and functioning of arteriesupstream of the BBB (Li et al., 2013; Lynch et al., 2013; Peppinget al., 2013). Of importance, increasing evidence indicates that suchvascular mechanisms are likely to be important components of thepathophysiological processes underlying vascular cognitiveimpairment and also AD (Gorelick et al., 2011).

3. Association of obesity with risk of dementias

As populations age, cognitive disorders including dementiasbecome more common. AD is the most common form of dementia,accounting for between 50% and 70% of all dementias. Vascular cog-nitive impairment is a spectrum of cognitive impairments caused byvarious types of cerebrovascular disease (e.g. stroke), and includesvascular dementia (VaD), which is the second most common formof dementia. Recent systematic reviews and meta-analyses reveal acomplex relationship between obesity and risk of dementias(Gorospe and Dave, 2007; Beydoun et al., 2008; Anstey et al.,2011). The majority of studies have found that higher BMI orwaist-to-hip ratio in mid-life are associated with an increased riskof developing AD and VaD later in life (Kivipelto et al., 2005;Gustafson, 2006; Whitmer et al., 2007, 2008; Fitzpatrick et al.,be explained by genetic factors leading to an independent or inter-related vulnerability to both obesity and cognitive impairment.However, this possibility is not likely to account for all cases. Stud-ies in animal models wherein the genetic background is identicalbut the diet is manipulated demonstrate diet has an important roleto play (e.g. (Molteni et al., 2002; Winocur and Greenwood, 2005;Jurdak et al., 2008; Stranahan et al., 2008b)). Furthermore,although BMI is thought to be between 40% and 70% heritable, lessthan 2% of gene loci with obesity susceptibility have been identi-ed (Loos, 2009).The genetic contribution to obesity-related out-comes therefore remains a question for future study.

2.3. Experimental studies of animals

Consistent with human studies, there is evidence of adverseeffects of experimental obesity on cognitive function in animalmodels. For instance, high fat diet feeding of rodents compromisesa range of memory and learning skills (Molteni et al., 2002;Winocur and Greenwood, 2005; Jurdak et al., 2008; Stranahanet al., 2008b). Experimental studies have also provided insight intothe potential mechanisms underpinning obesity-related cognitivedysfunction. For example, high fat feeding reduces synaptic plastic-ity in the hippocampus and cerebral cortex of rodents (Molteniet al., 2002; Wu et al., 2003; Stranahan et al., 2008b; Lynch et al.,2013), and there is evidence of increased neuronal apoptosis inthe hippocampus and hypothalamus (Moraes et al., 2009; Riveraet al., 2013). In addition, high fat diet feeding of mice disrupts cere-

r, and Immunity 42 (2014) 1021these vascular risk factors may also be risk markers for AD(Gorelick et al., 2011). Given obesity is a common denominator

atrophy can occur progressively with normal aging (Raz et al.,2005). Thus, obesity-associated atrophy may amplify the risk for

muscle, which contribute to systemic insulin resistance (Shu

leptin and insulin resistance, favoring weight gain and maintaining

aviodementia and/or cognitive decline by synergistically interactingwith the aging process. Consistent with this concept, higher BMIis correlated with brain atrophy in patients diagnosed with AD(Abiles et al., 2010). Furthermore, there is evidence that mid-lifeobesity is associated with an increased rate of total and hippocam-pal brain atrophy and cognitive decline a decade later (Debetteet al., 2011).

Amyloid plaques and neurobrillary tangles, consisting of amy-loid-beta peptides and hyperphosphorylated tau protein, respec-tively, are prominent neuropathological hallmarks of AD. In apost-mortem study of non-demented elderly (>65 years of age)obese individuals, Mrak found evidence of higher levels of hippo-campal amyloid-beta peptides, amyloid prescursor protein (APP;APP processing generates amyloid-beta), and tau, compared withnon-obese individuals (Mrak, 2009). Moreover, plasma levels ofamyloid peptides are elevated in obese individuals and correlatewith increased body fat (Balakrishnan et al., 2005; Lee et al.,2009). Numerous experimental studies have examined markersof amyloid and tau pathology in a variety of diet-induced obesityparadigms. In rats and wild-type mice, some but not all studiesreport elevations in APP, amyloid-beta, and tau phosphorylation(Thirumangalakudi et al., 2008; Jeon et al., 2012; Puig et al.,2012). Furthermore, with the exception of a few studies (Morozet al., 2008; Studzinski et al., 2009), diet-induced obesity increasesamyloid and tau pathology in transgenic mouse models of AD, andexacerbates cognitive decits (Levin-Allerhand et al., 2002;Thirumangalakudi et al., 2008; Julien et al., 2010; Maesako et al.,2012a, 2012b; Leboucher et al., 2013). Thus, while future studiesare necessary, these clinical and experimental studies raise thepossibility that obesity may amplify the risk of developing AD bymodulating cerebral amyloid and/or tau pathology.

