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Journal of Neuroimmunology 273 (2014) 8–21Contents lists available at ScienceDirectJournal of Neuroimmunologyj ourna l homepage: www.e lsev ie r .com/ locate / jneuro imReview articleInflammation and insulin/IGF-1 resistance as the possible link betweenobesity and neurodegenerationLindsay J. Spielman a, Jonathan P. Little b, Andis Klegeris a,⁎a Department of Biology, University of British Columbia Okanagan Campus, 3333 University Way, Kelowna, BC, V1V 1V7 Canadab School of Health and Exercise Sciences, University of British Columbia Okanagan Campus, 3333 University Way, Kelowna, BC, V1V 1V7 Canada⁎ Corresponding author. Tel.: +1 250 807 9557; fax: +E-mail address: andis.klegeris@ubc.ca (A. Klegeris).http://dx.doi.org/10.1016/j.jneuroim.2014.06.0040165-5728/© 2014 Elsevier B.V. All rights reserved.a b s t r a c ta r t i c l e i n f oArticle history:Received 20 November 2013Received in revised form 3 June 2014Accepted 4 June 2014Keywords:Adipose tissueCytokinesNeuroinflammationAlzheimer's diseaseParkinson's diseaseHuntington's diseaseObesity is a growing epidemic that contributes to several brain disorders including Alzheimer's, Parkinson's, andHuntington's diseases. Obesity could promote these diseases through several differentmechanisms. Herewe reviewevidence supporting the involvement of two recently recognized factors linking obesity with neurodegeneration:the induction of pro-inflammatory cytokines and onset of insulin and insulin-like growth factor 1 (IGF-1) resistance.Excess peripheral pro-inflammatorymediators, some ofwhich can cross the blood brain barrier, may trigger neuro-inflammation,which subsequently exacerbates neurodegeneration. Insulin and IGF-1 resistance leads toweakeningof neuroprotective signaling by these molecules and can contribute to onset of neurodegenerative diseases.© 2014 Elsevier B.V. All rights reserved.Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92. Inflammatory response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.1. Inflammation in the periphery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.2. Chronic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.3. Neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.4. Glial cell activation in obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93. Epidemiological evidence linking obesity and neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.1. Epidemiological evidence linking obesity and Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.2. Epidemiological evidence linking obesity and Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103.3. Epidemiological evidence linking obesity and Huntington's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114. Pathophysiological mechanisms of inflammation in adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115. Pathophysiological mechanisms of insulin/IGF-1 in obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.1. Insulin in the periphery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.2. IGF-1 in the periphery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.3. Insulin in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.4. IGF-1 in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126. Pathophysiological mechanisms of insulin/IGF-1 signaling in neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126.1. Obesity, insulin/IGF-1 resistance and Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146.2. Obesity, insulin/IGF-1 resistance and Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156.3. Obesity, insulin/IGF-1 resistance and Huntington's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 250 807 8830.http://crossmark.crossref.org/dialog/?doi=10.1016/j.jneuroim.2014.06.004&domain=pdfhttp://dx.doi.org/10.1016/j.jneuroim.2014.06.004mailto:andis.klegeris@ubc.cahttp://dx.doi.org/10.1016/j.jneuroim.2014.06.004http://www.sciencedirect.com/science/journal/016557289L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–211. IntroductionNeurodegenerative disorders include an array of devastatingdiseases characterized by the loss of neuronal function and viability.This leads to a decline in brain functions including coordination ofmovement, memory and other cognitive abilities (Hanson and Clarke,2013). According to theWorld Health Organization, 36.6 million peopleworldwide suffered from dementia in 2012, and the number of affectedpatients is rising at an alarming rate of 7.7 million new cases each year(World HealthOrganization, 2012). As the human population continuesto age, the incidence of age-dependent dementia will increase, which isa major medical concern (Rollero et al., 1998; Puglielli, 2008; WorldHealth Organization, 2012). With age, the brain undergoes physiologi-cal change, leading to decline in some cognitive abilities such asprocessing speed and memory; however, dementias that characterizeAlzheimer's disease (AD), Parkinson's disease (PD) and Huntington'sdisease (HD) are not a part of the normal aging process.The human brain is comprised of an elaborate system of neuronalcircuitry and supporting glial cells (astrocytes, microglia and oligoden-drocytes), which perform protective and supportive roles towardsneurons in the central nervous system (CNS). Glial cells play key rolesin neuroinflammatory processes that contribute to the pathogenesis ofneurodegenerative diseases (Block and Hong, 2005; Goll et al., 2013;Qin et al., 2013). The purpose of this review is to summarize publishedevidence on the role of obesity-induced inflammation and obesity-induced insulin/insulin like growth factor 1 (IGF-1) resistance in theonset and pathogenesis of neurodegenerative disorders. We will focuson AD, PD and HD (see Figs. 3–5), since evidence implicating braininflammation as the potential initiator or aggravator in these diseasesis most compelling (Uysal et al., 1997; Sathe et al., 2012; Hsiao et al.,2013).2. Inflammatory responseInflammation is part of the body's innate immune response to harm-ful stimuli, such as pathogens, damaged cells or noxious substances. Theinflammatory process is a natural physiological response with threemain functions: 1) wall off the infection, 2) call cells of the immunesystem to the area of injury, and 3) initiate the immune systemresponse. Ultimately, the goal of inflammation is to clear the harmfulsubstance and repair the associated damage (Davalos et al., 2005;Simard et al.,,2006; Soczynska et al., 2011; Smith et al., 2012).2.1. Inflammation in the peripheryUpon the appearance of inflammatory stimuli, the body respondsquickly by increasing blood vessel diameter (vasodilatation), thusallowing for an increase in blood volume. Also, blood vessel perme-ability increases. This leads to the movement of leukocytes fromthe blood vessels into the site of tissue damage (Laskin, 2009).Neutrophils phagocytose the invading pathogen or damaged cellsand release molecular mediators (cytokines and chemokines),which facilitate the inflammatory process via recruitment and acti-vation of other immune cells (Bryant et al., 1966; Strieter et al.,1990). Upon arrival, activated macrophages engage in the processof phagocytosis, and simultaneously secrete an array of cytokines in-cluding tumor necrosis factor alpha (TNFα), interleukin (IL)-6 andIL-1β, all of which are pleiotropic pro-inflammatory cytokines.These cytokines are pyrogenic, they increase blood vessel permeabil-ity, induce synthesis of acute-phase response proteins, and activateboth B and T lymphocytes (Duff and Durum, 