4. Obesity and cognitive function: cause or consequence?

While there is ample evidence that a relationship existsbetween obesity and brain health (function and structure), it isimportant to acknowledge that there still remains a question ofcausality. Indeed, the relationship between obesity and brainhealth may not be unidirectional. Obesity is associated with manypathophysiological changes that have the potential to negativelyimpact the brain, including inammation, which in turn may bea cause and a consequence of obesity. It is also possible thatreduced cognitive function, in particular executive functioning,could predispose individuals to obesity. Indeed, executive dysfunc-tion is associated with obesity-related behaviours, such asincreased food intake, dis-inhibited eating, and less physical activ-for many of these vascular risk factors; a potential associationbetween obesity and dementia is therefore hardly surprising. How-ever, as outlined in a recent meta-analysis, some evidence suggeststhat obesity plays an independent role in the aetiology of AD and insome cases of VaD, after controlling for various cardiovascular riskfactors (Beydoun et al., 2008).

The mechanisms by which obesity inuences risk of dementiaremain to be fully understood. As discussed above, there is ampleevidence of poor cognitive function and brain atrophy in variousage groups of non-demented obese individuals. It is well knownthat cognitive performance and markers of brain atrophy such astotal brain and hippocampal volumes are powerful predictors ofcognitive decline and dementia in the general population (Eliaset al., 2000; Amieva et al., 2005; Jack et al., 2005). Moreover, brain

A.A. Miller, S.J. Spencer / Brain, Behity (Reinert et al., 2013). This may prove to be more relevant forobesity in childhood and adolescence, a period characterized byan elevated body weight (De Souza et al., 2005; Posey et al., 2009).As with systemic increases in pro-inammatory cytokines,et al., 2012). Pro-inammatory cytokines, such as tumor necrosisfactor (TNF)a activate serine kinases that directly and indirectlyphosphorylate insulin receptor substrate (IRS) 1 and 2, resultingin a reduced ability of insulin to stimulate phosphatidylinositol-3kinase (PI-3K)-dependent pathways that normally result in glucoseuptake and metabolism (Hirabara et al., 2012). Feeding-relatedpathways in the hypothalamus are also disrupted by inammation,with insulin and leptin less able to suppress hunger and feeding,further contributing to the maintenance of a high fat diet and thusobesity (Thaler and Schwartz, 2010).

5.2. Central inammation

Obesity- and high fat diet-associated systemic inammationwas identied some time ago, with early reports suggesting obesehumans and high fat diet-fed rodents have elevated circulatingpro-inammatory cytokines compared with controls, and macro-phage inltration into the WAT (Pickup and Crook, 1998;Weisberg et al., 2003; Wellen and Hotamisligil, 2003). The sugges-tion that obesity can also result in central inammation, however,is a relatively recent one. In 2005, de Souza and colleagues showedhigh fat diet elevates the expression of pro-inammatory cytokinesand activation of the pro-inammatory transcription factor nuclearfactor jB (NFjB) in the hypothalamus (De Souza et al., 2005). Sev-eral other investigations followed, suggesting high fat diet cancause hypothalamic inammation and that this inammation caninterrupt normal feeding- and metabolism- related signaling. Thus,high fat feeding leads to inltration and activation of microglia (thebrains resident macrophages) in the hypothalamus, activation ofinammatory signaling, and increases in local inammatory medi-ators such as cytokines (Fig. 1) (De Souza et al., 2005; Zhang et al.,2008; Milanski et al., 2009; Posey et al., 2009; Thaler et al., 2012).Importantly, this central inammation can actually contribute torelative immaturity of executive cognitive domains coupled withthe relative maturity of reward processing (Reinert et al., 2013).

5. Obesity and inammation

5.1. Systemic inammation

It is now well accepted that obesity is associated with chroniclow-grade systemic inammation (Gregor and Hotamisligil,2011; Spencer, 2013). This pro-inammatory prole appears tobe both a cause and a consequence of obesity. Dietary factors suchas fatty acids lead to stimulation of the free fatty acid and lipopoly-saccharide (LPS) receptor, toll like receptor 4 (TLR4), on immunecells, and initiation of an inammatory cascade (Shu et al., 2012).High fat feeding is also associated with inltration of macrophages(phagocytotic peripheral immune cells differentiated from mono-cytes) into white adipose tissue (WAT), apoptosis of adipocytes,and reduced WAT vascularity, resulting in a pathological prepon-derance of macrophages in the WAT (Weisberg et al., 2003; Xuet al., 2003; Shu et al., 2012). This macrophage proliferation, cou-pled with increased TLR4 and other pattern recognition receptorson adipocytes, leads to an increase in the pro-inammatory cyto-kine prole (Hotamisligil et al., 1993, 1995; Uysal et al., 1997;Shu et al., 2012). Increased pro-inammatory cytokines, adipo-kines, and fatty acids then have downstream effects on liver and

r, and Immunity 42 (2014) 1021 13increases in TNFa, IL-6 etc. in the hypothalamus likely lead to anincrease in suppressor of cytokine signaling (SOCS)3 proteins,

ngissis

avioPVN

LH

HYPOTHALAMUS

VMH

ARC

Altered hypothalamic outputs

Synaptic remodeliNeuronal apoptos

Impaired neurogene

DMH

14 A.A. Miller, S.J. Spencer / Brain, Behleading to the phosphorylation of IRS and repression of leptin-receptor mediated activation of the Stat3 pathway, thus beingresponsible for the negative regulation of both insulin and leptinsignaling (Howard and Flier, 2006). Thus, blocking hypothalamicinammatory signaling, such as with pharmacological or geneticinhibition of JNK, IKKb/NFjB, or TLR4, leads to reduced food intakein high fat diet-fed animals, increased insulin sensitivity, and areduction in weight gain (De Souza et al., 2005; Milanski et al.,2009; Posey et al., 2009).

In addition to high fat per se inuencing brain function, studiesare now showing dietary composition is important in determiningthe central inammatory prole. For instance, Maric and col-leagues have recently demonstrated a diet high in saturated fatsresults in more hypothalamic inammation after 8 weeks thanone high in unsaturated fats (Maric et al., 2014). Furthermore, fatsfrom different sources can also have different neuroinammatoryeffects, with saturated fats from butter causing a more pronouncedpro-inammatory prole in the hypothalamus than saturated fatsfrom coconut oil (Maric et al., 2014). The mechanisms behind thesedifferences are currently unknown, but it is suggested saturatedfats stimulate hypothalamic inammation through direct action

BBBFree fatty

Systemic inf

High faObes

HPA axis dysregulation excess glucocorticoids

Fig. 1. Hypothesized mechanisms linking high fat diet/obesity and cognitive dysfunctionpro-inammatory cytokines, chemokines, and immune cells, which in turn gain accesseffective BBB (e.g. ARC). This initiates central inammation, including microglial inltrafactor NFjB; and increased expression of pro-inammatory mediators (e.g. cyclooxygenaneuronal apoptosis, and impaired neurogenesis. These processes disrupt internal hypothacognitive function (e.g. hippocampus). This hypothalamic remodeling may also resuglucocorticoids, which in turn may cause excess glutamate, calcium, and ROS productionFurthermore, prolonged high fat diet and/or obesity may compound this by directly promlong term changes in cell signaling and connectivity, even neurodegeneration and brain atobesity. Key: ARC (arcuate nucleus); BBB (bloodbrain barrier); DMH (dorsomedial hypoPVN (paraventricular nucleus of the hypothalamus); and VMH (ventromedial hypothalaHIPPOCAMPUSand other extra-hypothalamic regions

r, and Immunity 42 (2014) 1021on TLR4. This idea is supported by the nding that a high butter,but not a high coconut oil or low saturated- high-fat diet elevatesTLR4 expression in the hypothalamus (Maric et al., 2014). As wellas its effects on leptin and insulin sensitivity and feeding and met-abolic pathways, it is likely this central inammation associatedwith high fat diet also has effects that extend beyond the hypothal-amus. Indeed, emerging evidence indicates that inammationoccurs early after the onset of high fat diet in the hypothalamus(as little as three days to three weeks (Thaler et al., 2012)) andmay spread to extra-hypothalamic areas of the brain if theexposure to the high fat diet is prolonged (eight weeks plus(Thaler et al., 2012), see Section 6.3).

5.3. Mechanisms leading to central inammation

The arcuate nucleus (ARC) of the hypothalamus and other cir-cumventricular organs such as the subfornical organ and area pos-trema lack an effective BBB and are therefore in a prime position torespond directly to circulating factors such as nutrients and inam-matory mediators including cytokines (Williams, 2012). These cir-culating signals are likely to be a principal driving force for

acidslammation

Increased BBB permeability/Brain regions lacking a BBB

t dietity

. High fat diet and/or obesity lead to increased levels of circulating free fatty acids,to the hypothalamus by increasing BBB permeability and/or via areas that lack antion, activation and proliferation; activation of the pro-inammatory transcriptionse) and cytokines. Collectively, central inammation results in synaptic remodeling,lamic circuitry and potentially hypothalamic outputs to brain regions important forlt in dysregulation of the HPA axis and the subsequent production of excess, reduction in neuronal spine density, and neuronal apoptosis in the hippocampus.oting inammation in these brain regions. Together these mechanisms may lead torophy, and may ultimately be responsible for the changes in cognitive health seen inthalamus); HPA (hypothalamicpituitaryadrenal axis); LH (lateral hypothalamus);mus).