1982; Kopf et al.,1994; Biffl et al., 1996; Sahan et al., 2013). Thus, the process ofinflammation is self-perpetuating, and only ends when the injury isfully repaired or invading pathogens are removed.2.2. Chronic inflammationIn chronic inflammation, the normal physiological process ofdefense and removal of unwanted noxious substances becomes disor-dered and persists even in the absence of the original stimuli; however,the mechanism by which acute self-resolving inflammation switches tochronic, persistent inflammation is not fully understood (Buckley,2011). During the chronic inflammatory process, healthy neighboringcells suffer collateral damage as a result of the misdirected, unendingimmune attack (Frank-Cannon et al., 2009). Chronic inflammation pro-liferates several disease states in both the periphery and CNS includinginflammatory bowel disease, arthritis, Crohn's disease, diabetesmellitus, Graves' disease, ulcerative colitis, multiple sclerosis (MS), arte-riosclerosis and gastritis, to name a few (Naugler and Karin, 2008;Bende et al., 2009; Meijer et al., 2011). In addition to these previouslywell-characterized inflammatory diseases, obesity is now also regardedas a chronic pro-inflammatory disease state.2.3. NeuroinflammationNeurodegeneration is defined as the loss of neuronal cell structureand function, ultimately leading to neuronal death, and is an umbrellaterm for many disorders leading to dementia. Although several distinctmechanisms may trigger neurodegeneration, brain-specific inflamma-tion is almost universally associated with this process (Block andHong, 2005; Cunningham, 2013). Neuroinflammation is the state of anactive immune system in the CNS, and is carried out by glial cells.Astrocytes are involved in an array of significant functions, includingmaintenance of the blood brain barrier (BBB), physical support to neu-rons, modulation of synaptic transmission, and supplying neuronswith nourishment (Dehouck et al., 1990; Rubin et al., 1991; Denis,2013). Microglia are macrophages, which function as innate immunecells of the brain, continually monitoring the CNS for damaged cells,irregular proteins and infectious agents (Magnus et al., 2001; Jessen,2004; Tambuyzer et al., 2009). Both glia and neurons benefit from theinflammatory process, since this response under normal physiologicalcirc*mstances minimizes further cellular damage (Laroux, 2004).However, in chronic neuroinflammatory conditions, glial cells areconstitutively activated, which may have detrimental effects.Activation of glial cells leads to production of reactive oxygen andnitrogen species, initiation of phagocytosis and upregulation of anti-proliferative and pro-inflammatory mediators, all of which can contrib-ute to neuronal damage and death (Mandrekar-Colucci and Landreth,2010; Smith et al., 2012; Ruiz-Nunez et al., 2013). The damagedneuronsare in-turn capable of further activating glial cells through release of sol-uble cellular factors, such as damage-associated molecular patterns(DAMPs) (Block and Hong, 2005; Lull and Block, 2010; Liu et al.,2012). This process leads to a vicious cycle of self-propelling inflamma-tion and cell death that is sustained even after the removal of the initialstimuli (Block and Hong, 2005; Smith et al., 2012). This perpetual pro-inflammatory microenvironment is hypothesized to propagate condi-tions that lead to neurodegeneration (Pais et al., 2008; Frank-Cannonet al., 2009; Cunningham, 2013); it also sets the groundwork for severalneurological diseases including: AD, PD, schizophrenia, major depres-sive disorder (MDD), bipolar disorder, amyotrophic lateral sclerosisand HD (Soczynska et al., 2011; Soulet and Cicchetti, 2011; Smithet al., 2012; Cai, 2013).2.4. Glial cell activation in obesityAs already discussed, glial cells can be activated by many substancesincluding such adipose tissue derived molecules as ceramide and thesaturated fatty acid palmitate. Thesemolecules are, for example, capableof inducingmonocytic cell cytotoxicity (Little et al., 2012). High fat diet-fed obese pups express increased concentration of IL-1β in their hippo-campus compared to their lean counterparts (Bilbo and Tsang, 2010).10 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Other studies have shown that diet-induced obesity (DIO) selectivelyincreases IL-6 in cerebral amyloid angiopathy mice, while decreasinglevels of TNFα in non-diseased control mice (Zhang et al., 2013). Chron-ic exposure of mice to the high fat ‘western diet’, results in exacerbatedCNS (hypothalamus and hippocampus) TNFα, IL-6, IFNγ and IL-1β inresponse to peripheral lipopolysaccharide treatment when comparedto normal chow-fed control mice (Milanski et al., 2009; Andre et al.,2014). Increase in cytokine expression in the brains of obese mice oc-curs through activation of toll-like receptor 4 (TLR4) by long-chainfatty acids (Milanski et al., 2009).Studies have also shown that in rodent models of diet-induced obe-sity there is higher CNS macrophage infiltration and activation (up to53% increase) compared to the lean control animals (Drake et al.,2011), aswell as an increase in total number of microglia and astrocytesin the CNS (Koga et al., 2014). Markers of microglia activation, such ascluster of differentiation 11b (CD11b) and TLR4, are significantlyupregulated (up to 2 fold and 1.8 fold respectively) in the hippocampusof maternal diet-induced obese pups as early as one day after birth(Bilbo and Tsang, 2010). Additionally, the ratio of activated vs. restingmacrophages in the CNS of obese/high fat diet-fed mice is 30% highercompared to lean/normal chow-fed mice, reflecting either an increasein activation of resident microglia, or increased infiltration ofmonocytes/macrophages from the periphery (Buckman et al., 2014).However, others argue that the high fat diet-induced microglia activa-tion in the hippocampus of mice is independent of body weight (Gaoet al., 2014).3. Epidemiological evidence linking obesity andneurodegenerative diseasesThe relationship betweenobesity (excess body fat) andneurodegen-eration is likely complex. High adiposity (fat) levels are associated withan environment of chronic low-grade inflammation in the periphery,which may contribute to neurological disorders through elevatedlevels of inflammatory cytokines, such as IL-6, IL-1β and TNFα (Iidaet al., 2001; Weisberg et al., 2003; Brundage et al., 2008; Gregor andHotamisligil, 2011). It is important to note that not all obese individualsexhibit an increase in systemic cytokine levels. Some studies report thatup to 23% of people who are obese demonstrate no signs of inflamedadipose tissue (Farb et al., 2011). Other reports have identified genderdifferences with 92% of obese males and only 63% of obese femaleshaving inflamed adipose tissue (Bigornia,et al., 2012). The cause forsuch difference is poorly understood.In addition to increased secretion of pro-inflammatory mediators,obese andoverweight individuals exhibit altered insulin/IGF-1 signaling(Polonsky et al., 1988; Bosello and Zamboni, 2000). Evidence supportsassociation of more than twenty different neurological syndromeswith insulin/IGF-1 signaling malfunctions and obesity. They includeschizophrenia, bipolar disorder and MDD in addition to AD, HD andPD (Lopresti and Drummond, 2013); however, the cellular andmolecu-lar mechanisms linking obesity and neurodegenerative diseases areonly beginning to be unraveled. Obesity-induced insulin and IGF-1resistance, along with chronic low-grade inflammation, represent twoFig. 1. Possible links between obesity and neurodegeneration. Obesity promotes chronic low-grsulin and IGF-1 resistance. Chronic inflammation, coupled with insulin and IGF-1 resistance, prof the possible mechanisms behind this. In addition, inflammationmay induce or exacerbate insulin/IGF-1 resistance, compounding theimpact of obesity on the neurodegenerative disease process (Fig. 1).3.1. Epidemiological evidence linking obesity and Alzheimer's diseaseAD is characterized by the gradual and progressive decline in cogni-tive ability and function. At the cellular level, AD possesses two charac-teristic hallmarks: amyloid-beta (Aβ) plaques and neurofibrillarytangles (NFTs) (Hauw et al., 1990; Pitt et al., 2013). NFTs consist of ab-normally phosphorylated tau protein, which causes the cytoskeletonto disconnect and neurons to shrivel into disconnected cellular masses(Hauw et al., 1990). Aβ plaques are extracellular masses of aggregatedAβ that form due to the over production of abnormal Aβ protein,which cannot be cleared by proteases or immune defenses (Beachet al., 1989; Orre et al., 2013). Inflammation is fundamental to AD pro-gression acting as a robust pathogenic force (Salminen et al., 2009;Tyagi et al., 2013). It is characterized by sustained glial cell activationin response to abnormal structures associated with the AD pathology:Aβ plaques, NFTs and necrotic cellular fragments (Beach et al., 1989;Hauw et al., 1990; Pitt et al., 2013).Although the exact mechanisms are currently unclear, obesity isassociated with changes in brain structure and function, a decline incognitive ability leading to dementia and AD (Gustafson et al., 2003,2012; Businaro et al., 2012; Arnoldussen et al., 2014). Body massindex (BMI), which is ameasure of adiposity, declines with the progres-sion of AD, especially at the late stages of the disease (Gilette-Guyonnetet al., 2000); however, it has been reported that an increase in BMI inmid-life correlates to an increased risk for the development of ADlater on in life (Gustafson et al., 2003, 2012). This correlation wasfound to be particularly of concern for females (Gustafson et al.,2003). However, other studies have concluded that obesity negativelyaffects cognitive ability inmen, but not women (Elias et al., 2003, 2005).Obese males scored significantly lower than non-obese males in avariety of cognitive ability tests, including visual memory, verballearning, visual organization, concentration and abstract reasoning(Elias et al., 2003). Others report that overweight individuals (25b BMI N 30) have a 2-fold increase in risk for developing AD, andobese individuals (BMI N 30) have a 3-fold increase risk for AD, com-pared to normal weight controls (BMI b 25), regardless of gender(Whitmer et al., 2007). This epidemiological evidence indicates thatone or possibly many factors related to obesity positively correlateswith decreased cognitive ability and increased risk for developing AD.This association of obesity and neurodegeneration is not unique to AD,but also applies to other neuropathologies including HD and PD.3.2. Epidemiological evidence linking obesity and Parkinson's diseasePD is an age-related neurodegenerative disease characterized bymuscle rigidity, slowness of voluntary movement (bradykinesia),resting tremor and postural instability (Mahlknecht and Poewe, 2013;Santiago and Potashkin, 2013). PD brains are characterized by the ag-gregation of filamentous α-synuclein protein forming insoluble Lewyade peripheral inflammation and insulin and IGF-1 resistance. Inflammation enhances in-omotes neurodegenerative pathologies.11L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21bodies, and also by selective loss of dopaminergic neurons especially inthe substantia nigra pars compacta (SNpc) region of the brain (Morriset al., 2011; Marques and Outeiro, 2012; Mahlknecht and Poewe,2013). α-Synuclein aggregates activate microglia by stimulating thenicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent production of reactive oxygen species (ROS), which inducesoxidative stress in the microglia, and amplifies their activation (Zhanget al., 2005; Klegeris et al., 2008; Qin et al., 2013). Activated microgliacan summon T lymphocytes to the site of inflammation, where theymaybecome toxic towards dopaminergic neurons, resulting in neuronalcell death (Benner et al., 2008).Not without controversy, high BMI (N30) has been identified as oneof the risk factors for PD (Abbott et al., 2002; Hu et al., 2006; Palacioset al., 2011). A recent meta-analysis determined that being overweight(BMI N 25) is a risk factor (up to 1.39 relative risk) for PD (J. Chen et al.,2014). Others have reported that the prevalence of obesity is higher inindividuals with PD compared to the prevalence of obesity in the gener-al population in Italy (Barichella et al., 2003; Cereda et al., 2013). Morespecifically, it has been determined that obese individuals demonstratedepletion of striatal dopamine receptors compared to non-obese con-trols (Wang et al., 2001). Both central (abdominal) and total obesityhave been shown to negatively impact performance on motor speedand manual dexterity tests (Waldstein and Katzel, 2006), which couldalso contribute to the observed link between obesity and PD.3.3. Epidemiological evidence linking obesity and Huntington's diseaseHD is an inherited neurodegenerative disease characterized byabnormal involuntary and voluntary movements including jerky limbmovements; bradykinesia; irregular movements of the face, neck orrespiratory muscles, referred to as choreoathetosis; interference withvocalization, chewing and swallowing; apathy; irritability; lack ofimpulse control; intellectual impairment; and decrease in memoryand learning ability (Cummings and Benson, 1988; Podoll et al., 1988;Rothlind et al., 1993; Purdon et al., 1994). As the disease progresses,symptoms become increasingly worse.The two main pathological features of HD are selective loss ofneurons in the striatum and cortex of the brain, and aggregation ofhuntingtin protein (Htt) (Hsiao and Chern, 2010). Irregular Htt arisesfrom the expanding CAG triplet repeat in the huntingtin gene (HTT)(Ha and Fung, 2012). The length of CAG repeat has approximatelya 70% contribution to the variability in the age of HD onset (Wexleret al., 2004), which indicates that there are other genetic and environ-mental factors contributing to the disease (Byars et al., 2012).Although cachexia is well characterized in HD, this symptom appearsafter the disease onset due to persistent involuntarymovements causingexcess energy expenditure, difficulty swallowing, malabsorption orunderlying metabolic defects (Fain et al., 2001; Marder et al., 2013).Thus, cachexia and weight loss are an aftermath of HD progression.Obesity, on the other hand, has been identified as one of the potentialcauses of earlier age of HD onset (Lundh et al., 2012). Other studiesargue, however, that early onset of HD is due to an increase in caloric in-take, independent of BMI (Marder et al., 2009). Moreover, increased BMIin HD patients does not correlate with increase in leptin, the satietyhormone, as it does in control subjects,matched for elevated BMI (Azizet al., 2010). This indicates that irregularities in adipose tissue functionare present in HD patients, which may include insulin resistance andheightened inflammatory response (Lundh et al., 2012).4. Pathophysiological mechanisms of inflammation inadipose tissueAdipose tissue represents loose connective tissue comprised mainlyof adipocytes (fat cells), but also containing