cytokines and prostaglandins that stimulate centrally projectingneurons (Blatteis, 2007), and by increasing BBB permeability allow-

avioing peripheral cytokines and immune cells to enter (Lu et al., 2009)(see Section 7). Interestingly, the effects of high fat diet exposureseem to contrast markedly with what we would expect from acutepro-inammatory cytokine exposure, such as occurs with a bacte-rial infection or a single injection of LPS. In this situation, theinammatory response is short-lived and results in hypophagia. Itappears this acute hypophagia is at least partly due to leptinsactions on the ObR and the action of other pro-inammatory cyto-kines will, over time, stimulate SOCS3 expression, contributing tonegative feedback on this leptin signaling and thus stimulation offeeding (Fruhbeck, 2006; Qin et al., 2007). It is worth noting thatmultiple exposures to LPS results in tolerance to the anorexigeniceffects of the endotoxin so that LPS-induced hypophagia is nolonger seen (Borges et al., 2011). The mechanism for this is likelysimilar to that involved in high fat diet as acute LPS does not stim-ulate such sickness behavior in high fat fed animals (Borges et al.,2011). It is thus likely the effects of systemic and central inamma-tion on feeding pathways may be similar irrespective of the cause,but may be dependent upon duration of the stimulus.

6. Is central inammation a link between obesity and cognitivedysfunction?

6.1. Systemic inammation and cognitive dysfunction

Systemic inammation, independently of and associated withobesity, has been linked to faster cognitive decline in the elderly(Marioni et al., 2010; Trollor et al., 2012) and with dementiasincluding AD (Hall et al., 2013). Thus, metabolic syndrome (includ-ing inammation and obesity) and systemic inammation haveboth been identied as independent risk factors for depressivesymptoms, cerebral white matter lesions and cognitive dysfunc-tion in older people (van Dijk et al., 2005; Viscogliosi et al.,2013). Moreover, higher plasma levels of interleukin (IL)-12 and6 are linked to reduced speed in processing information and a fas-ter rate of cognitive decline (Schram et al., 2007; Marioni et al.,2010; Trollor et al., 2012). Systemic inammation (induced byLPS) also leads to memory decits in a rodent model of obesity,as well as accumulation of beta amyloid, a neuropathological hall-mark of AD (Lee et al., 2008). However, systemic inammation iscentral inammation during prolonged high fat feeding. TLR4, forinstance, is a molecular pattern recognition receptor that respondsdirectly to inammatory stimulation with LPS, and also to extracel-lular lipids (Kawai and Akira, 2005; Erridge, 2010). Thus, elevatedfree fatty acids, that enter the brain at the level of the ARC upon con-sumption of a high fat diet, activate TLR4 on microglia and astro-cytes and initiate an inammatory cascade (Milanski et al., 2009).In this regard, mice decient in MyD88 (an essential adaptor mole-cule for TLR4) are resistant to the leptin-resistance and obesityassociated with a high fat diet (Kleinridders et al., 2009). Similarly,circulating pro-inammatory cytokines (as a result of high fat diet-induced systemic inammation) can also access the brain at themediobasal hypothalamus where they can activate cytokine recep-tors (Cai and Liu, 2012). The result of this is free fatty acid- and cyto-kine-mediated perpetuation of the inammatory signal in the brainthrough initiation of local pro-inammatory cytokine production(Cai and Liu, 2012). Aside from direct entry of cytokines, chemo-kines, and free fatty acids into the brain at areas lacking a BBB, sys-temic inammation and excess free fatty acids may also promotecentral inammation by initiating a cascade of pro-inammatory

A.A. Miller, S.J. Spencer / Brain, Behnot linked to cognitive dysfunction in all studies. For instance, arecent (small) study showed diabetic patients have lower cognitivefunction scores than age-matched controls, but that this was notassociated with systemic inammatory markers nor with obesityalone (Pedersen et al., 2012). Similarly, the link between obesityand cognitive dysfunction is also not consistent. Elevated circulat-ing IL-12 and IL-6 are both linked to slower processing speeds andpoorer executive function, even independently of metabolic riskfactors (Trollor et al., 2012). Here we argue the inammatory-mediated link between obesity and cognitive dysfunction isprimarily due to obesity and high fat diet precipitating centralinammation, which, in turn, alters cognition.