pre-adipocytes (adipocytesnot yet containing lipids), leukocytes, T-cells and macrophages (Doyleet al., 2012; Little et al., 2012). Adipose tissue functions primarily as anenergy storage reservoir. It is also an endocrine organ secretingcytokines and inflammatory mediators, known as adipokines, whichare capable of acting locally as well as systemically. Obese individualsgenerally have higher amounts of hypoxic adipocytes, which attract in-filtrating macrophages leading to peripheral inflammation (Olli et al.,2013). Adipocytes themselves are a known source of IL-6, TNFα, andIL-1β, and most of obese individuals secrete superfluous amounts ofthis pro-inflammatory co*cktail (Hotamisligil et al., 1993; Stenlof et al.,2003; Nov et al., 2013). Adipocytes also secrete the anti-inflammatoryadipokine adiponectin (Scherer et al., 1995),which is inversely associat-ed with adiposity (Arita et al., 1999; Cnop et al., 2003). Thus obese indi-viduals have lower circulating levels of this anti-inflammatory signal.The chronic low-grade inflammatory state of obesity may contributeto neurological disorders, through the secretion of specific mediators(Hotamisligil et al., 1993; Banks et al., 1995; Cai, 2013). Moreover,both an increase in BMI and a decrease in insulin sensitivity lead to re-lease of free fatty acids, which upregulate pro-inflammatory cytokinesthat have been implicated in exacerbation of neuroinflammation(Suganami et al., 2005; Little et al., 2012).The pro-inflammatory mixture of excess TNFα, IL-6 and IL-1β elicitsa variety of systemic responses (Duff and Durum, 1982; P.A. Kern et al.,2001;Meijer et al., 2011). TNFα is central to the inflammatory response.TNFα impacts immune responses via activation of macrophages andneutrophils, induction of apoptosis, regulation of lipid metabolism andinsulin signalingwithin adipose tissue (Simons et al., 2007). Additional-ly, TNFα suppresses the release of the anti-inflammatory moleculeadiponectin,while inducing the secretion of the pro-inflammatory cyto-kine IL-6 from adipose tissue (Berg et al., 1994; P.A. Kern et al., 2001;Simons et al., 2007).IL-6 is a powerful pro-inflammatory cytokine, which regulates B andT cell functions, induces hematopoiesis, stimulates platelet production,immunoglobulin synthesis and acute-phase response (Kopf et al.,1994; Yamash*ta et al., 1994; Biffl et al., 1996). IL-6 affects energyhomeostasis, and controls appetite and nutrient consumption via hypo-thalamic regulation (Stenlof et al., 2003). When left unchecked, IL-6promotes chronic inflammatory conditions, such as those involved inthe perpetuation of obesity, insulin resistance, inflammatory bowel dis-ease and inflammatory arthritis (Naugler and Karin, 2008).More specif-ically, IL-6 is critical in the transition fromacute to chronic inflammationby promoting the changeover fromneutrophil tomonocyte recruitmentat the site of inflammation (Hurst et al., 2001; Marvin et al., 2001).IL-1β regulates fibroblast proliferation, platelet production and theinduction of pro-inflammatory cytokines (e.g., IL-6) and chemokines(e.g., IL-8) (Zetterstrom et al., 1998; Chiaretti et al., 2013). Since IL-1βis secreted by adipose tissues and induces secretion of other pro-inflammatory molecules, IL-1β has emerged as a central molecule inobesity-induced systemic inflammation (Stienstra et al., 2012).Adiponectin, which is diminished in obese individuals, is typicallyregarded as an anti-inflammatory mediator inhibiting the productionof the pro-inflammatory cytokines TNFα and IL-6 by adipocytes (Folcoet al., 2009), and suppressing IL-6 release from endothelial cells at theBBB (Spranger et al., 2006). Thus, excessive adiposity not only increasesthe number of pro-inflammatorymolecules, such as IL-1β, TNFα and IL-6, but also leads to decreased anti-inflammatory signal, adiponectin(Arnoldussen et al., 2014). A number of other adipokines includingleptin, ghrelin, resistin, and visfatin have been implicated as regulatorsof neuroinflammation and their CNS effects have been highlighted inseveral recent reviews (Al-Suhaimi and Shehzad, 2013; Park andAhima, 2013; Arnoldussen et al., 2014; Prodam and Filigheddu, 2014).Given the excess levels of inflammatory adipose tissue secretions, itis understandable that overweight and obese individuals are in a chron-ic state of low-grade inflammation (Xu et al., 2003; Mathis, 2013). Theadipose tissue of obese individuals could be a trigger or a risk factorfor many illnesses, including: type 2 diabetes (T2D), cardiovasculardisease (Hubert et al., 1983), stroke (Kurth et al., 2002), and certain can-cers, such as breast and prostate cancers (Weisberg et al., 2003; Doyle12 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21et al., 2012). Elevated levels of circulating cytokines are also a risk factorfor neurodegenerative diseases including AD, PD and HD (Sun et al.,2003; Bjorkqvist et al., 2008; Cai, 2013; Trager and Tabrizi, 2013). Cyto-kines can cross the BBB and activate the Jun N-terminal kinase (JNK),protein kinase C (PKC) and IkappaB kinase β (IKKβ) pathways, whichultimately lead to transcription of pro-inflammatory cytokines andchemokines within the CNS (Solinas and Karin, 2010). These pathwaysinhibit insulin receptor substrates (IRS) 1 and 2, which are critical forinitiating insulin signaling and propagating it from the extracellularspace to intracellular targets (He et al., 2006; Solinas and Karin, 2010).Therefore, chronic low-grade peripheral inflammation could be one ofthe key mechanisms linking obesity with several disease states, butobesity-induced insulin/IGF-1 resistance represents another distinctpossible mechanism.5. Pathophysiological mechanisms of insulin/IGF-1 in obesityIt is now widely accepted that the state of obesity leads to insulin/IGF-1 resistance (Bosello and Zamboni, 2000; P.A. Kern et al., 2001;Mallea-Gil et al., 2012). Insulin/IGF-1 resistance is a state of weakenedcellular response to these hormones, which is highly consequentialsince insulin and IGF-1 are critical for a number of peripheral functionsas well as for the CNS health. The exact molecular mechanisms are stillunder investigation, but pro-inflammatory cytokines have been shownto directly alter insulin/IGF-1 signaling in a wide range of cell and tissuetypes (Hotamisligil et al., 1993; Xu et al., 2003).5.1. Insulin in the peripheryInsulin is a 51 amino acid peptide hormonemainly produced bypan-creatic β-cells (Harfenist and Craig, 1952). Insulin belongs to the familyof insulin-like hormones, which also includes IGF-1 and IGF-2. Insulin ismost recognized for its role in regulation of blood glucose levels (Duarteet al., 2012). In addition to its effects on glucose metabolism, insulindown-regulates gluconeogenesis, increases glycogen synthesis, in-creases adiposity, promotes lipid synthesis, and inhibits lipolysis andfatty acid esterification (Wagle et al., 1975; Beynen et al., 1980; Baskinet al., 1999).Insulin resistance initially results in increased insulin secretion fromthe pancreatic β-cells, in a compensatory effort to maintain normalblood glucose levels. Over time, however, the pancreatic β-cells beginto fail and start to produce less insulin. Insulin resistance itself is not rec-ognized as a disease state, but can lead to the development of T2D(Santiago and Potashkin, 2013). This transition from insulin resistanceto T2D is due to partial loss of pancreatic β-cell function. Recent studiesindicate that T2D is a significant risk factor for certain forms,of demen-tia, most notably AD (Li and Holscher, 2007) and