6.2. Hypothalamic inammation and cognitive dysfunction

The hypothalamus is directly or indirectly responsible for awide range of physiological functions including, of course, feedingand metabolism, but also stress regulation, reproduction, waterbalance, cardiovascular function, the list continues. Many of thesefunctions are inter-related with attention, learning, and memoryaspects of cognition (Koessler et al., 2009). For instance, dysregula-tion of the HPA axis, the apex of which lies in the paraventricularnucleus of the hypothalamus (PVN), is associated with impairedcognitive function. Thus, depressive patients have impairments inexecutive function and memory recall and this is directly relatedto HPA axis function reected in morning cortisol levels (Egelandet al., 2005). The hippocampus contains among the highest concen-trations of glucocorticoid receptors (GR) in the brain and is a prin-cipal target of GC negative feedback (McEwen et al., 1968; Sapolskyet al., 1983). Sustained exposure of the hippocampus to GC, as canoccur with HPA axis dysregulation and in cases of obesity(Sapolsky, 1996, 2000; Stranahan et al., 2008a; Hillman et al.,2012), can result in excess glutamate, calcium, and accumulationof reactive oxygen species (ROS), reduction in hippocampal neuro-nal spine density, apoptosis, and even reduced hippocampal vol-umes (Sapolsky, 1985; Woolley et al., 1990; Kerr et al., 1991;Magarinos and McEwen, 1995). Thus, elevated GC concentrationsat the hippocampus or any dysfunction in GC negative feedbackcaused by dysregulation of the HPA axis causes hippocampal dis-ruption and is likely to lead to cognitive dysfunction.

There is evidence that obesity is associated with HPA axis dys-regulation (Spencer and Tilbrook, 2011). Indeed, HPA axis dysfunc-tion and obesity are closely linked, with obese people beingsignicantly more likely to develop depression and other stress-related mood disorders than non-obese (Doyle et al., 2007; Scottet al., 2008; Abiles et al., 2010). As discussed, consistent evidencedoes suggest obesity leads to inammation in the ARC (and lateralhypothalamus; LH) (De Souza et al., 2005; Zhang et al., 2008;Milanski et al., 2009; Posey et al., 2009; Thaler et al., 2012). How-ever, whether obesity-associated central inammation per se con-tributes to HPA axis dysfunction is unclear, as no study has yetdissected hypothalamic inammation in the context of obesity tothis degree of detail. It is worth noting, central inammation in con-texts other than obesity certainly leads to HPA axis dysfunction. Forinstance, brain pro-inammatory cytokine levels and other inam-matory markers are elevated in rodent models of depression (Patkiet al., 2013). Chronic stress can lead to increased hypothalamic pro-inammatory cytokine (IL-1b, TNFa) expression, as well as to therecruitment of peripherally-derived monocytes (bone marrow-derived immune cells that will differentiate intomacrophages uponentry into tissues) into the brain, including to anxiety-related brainregions such as the amygdala (Johnson et al., 2002; Wohleb et al.,2013b). This effect is linked to anxiety-related behavior and poten-tially to anxiety-related mood disorders, with a stress-sensitizedmonocyte response contributing to excessive anxiety inmice previ-ously exposed to chronic social defeat (Wohleb et al., 2013a,b). ICV

r, and Immunity 42 (2014) 1021 15LPS leads to PVN activation and an increase in IL-1b in this regionand an increase in arginine vasopressin (Xia and Krukoff, 2003).In addition, icv IL-1b administration induces muscle atrophy in

This impairment is associated with enhanced TNFa and Iba1expression in the hippocampus and both the behavioral decit

aviomice and this effect is mediated by the HPA axis (Braun et al., 2011).Notably, the PVN and ARC are also reciprocally interconnected, asare feeding and stress (Shin et al., 2009). Thus, any adverse effecton the ARC, including inammation, can potentially affect PVNfunction even if inammation does not occur in the PVN itself.

It is now apparent that our sensing and regulation of food intakeis not simply determined by the ARC sensing peripheral nutritionalsignals and translating these into an eat/do not eat command.Rather, the ARC is intimately connected with other regions of thehypothalamus and the rest of the brain to integrate the bodysnutritional needs with the external environment and the bodysother demands (Shin et al., 2009). Thus, the hypothalamus is clo-sely connected with motivation and reward pathways in orbito-frontal cortex, hippocampus, mesolimbic dopamine system,nucleus accumbens, striatum and prefrontal cortex, as well as sen-sory and memory systems (Shin et al., 2009). Thus, inammation inthe ARC that disrupts feeding signals there will undoubtedly alsodisrupt signaling to, and potentially from, these brain regionsand thus potentially impair cognitive function (Fig. 1).