PD (Hu et al., 2007).5.2. IGF-1 in the peripheryIGF-1 is a 70 amino acid peptide hormone primarily synthesized inthe liver and secreted in response to increased concentrations of growthhormone (a.k.a somatotrophin). IGF-1 production is influenced by sev-eral other factors, including nutritional status and age (Marcovecchioand Chiarelli, 2013). The secretion of IGF-1 requires adequate nutrition,as it has been shown that during states of malnourishment, even in thepresence of growth hormone, IGF-1 secretion does not occur (Corpaset al., 1993; Moloney et al., 2010). IGF-1 has many functions, includingacting as amitogenic growth factor, cell survival stimulant, apoptosis in-hibitor, aswell as inducing fat breakdown and glucose uptake bymusclecells (Rollero et al., 1998; Chen et al., 2000; Trumper et al., 2000;Troncoso et al., 2012). Concentrations of circulating IGF-1 as a growthfactor rise and fall at different developmental stages. IGF-1 productionand secretion is increased during periods of growth and development,such as during puberty, and is decreased during times of stasis (Clarket al., 1998; Lacau-Mengido et al., 2000).5.3. Insulin in the brainOriginally, the brain was considered to be an insulin insensitiveorgan. It has since been discovered that insulin performs many func-tions in the CNS critical to neuronal survival. Insulin affects CNSmetab-olism by triggering glucose uptake by glial cells (Werner et al., 1989;Duarte et al., 2012). It is also a neuromodulator, which enhances seroto-nin (5-HT) synthesis and inhibits reuptake of norepinephrine by pre-synaptic neurons (Crandall et al., 1981; Chen and Yang, 1991). Insulinpromotes cell survival through the inhibition of apoptosis-inducingpeptides, facilitates neuronal growth and differentiation by enhancingneurite outgrowth and synapse formation, and regulates learning andmemory through its effects on synaptic function (Schulingkamp et al.,2000; W. Kern et al., 2001; Banks, 2004; Benedict et al., 2007;Soczynska et al., 2011). Thus, insulin positively regulates synaptic plas-ticity by inducing internalization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors leading to upregulation ofactivity-regulated cytoskeleton-associated protein (Arc). Arc is one ofseveral proteins responsible for the balance between the long-term po-tentiation and long-term depression, two of the phenomena responsi-ble for synaptic plasticity (T.J. Chen et al., 2014). Due to its importancein neuronal survival and cognitive functions, insulin has moved to theforefront of neurodegeneration research.5.4. IGF-1 in the brainIGF-1 has long been recognized for its role in the periphery as amet-abolic and anabolic hormone. It was not until recently, however, thatIGF-1 was deemed a neurotrophic peptide. In the CNS, IGF-1 plays akey role in brain development, maturation and function (Landi et al.,2009; Castilla-Cortazar et al., 2014). IGF-1 acts as a pro-survival signalresponsible for activation of anti-apoptotic cascades, enhancement ofnerve cell growth and promotion of synaptic plasticity (Chen et al.,2000; Trumper et al., 2000; Castilla-Cortazar et al., 2014). IGF-1 inducesmyelination both in vivo (Mozell and McMorris, 1991) and in vitro(McMorris et al., 1986), and enhances survival of cultured rat oligoden-drocytes (Barres et al., 1993). These combined functions are critical forprotection of nerve cells against toxic insults associated with neurode-generative processes. Decrease in IGF-1 concentration and resulting sig-naling errors have been associated with such pathological states as AD,PD, HD, MS and depressive disorders (Rollero et al., 1998; Humbertet al., 2002; Talbot et al., 2012; Pellecchia et al., 2014). It is, therefore,of critical importance to study the role of IGF-1 signaling in neurodegen-erative disease onset and progression.6. Pathophysiological mechanisms of insulin/IGF-1 signaling inneurodegenerative diseasesThere is a growing body of evidence to support the hypothesis thatirregular insulin and IGF-1 hormone levels and resulting impairedinsulin/IGF-1 signaling contribute to neurodegenerative processes.Obesity is one of the main causes of insulin/IGF-1 resistance in theperiphery, which correlates with central insulin/IGF-1 resistance (P.A.Kern et al., 2001; Bigornia et al., 2012).Insulin and IGF-1 CNS signaling cascades share a remarkable amountof overlap (de la Monte and Wands, 2005; Moloney et al., 2010). Thissimilarity likely stems from significant hom*ology in their amino acid se-quences and the similar receptor structures. Both the IGF-1 receptor(IGF-1R) and insulin receptor (INSR) are receptor tyrosine kinases,which are tetrameric in structure, and comprised of two extracellularα-subunits disulfide-linked to two transmembrane β-units (Lawrenceet al., 2007; Glendorf et al., 2011). In addition to binding its own recep-tor, insulin is capable of binding (and activating) the IGF-1R. Conversely,IGF-1 is able to bind (and activate) the INSR (Fujita et al., 2013). Howev-er, each ligand has a 100–500 fold higher affinity for its own receptor(Conejo and Lorenzo, 2001). The functional and structural similarity13L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21between these two receptors is best illustrated by the fact that theirsubunits can combine (Li and Holscher, 2007; Duarte et al., 2012) byone INSR α- and β-subunit binding to an IGF-1R α- and β-subunitforming a hybrid heterotetrameric receptor (Lawrence et al., 2007).The functional significance of this phenomenon is not understood.The INSR and the IGF-1R interact with several common receptorsubstrates, which are responsible for the initial transduction of the sig-nal once the receptor has been activated. INSR and IGF-1R share IRS-1,IRS-2, and the Src hom*ologous and collagenous protein (Shc) ascommon receptor substrate molecules (Ariga et al., 2000; Strack et al.,2000). Thus, binding of IGF-1 and insulin to their corresponding recep-tors leads to parallel pathway activation and subsequent identicaldownstream responses (Yu et al., 2003). In the CNS, IRS-1 and IRS-2are redundant proteins as they are used interchangeably in the samesignaling pathway (Moloney et al., 2010). Activation of IRS-1/2 sets offthe main signaling cascade common to insulin and IGF-1: the phos-phatidylinositol 3-kinase (PI3K)-dependent pathway (Yu et al., 2003;Moloney et al., 2010). Protein kinase B (Akt) is central to the PI3K path-way (Banfic et al., 1998); it is pivotal to cell survival, as it phosphorylatesproteins subsequently initiating several critical cross talking pathwaysincluding: 1) activation of γ-aminobutyric acid (GABA) A receptors,which are responsible for synaptic signaling (Wan et al., 1997; Maet al., 2003); 2) phosphorylation of IkappaB kinase α (IKKα), whichactivates the nuclear factor kappa B (NFkB) leading to transcription ofapoptosis regulators, cytokines, chemokines and growth factors (Ghoshet al., 1998; Nomura et al., 2000); 3) phosphorylation of huntingtin pro-tein, which blocks aggregation of mutant huntingtin, thus promotingneuronal survival (Humbert et al., 2002; Rangone et al., 2004); and 4)activation of glycogen synthase, which induces glycogen synthesis, toname just a fraction of the molecules and resulting signaling cascadesaffected by Akt activation (Delcommenne et al., 1998).Activation of the Shc receptor substrate, on the other hand, leads toinitiation of the mitogen-activated protein kinase (MAPK) pathway.This pathway facilitates cellular growth, proliferation and differentia-tion (Delafontaine et al., 2004; Yoon and Seger, 2006), promotes pro-Fig. 2. The overlapping pathways and functions of insulin and IGF-1. IRS-1, insulin receptor sprotein; MAPK, mitogen activated protein kinase; GABA A, gamma-aminobutyric acid A; IKKαinflammatory cytokine transcription (Soczynska et al.,,2011; Stienstraet al., 2012), and regulates protein translation (Yoon and Seger, 2006;Soczynska et al., 2011). Thus, induction of the insulin/IGF-1 signalingcascades leads to complex cellular responses (Fig. 2).Although insulin and IGF-1 share a remarkable hom*ology in their re-ceptor structure and signaling cascades, the physiological responsestriggered by these two hormones differ. Several mechanisms havebeen proposed to explain this paradox including differential tissue andsub-cellular distribution of the INSR and IGF-1R resulting in distinctbiological effects (Bondy et al., 1990; Zapf et al., 1994). In addition, theligand–receptor interaction affinities for insulin and IGF-1 are different(Mastick et al., 1998), which is particularly relevant since peripheral in-sulin typically circulates at concentrations in the order of pg/ml (Craftet al., 1998), while IGF-1 circulates at ng/ml concentrations (Karabulutet al., 2014). Experiments using INSR and IGF-1R isolated from kidneycells showed that affinity of IGF-1 towards its receptor is much higherrelative to insulin-INSR binding affinity (Hansen et al., 2012). Insulindissociates from its receptor more readily than IGF-1 from IGF-1R(Zapf et al., 1994), and INSR activation leads to higher phosphorylationof IRS-1, while activation of IGF-1R leads to higher phosphorylation ofIRS-2 (Urso et al., 1999). INSR-induced phosphorylation of IRS-1 favorsactivation of the PI3K pathway, while IGF-1R-induced phosphorylationof IRS-1 leads to preferential activation of the MAPK pathway (Amouiet al., 2001). The above observations identify molecular mechanismthat could explainwhy deficit of insulin or IGF-1 could not be fully com-pensated in those cases where the other hormone is present in normalquantities, even though the receptors and signaling cascades engagedby both of these hormones overlap heavily (Boulware et al., 1994;Russell-Jones et al., 1995; de la Monte and Wands, 2005; Moloneyet al., 2010).Insulin/IGF-1 signaling outcomes are major factors in the biologicalaging process (Rollero et al., 1998; Aimaretti et al., 2008). Up- ordown-regulation of the insulin/IGF-1 signaling cascades could resultfrom changes in brain insulin and IGF-1 levels (Bondy and Cheng,2004), change in INSR and IGF-1R distribution (Schulingkamp et al.,ubstrate 1; IRS-2, insulin receptor substrate 2; Shc, the Src hom*ologous and collagenous, IkappaB kinase alpha; NFkB, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase.image of Fig.�214 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–212000; Bondy and Cheng, 2004) or receptor activity (Moloney et al.,2010), and change in IRS-1/2 and Shc protein levels or activity(Nemoto et al., 2009). Such alterations, depending on the cell type andbrain region affected, could also contribute to several CNS diseases(Humbert et al., 2002; Altar et al., 2008;Moloney et al., 2010). For exam-ple, individuals with schizophrenia have higher circulating levels of in-sulin, compared to healthy control patients (Venkatasubramanian et al.,2007; Guest et al., 2011). This correlates with lower circulating levels ofIGF-1 in schizophrenia patients, which may be due to compensatorymechanism responding to the elevated levels of insulin (Guest et al.,2011). AD patients show an increase in IGF-1R in astrocytes, and a de-crease in IGF-1R in neurons, compared to healthy controls (Moloneyet al., 2010). IGF-1 is reduced in the brains of HD patients, and additionof IGF-1 to striatal neurons, can block the formation of mutanthuntingtin-induced cell death and formation of intranuclear inclusions(Humbert et al., 2002). In addition, tissue-specific knock-out mice stud-ies show that decrease in hippocampal IGF-1 levels leads to lowerserum IGF-1 levels, which correlates with depression-like phenotypein the affected mice (Mitschelen et al., 2011). Positive correlationbetween insulin resistance and severity of symptoms in MDD has alsobeen reported (Timonen et al., 2005; Shomaker et al, 2010), whichmay be due in part to the role that insulin signaling plays in regulatingdopamine neurotransmission (Speed et al., 2010;Williams et al., 2010).The role of IGF-1 in MS and its animal model, experimental autoim-mune encephalomyelitis (EAE), was first investigated due to the obser-vations that IGF-1 promotes myelination (McMorris et al., 1986; MozellandMcMorris, 1991) and oligodendrocyte survival (Barres et al., 1993).The initial EAE studies in rodents showed that administration of IGF-1decreased disease symptoms, diminished lesions and reduced inflam-mation (Liu et al., 1997). However, studies exploring the role of IGF-1in MS, showed that IGF-1R expression levels were similar in the brainsof healthy individuals and patients with MS (Wilczak and De Keyser,Fig. 3. Obesity and obesity-induced insulin/IGF-1 resistance contribute to the Alzheimer's disebeta; INSR, insulin receptor; IGF-1R, IGF-1 receptor; Shc, the Src hom*ologous and collagenouIRS-2, insulin receptor substrate 2; PI3K, phosphatidylinositol 3-kinase.1997). IGF-1 treatment was also ineffective in EAEmodel and in clinicalstudies involving MS patients (Cannella et al., 2000; Andreassen et al.,2010).The above diseases could be provoked at least in part by obesity-induced insulin and IGF-1 resistance (Morris et al., 2010; Kwon andPessin, 2013), and the resulting insulin/IGF-1 signaling impairment.Insulin/IGF-1 resistance typically goes hand-in-handwith inflammationsince obese adipose tissue chronically secretes a co*cktail of pro-inflammatory mediators. Thus, insulin/IGF-1 resistance and chronicneuroinflammation could help mechanistically explain the links be-tween obesity and neurodegenerative conditions. The role of insulinand IGF-1 signaling alterations in three such pathologies (AD, PD andHD) is discussed below.6.1. Obesity, insulin/IGF-1 resistance and Alzheimer's diseaseThe role of insulin, IGF-1 and obesity in the onset and pathogenesisof AD has been the subject of a series of recent studies. Insulin andIGF-1 resistance has moved to the forefront of AD research. Some ex-perts consider AD to be a direct result of brain insulin resistance, evennaming AD “Type 3 Diabetes” (Duarte et al., 2012; Vagelatos andEslick, 2013). In a normal brain, insulin signaling hinders the formationof Aβ plaques and abnormal phosphorylation of tau protein. However,in an insulin resistant AD brain this signaling cascade is diminished,thus contributing to the formation of Aβ plaques and NFTs (Hauwet al., 1990; Goll et al., 2013) (Fig. 3). Since binding of insulin andIGF-1 to their corresponding receptors sets off almost identical signalingcascades (Bondy and Cheng, 2004), reduced levels of IGF-1, the down-regulation of its receptor and the ensuing signaling cascade could alsocontribute to the formation of Aβ plaques and NFTs in a manner similarto insulin resistance. Decreased activation of the insulin/IGF-1 signalingase pathology. TNFα, tumor necrosis factor alpha; IL-6, interleukin 6; IL-1β, interleukin 1s protein; MAPK, mitogen activated protein kinase; IRS-1, insulin receptor substrate 1;image of Fig.