6.3. Extra-hypothalamic inammation and cognitive dysfunction

There is currently a good body of evidence to suggest high fatfeeding leads to inammation within the hypothalamus. However,fewer studies have examined if this inammation is specic tohypothalamus or extends into other brain regions. In their earlystudy, De Souza and colleagues identied elevated TNFa stainingonly in the ARC and LH after high fat feeding, and not in other brainregions examined (De Souza et al., 2005). The macrophage markerF4/80 has also been evaluated in extra-hypothalamic regionsincluding cortex and thalamus and is unaffected anywhereassessed other than the hypothalamus (Milanski et al., 2009). Sim-ilarly, microglial accumulation and activation occurs in the ARC butnot in other regions of the hypothalamus and not in extra-hypo-thalamic regions such as the cortex or hippocampus after twoweeks high fat diet or less (Thaler et al., 2012). Although thesestudies have found no inammation outside the hypothalamus,tantalizing evidence does suggest central inammation can extendbeyond the hypothalamus in obesity with longer high fat feedingregimes. The hippocampus, an important region in cognitive pro-cessing, learning and memory, may be particularly vulnerable toinammation in obesity, with elevated TNFa and ionized cal-cium-binding adaptor molecule 1 (Iba1; microglial marker) levelsin this region seen after 20 weeks high fat feeding (Jeon et al.,2012). The astrocyte marker, glial brillary acidic protein (GFAP),and APP, an indicator of AD-like pathology, are also increased inthe hippocampus after long-term (22 weeks) high fat feeding(Puig et al., 2012). These differences in timing of appearance ofcentral inammation in difference in brain regions (albeit in differ-ent studies) lead us to speculate hypothalamic inammation mayprecede that of other brain regions.

Other brain regions than the hippocampus may also be subjectto inammation-associated cognitive decits with obesity. Thus,markers of astrocytes (GFAP) and microglia (Iba1) are elevated inthe frontal cortex of mice fed a high fat diet for 14 weeks comparedwith controls (Pepping et al., 2013). Cortical tissue has shownincreased cyclooxygenase 2 and prostaglandin E2 levels as wellas increases in phosphorylated IjB and NFjB after ve monthshigh fat diet (Zhang et al., 2005). Isolated cortical microglia frommice fed a high fat diet for 22 weeks also release more TNFa thanthose of control mice (Puig et al., 2012). In humans, levels of brin-ogen (a marker of inammation) in the amygdala are signicantlycorrelated with overweight and obesity (Cazettes et al., 2011). Fur-

16 A.A. Miller, S.J. Spencer / Brain, Behthermore, animals made overweight due to a high fat diet in uteroand during the suckling period have elevated expression of thepro-inammatory genes NFjB and IL-6 in the amygdala comparedand the hippocampal inammatory prole are signicantlyimproved by treatment with the anti-inammatory anti-oxidant,Resveratrol (Jeon et al., 2012). Lifetime, including in utero, highfat diet has similar effects on brain inammation and Morris WaterMaze performance (White et al., 2009). An unrelated study by Luand colleagues was also able to show impaired Morris Water Mazeperformance after 20 weeks high fat diet that was linked toincreased inammatory signaling in the hippocampus. In this caseursolic acid, an anti-oxidant and anti-inammatory, was able toimprove hippocampal inammation and Water Maze performance(Lu et al., 2011).

It is interesting to note that Bilbo and colleagues have shownrats fed a high fat diet in utero and throughout suckling also havea pro-inammatory prole in the hippocampus, including higherpopulations of activated microglia, but that this prole is linkedto improved, not disturbed, performance in the Morris WaterMaze. These data potentially reect the crucial neurodevelopmen-tal effects of fatty acids and IL-1b, but at least highlight the impor-tance of the early life programming period and the potential for ahigh fat diet at this time to affect the animal differently from inadulthood (Bilbo and Tsang, 2010).

The correlative nature of these studies means more evidence isneeded to determine if inammation in extra-hypothalamicregions is directly responsible for cognitive changes seen in obes-ity. However, existing evidence makes this a highly likely scenario.