�315L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21pathway has been detected in AD (Andreassen et al., 2002; Solas et al.,2013; Pellecchia et al., 2014).Individuals with chronic peripheral hyperinsulinemia, such asmanyobese individuals, experience decreased brain insulin signaling. This de-crease in signaling is mainly due to lower CNS insulin concentrations asa direct result of down-regulated transport of insulin into the brain(Stein et al., 1987; Kaiyala et al., 2000). Moreover, IGF-1R and INSR areupregulated in areas surrounding Alzheimer Aβ plaques (Jafferaliet al., 2000). Receptor upregulation is a common compensatory mecha-nismobservedwhen their ligand, in this case insulin and IGF-1, is low orabsent. In addition to the decrease in the CNS insulin levels, individualswith AD demonstrate,decreased levels of IRS-1/2, which furtheramplifies insulin/IGF-1 resistance (Moloney et al., 2010).The chronic low-grade inflammation inmost obese individuals leadsto increased levels of local and circulating cytokines such as TNFα,which have an inhibitory effect on the tyrosine kinase activity of theINSR and IGF-1R, thus reducing the insulin/IGF-1 signaling cascadeand associated down-stream mechanisms (Hotamisligil et al., 1996;P.A. Kern et al., 2001).It has been demonstrated that peripheral pro-inflammatory cyto-kines are capable of crossing the BBB by distinctive saturable transportsystems, and therefore can act in the CNS (Banks et al., 1995; Ericksonet al., 2012). The central effects of TNFα could be responsible for the ob-served positive association between an increased systemic level of thiscytokine and accelerated cognitive decline in AD patients (Holmeset al., 2009). Moreover, high fat diet studies involving mice haveshown increase in brain cytokine levels associated with obesity(Zhang et al., 2013). It is possible that decreased insulin/IGF-1, com-bined with actions of pro-inflammatory cytokines, inhibits insulin/IGF-1 signaling systemically as well as in the CNS and therefore exacerbatesAD pathogenesis in obesity (Fig. 3). This process is not exclusive to AD;similar errors contribute to other neurodegenerative conditions, includ-ing PD and HD.Fig. 4.Obesity and obesity-induced insulin/IGF-1 resistance contribute to the Parkinson’s diseaseFFA, free fatty acids; DA, dopamine; SNpc, substantia nigra pars compacta; INSR, insulin recept6.2. Obesity, insulin/IGF-1 resistance and Parkinson's diseaseIt has also been discovered that insulin receptors are decreased inthe SNpc region of the PD brains (Moroo et al., 1994; Takahashi et al.,1996), thus reducing the beneficial growth and proliferation promotingeffects of the insulin signaling cascade, and thereby contributing to PD.Decreased insulin concentration has been shown in PD brains (Duarteet al., 2011), and could contribute to α-synuclein deposition, which isthe characteristic feature of PD (Frank-Cannon et al., 2009). Huanget al. (2003) showed that insulin promotes normal function of CNS mi-tochondria. Absence of insulin causes depolarization of mitochondria,which leads to the generation of excess ROS, which may contribute toPD pathology (Gao et al., 2008).Impaired insulin signaling may decrease glucose uptake in the brain,and specifically in the SNpc region of the brain, which could lead to a de-crease in the intracellular ratio of ATP to ADP (Levin, 2000). Such imbal-ance is known to trigger the activation of ATP-sensitive potassium (KATP)channels. Dopamine release from dopaminergic neurons is affected byglucose levels and is under control of KATP channels (Santiago andPotashkin, 2013). Studies have shown that depending on its severity, in-sulin resistance decreases both the release of DA fromdopaminergic neu-rons and clearance of DA following synaptic release (Morris et al., 2011).Likewise, IGF-1 has been shown to protect DA neurons, but CNS levels ofIGF-1 are decreased in PD patients (Ebert et al., 2008). IGF-1 resistancehas also been observed in patients experiencing neurodegeneration asso-ciated with PD (Trejo et al., 2004). Thus, the inflammation, as well as in-sulin and IGF-1 resistance caused by obesity, contributes to thepathogenesis of PD in a multifaceted manner (Fig. 4).6.3. Obesity, insulin/IGF-1 resistance and Huntington's diseaseObesity may provoke HD onset through insulin resistance anddecreased circulating IGF-1 levels (Podolsky and Leopold, 1977; Lalicpathology. IL-6, interleukin 6; IL-1β, interleukin 1 beta; TNFα, tumor necrosis factor alpha;or; ROS, reactive oxygen species.image of Fig.�416 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21et al., 2008; Hsiao and Chern, 2010; Lundh et al., 2012). This acceleratesHD pathology, as insulin participates in the regulation of severalHD-related genes (Crocker et al., 2006). For example, insulin signalingpromotes clearance of abnormal Htt aggregates (Yamamoto et al.,2006). Animal models of HD have demonstrated that Akt protein,which is central in the insulin/IGF-1 signaling cascade, is down-regulated in HD (Colin et al., 2005) and its down-regulation is associatedwith early onset of HD (Andreassen et al., 2002). As previously discussed,the PI3K/Akt signaling cascade promotes neuronal survival througha number of different mechanisms including phosphorylation ofhuntingtin protein (Humbert et al., 2002).Chronic peripheral inflammation has also been noted in patientswith HD, and may be a contributing factor (Frank-Cannon et al.,2009). Elevated circulating and CNS cytokine levels, particularly ofIL-6, have been observed in HD patients several years prior to onset ofclassical HD symptoms (Bjorkqvist et al., 2008). Since excess adiposetissue is a trigger for early onset of HD and is a source of IL-6 andother cytokines, it is possible that obesity-induced earlier onset of HDis a result of increased pro-inflammatory mediators (Fig. 5). Eventhough obesity, insulin and IGF-1 disturbances do not cause HD, highadiposity may induce earlier disease onset and exacerbation of HDprogression.7. ConclusionsCompelling evidence indicates that excess adiposity contributes toseveral neurodegenerative diseases including AD, PD and HD (Kaiyalaet al., 2000; Sun et al., 2003; Beydoun et al., 2008; Bjorkqvist et al.,2008; Trager and Tabrizi, 2013). One possible mechanism responsiblefor this link involves excess secretion of pro-inflammatory cytokinesin the periphery, leading to their brain uptake and resulting exacerba-tion of neuroinflammation (Gonzales et al., 2012; Hsuchou et al.,2012). A second mechanism linking obesity to neurodegeneration isFig. 5. Obesity-induced insulin/IGF-1 resistance contributes to Huntington's disease pathologykinase.insulin/IGF-1 resistance, which has far-reaching effects in the CNS(Hallschmid and Schultes, 2009; Gregor and Hotamisligil, 2011). Thesetwo mechanisms may interact; obesity-related insulin resistance andreduced insulin signaling in the brainmay be exacerbated by the chron-ic peripheral and CNS inflammatory environment associated withobesity (Fig. 1). Studies investigating use of intranasal insulin as a treat-ment for mild cognitive impairment have shown promising results(Benedict et al., 2007; Craft et al., 2012). Intranasal IGF-1 treatment reg-imen has been investigated for treatment of depression (Paslakis et al.,2012) and also as a treatment for brain injury (Lin et al., 2009). Thesetherapies could show promise in other neurodegenerative conditionsassociated with defective insulin/IGF-1 signaling. Further investigationinto the role of obesity-induced insulin and IGF-1 resistance as the pos-sible contributor to neurodegeneration is required. Elucidation of therole of these hormones in neurodegeneration will strengthen ourunderstanding of the pathogenic mechanisms of neurodegenerationand may ultimately lead to identification of novel targets for effectivetreatment strategies in AD, PD and HD.AcknowledgementsThis work was supported by grants from the Natural Sciences andEngineering Research Council of Canada and the Jack Brown and FamilyAD Research Foundation.ReferencesAbbott, R.D., Ross, G.W., White, L.R., Nelson, J.S., Masaki, K.H., Tanner, C.M., Curb, J.D.,Blanchette, P.L., Popper, J.S., Petrovitch, H., 2002. Midlife adiposity and the futurerisk of Parkinson's disease. Neurology 59, 1051–1057.Aimaretti, G., Boschetti, M., Corneli, G., Gasco, V., Valle, D., Borsotti, M., Rossi, A., Barreca,A., Fazzuoli, L., Ferone, D., Ghigo, E., Minuto, F., 2008. Normal age-dependent values ofserum insulin growth factor-I: results from a healthy Italian population. J. Endocrinol.Investig. 