7. Potential mechanisms of neuronal dysfunction leading tocognitive impairment

Microglia and astrocytes are the brains resident immune cellsand can be directly activated by inammatory mediators includingpro-inammatory cytokines, prostaglandins, and nitric oxide(Loane and Byrnes, 2010). They are also the major brain cell popu-lation to express TLR4 (Lehnardt et al., 2003). Upon activation,microglia undergo signicant morphological changes. After as littleas one week on a high fat diet, microglia demonstrate a reactivegliosis with signicant proliferation and an activated morphology(Thaler et al., 2012). This prole initially may be protective or anti-inammatory as it resolves, only to return after prolonged high fatdiet (Thaler et al., 2012). However, in this proliferated, activatedstate, microglia are in a position to signicantly impact upon syn-aptic and neuronal plasticity. Part of the role of microglia is to sur-vey the synapse and in doing so they phagocytose synapticwith controls. They also have changes in expression of anti-inam-matory IjBa, mitogen-activated protein kinase phosphatase-1(MKP-1), and interleukin receptor antagonist (IL-1Ra) in the amyg-dala and hippocampus (Sasaki et al., 2013). Although high fat dietfor 911 months did not inuence striatal inammation in controlmice, it did exacerbate IL-6 concentrations (but not markers of gli-osis) in this region in a mouse model of cerebral amyloid angiopa-thy (Zhang et al., 2013). All these data support the idea thatobesity-associated inammation can extend beyond the hypothal-amus and into brain regions directly involved in cognitive function.

Crucially, there is also evidence that obesity-associated extra-hypothalamic inammation may be responsible for the compro-mised cognitive function seen in many obese individuals. Forinstance, 20 weeks high fat feeding in mice signicantly impairsperformance in the Morris Water Maze. The mice take longer tolearn the location of the escape platform and are less able to recalltheir training when the platform is removed than control mice.

r, and Immunity 42 (2014) 1021components to shape neuronal circuitry (Wake et al., 2009;Tremblay et al., 2010; Paolicelli et al., 2011). This process is partic-ularly aggressive during injury and inammation when the

stress (Cullinan and Diehl, 2006; Nadanaka et al., 2007). Thus,inammation-related ER stress may also contribute to neuronal

aviomicroglia are in an activated state and thus chronic microglialactivation can lead to extensive synaptic remodeling (Miyamotoet al., 2013). It is noteworthy that microglial-associated inamma-tion, seen in diabetic rat hippocampus, contributes to elevatedbeta-amyloid protein and tau pathology characteristic of AD (Caiet al., 2013). Minocycline, an anti-inammatory that acts princi-pally on microglia (Tikka et al., 2001; Tikka and Koistinaho,2001), alleviates this pathology (Cai et al., 2013); although it is pos-sible this outcome is also due to downstream effects of minocy-clines peripheral actions (Orsucci et al., 2012).

In addition to the microglia themselves, microglia- and system-ically-derived pro-inammatory cytokines can also inuence neu-ronal health. Cytokines are, of course, essential for an appropriateinammatory response, fever generation, and combatting patho-gens (Spencer et al., 2011). However, many pro-inammatory cyto-kines also have a role in neurodegenerative disease. For example,IL-6 can have a neurotrophic role in response to neuronal damagebut is also neurodegenerative in several brain diseases (Erta et al.,2012). TNFa, too, promotes cell survival depending upon the tim-ing and degree of expression, but can also mediate neurodegener-ation by increasing cellular glutamate production (Ye et al., 2013).Evidence suggests prolonged central pro-inammatory cytokineproduction is a facet of many cognitive disease states and is likelyto contribute to neurodegeneration therein. For example, high con-centrations of circulating and central pro-inammatory cytokinesare seen in AD (Blum-Degen et al., 1995; Tarkowski et al., 2002;Mrak and Grifn, 2005) and directly promote beta-amyloid forma-tion (Goldgaber et al., 1989; Ringheim et al., 1998). In Huntingtonsdisease, circulating IL-6 levels are elevated and neurodegenerativedecits are at least partially mediated by this cytokine (Bouchardet al., 2012). In a mouse model of prion disease, LPS-induced cog-nitive decits are mediated in part by microglia-derived cyclooxy-genase 1 and prostaglandin synthesis and these are directlyinduced by IL-1b (Grifn et al., 2013). Thus, the microglia- (andsystemically-) derived inammatory milieu can also contribute tothe fate of the neuron.

In addition to disrupting existing neurons, central inammationis also likely to affect neurogenesis. For instance, neurogenesis inthe adult rat hippocampus is impaired in neuroinammation asso-ciated with LPS, and this can be restored with minocycline (Ekdahlet al., 2003). Similar ndings have been demonstrated with inam-mation due to cranial radiation therapy (Monje et al., 2003). Like-wise, high fat diet-feeding can reduce levels of hypothalamicneurogenesis and this is likely to be related to high fat diet-inducedinammation in the region (Bilbo and Tsang, 2010; McNay et al.,2012). Thus, inammation likely contributes to preventing prolif-eration and differentiation of new neurons as well as damagingexisting ones (Freeman et al., 2013; Purkayastha and Cai, 2013).

Inammation also has the potential to inuence neuronalhealth indirectly via its interactions with other pathological mech-anisms such as oxidative stress and endoplasmic reticulum (ER)stress. Oxidative stress, characterized by excessive levels of ROSsuch as superoxide and hydrogen peroxide, has been implicatedin neuronal injury and cell death associated with neurodegenera-tive diseases including AD (Barnham et al., 2004). It is well knownthat activated immune cells generate large amounts of ROS, andpro-inammatory cytokines can promote ROS production in vari-ous cell types. In turn, ROS can activate NFjB and promote the pro-duction of pro-inammatory cytokines (Clark and Valente, 2004;Turchan-Cholewo et al., 2009). Thus, inammation and oxidativestress are closely interrelated pathological mechanisms and henceoften co-exist. Not surprisingly, therefore, several studies havefound evidence that high fat diet feeding is associated with oxida-

A.A. Miller, S.J. Spencer / Brain, Behtive stress in several brain regions including the hippocampus(Zhang et al., 2005; Morrison et al., 2010; Stranahan et al., 2011;Freeman et al., 2013; Pepping et al., 2013; Tucsek et al., 2013).dysfunction either directly or by modulating oxidative stress andinammation.

It is clear, therefore, that inammation has the potential toinuence synaptic remodeling and neuronal function via multiplemechanisms. Together these mechanisms may lead to long-termchanges in cell signaling and connectivity, even neurodegenerationand brain atrophy, and may ultimately be responsible for changesin cognition seen in obesity. To our knowledge, the evidenceregarding mechanisms of central inammation in obesity has lar-gely been derived from studies of the hypothalamus. Thus, futurework is needed to determine whether such principles translate toextra-hypothalamic inammation and ultimately cognitive func-tion. Nonetheless, it is clear high fat feeding is able to inuencecentral circuitry in a variety of ways and thus contribute to cogni-tive dysfunction in the long term.

8. Summary and conclusion

Obesity and/or a high fat diet appear to have a signicant role toplay in cognitive dysfunction and ageing-associated cognitive dis-orders like dementia. Systemic inammation has long beenregarded as a contributing factor to these outcomes. However,there is now accumulating evidence that this peripheral inamma-tion precipitates local inammation within the hypothalamus thatalters synaptic plasticity, contributes to neurodegeneration, andeven initiates brain atrophy. These events will culminate in a dis-turbance of extra-hypothalamically-mediated cognitive function.Research is still needed on the potential for direct inuence of cen-tral inammation on structures and functions that lie outside thehypothalamus.

Importantly, interventions to treat obesity and central inam-mation, such as calorie restriction, exercise, and bariatric surgeryare already showing promise in improving some aspects of cogni-tive function. For instance, in patients tested up to three years aftera successful bariatric surgery procedure, attention, executivefunction, and memory were all improved compared with immedi-ately after the surgery (Alosco et al., 2013, 2014; Miller et al.,2013). In an animal model, weight loss with calorie restriction orMoreover, brain oxidative stress is reported to be closely associ-ated with astrocyte activation, brain pro-inammatory cytokineproduction, and cognitive impairment following high fat diet feed-ing (Pistell et al., 2010; Pepping et al., 2013). Thus, inammationmay inuence neuronal function and death during obesity/highfat feeding by promoting oxidative stress or vice versa.

ER stress refers to the presence of excess newly synthesized ormis-folded proteins in the lumen of the ER. Usually this is resolvedefciently and without negative consequences, but, if not, this canlead to pathological changes to the cell. ER stress is reported tooccur in hypothalamic and extra-hypothalamic brain regions dur-ing obesity (Cakir et al., 2013; Castro et al., 2013), and has beenimplicated in perpetuating the development of obesity (Williams,2012). Moreover, excessive ER stress can lead to apoptosis (Raoet al., 2004; Ron and Walter, 2007), neurodegeneration (Ueharaet al., 2006; Sokka et al., 2007; Tabas and Ron, 2011), and eventu-ally brain atrophy. The beta amyloid-induced apoptosis seen in AD,for instance, may be at least partly due to ER stress-related disrup-tion of calcium homeostasis within the cell and ER stress-mediatedrelease of caspases (Fonseca et al., 2013). Importantly, ER stress canalso exacerbate cellular inammatory pathways (Hotamisligil,2010) and cause ROS production, which in turn can promote ER

r, and Immunity 42 (2014) 1021 17Roux-en-Y gastric bypass improved both hippocampal-based learn-ing and memory and hippocampal inammation (Grayson et al.,2014). Physical activity is also certainly benecial in many

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Acknowledgments

This work was supported by a Discovery Project Grant from theAustralian Research Council (ARC) to SJS (DP130100508), and aProject Grant from the National Health and Medical ResearchCouncil (NHMRC) to AAM and SJS (APP1068442). SJS is an ARCFuture Fellow (FT110100084) and an RMIT University VC SeniorResearch Fellow. AAM is an RMIT University VC Senior ResearchFellow.

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