31, 445–449.Al-Suhaimi, E.A., Shehzad, A., 2013. Leptin, resistin and visfatin: the missing link betweenendocrine metabolic disorders and,immunity. Eur. J. Med. Res. 18, 12.. IL-6, interleukin 6; Htt, huntingin protein; HTT, huntingtin gene; Akt, serine/threoninehttp://refhub.elsevier.com/S0165-5728(14)00175-1/rf0005http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0005http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0010http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0010http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0010http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0015http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0015image of Fig.�517L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Altar, C.A., Hunt, R.A., Jurata, L.W., Webster, M.J., Derby, E., Gallagher, P., Lemire, A.,Brockman, J., Laeng, P., 2008. Insulin, IGF-1, and muscarinic agonists modulateschizophrenia-associated genes in human neuroblastoma cells. Biol. Psychiatry 64,1077–1087.Amoui, M., Craddock, B.P., Miller, W.T., 2001. Differential phosphorylation of IRS-1 byinsulin and insulin-like growth factor I receptors in Chinese hamster ovary cells. J.Endocrinol. 171, 153–162.Andre, C., Dinel, A.-L., Ferreira, G., Laye, S., Castanon, N., 2014. Diet-induced obesity pro-gressively alters cognition, anxiety-like behavior and lipopolysaccharide- induceddepressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation.Brain Behav. Immun. http://dx.doi.org/10.1016/j.bbi.2014.03.012.Andreassen, O.A., Dedeoglu, A., Stanojevic, V., Hughes, D.B., Browne, S.E., Leech, C.A.,Ferrante, R.J., Habener, J.F., Beal, M.F., Thomas, M.K., 2002. Huntington's disease ofthe endocrine pancreas: insulin deficiency and diabetes mellitus due to impairedinsulin gene expression. Neurobiol. Dis. 11, 410–424.Andreassen, M., Frystyk, J., Miller, K.K., Kristensen, L.O., 2010. Interferon-β treatmentassociated with a biochemical profile suggestive of acromegaly. A case report of a pa-tient treated for multiple sclerosis. Scand. J. Clin. Lab. Invest. 70, 519–522.Ariga, M., Nedachi, T., Akahori, M., Sakamoto, H., Ito, Y., Hakuno, F., Takahashi, S., 2000.Signalling pathways of insulin-like growth factor-I that are augmented by camp inFRTL-5 cells. Biochem. J. 348 (Pt 2), 409–416.Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., Hotta, K., Shimomura,I., Nakamura, T., Miyaoka, K., Kuriyama, H., Matsubara, K., Muraguchi, M., Ohmoto, Y.,Funahashi, T., Matsuzawa, Y., 1999. Paradoxical decrease of an adipose-specific pro-tein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 257, 79–83.Arnoldussen, I.A.C., Kilaan, A.J., Gustafson, D.R., 2014. Obesity and dementia: adipokinesinteract with the brain. Eur. Neuropsychopharmacol. http://dx.doi.org/10.1016/j.euroneuro.2014.03.002.Aziz, N.A., Pijl, H., Frolich, M., van der Graaf, A.W., Roselfsema, F., Roos, R.A., 2010. Leptinsecretion rate increases with higher CAG repeat number in Huntington's diseasepatients. Clin. Endocrinol. 73, 206–211.Banfic, H., Tang, X., Batty, I.H., Downes, C.P., Chen, C., Rittenhouse, S.E., 1998. A novelintegrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets. J. Biol. Chem. 273,13–16.Banks, W.A., 2004. The source of cerebral insulin. Eur. J. Pharmacol. 490, 5–12.Banks, W.A., Kastin, A.J., Broadwell, R.D., 1995. Passage of cytokines across the blood–brain barrier. Neuroimmunomodulation 2, 241–248.Barichella, M., Marczewska, A., Vairo, A., Canessi, M., Pezzoli, G., 2003. Isunderweightness still a major problem in Parkinson's disease patients? Eur. J.Clin. Nutr. 57, 543–547.Barres, B.A., Schmid, R., Sendnter, M., Raff, M.C., 1993.Multiple extracellular signals are re-quired for long-term oligodendrocyte survival. Development 118, 283–295.Baskin, D.G., Figlewicz Lattemann, D., Seeley, R.J., Woods, S.C., Porte Jr., D., Schwartz, M.W.,1999. Insulin and leptin: dual adiposity signals to the brain for the regulation of foodintake and body weight. Brain Res. 848, 114–123.Beach, T.G., Walker, R., McGeer, E.G., 1989. Patterns of gliosis in Alzheimer's disease andaging cerebrum. Glia 2, 420–436.Bende, R.J., van Maldegem, F., van Noesel, C.J., 2009. Chronic inflammatory disease,lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas.Haematologica 94, 1109–1123.Benedict, C., Hallschmid, M., Schultes, B., Born, J., Kern, W., 2007. Intranasal insulin to im-prove memory function in humans. Neuroendocrinology 86, 136–142.Benner, E.J., Banerjee, R., Reynolds, A.D., Sherman, S., Pisarev, V.M., Tsiperson, V.,Nemachek, C., Ciborowski, P., Przedborski, S., Mosley, R.L., Gendelman, H.E., 2008.Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergicneurons. PLoS One 3, e1376.Berg, M., Fraker, D.L., Alexander, H.R., 1994. Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3 t3-l1adipocytes. Cytokine 6, 425–432.Beydoun, M.A., Beydoun, H.A., Wang, Y., 2008. Obesity and central obesity as risk factorsfor incident dementia and its subtypes: a systematic review and meta-analysis. Obes.Rev. 9, 204–218.Beynen, A.C., Vaartjes,W.J., Geelen, M.J., 1980. Acute effects of insulin on fatty acidmetab-olism in isolated rat hepatocytes. Horm. Metab. Res. 12, 425–430.Biffl, W.L., Moore, E.E., Moore, F.A., Barnett Jr., C.C., Silliman, C.C., Peterson, V.M., 1996.Interleukin-6 stimulates neutrophil production of platelet-activating factor. J. Leukoc.Biol. 59, 569–574.Bigornia, S.J., Farb, M.G., Mott, M.M., Hess, D.T., Carmine, B., Fiscale, A., Joseph, L., Apovian,C.M., Gokce, N., 2012. Relation of depot-specific adipose inflammation to insulinresistance in human obesity. Nutr. Diabetes 5, e30.Bilbo, S.D., Tsang, V., 2010. Enduring consequences of maternal obesity for brain inflam-mation and behavior of offspring. FASEB J. 24, 2014–2015.Bjorkqvist, M., Wild, E.J., Thiele, J., Silvestroni, A., Andre, R., Lahiri, N., Raibon, E., Lee, R.V.,Benn, C.L., Soulet, D., Magnusson, A., Woodman, B., Landles, C., Pouladi, M.A., Hayden,M.R., Khalili-Shirazi, A., Lowdell, M.W., Brundin, P., Bates, G.P., Leavitt, B.R., Moller, T.,Tabrizi, S.J., 2008. A novel pathogenic pathway of immune activation detectablebefore clinical onset in Huntington's disease. J. Exp. Med. 205, 1869–1877.Block, M.L., Hong, J.S., 2005. Microglia and inflammation-mediated neurodegeneration:multiple triggers with a common mechanism. Prog. Neurobiol. 76, 77–98.Bondy, C.A., Cheng, C.M., 2004. Signaling by insulin-like growth factor I in brain. Eur. J.Pharmacol. 490, 25–31.Bondy, C.A., Werner, H., Roberts Jr., C.T., LeRoith, D., 1990. Cellular pattern of insulin-like growth factor-1 (IGF-1) and type 1 IGF receptor gene expression in earlyorganogenesis: comparison with IGF-2 gene expression. Mol. Endocrinol. 4,1386–1498.Bosello, O., Zamboni, M., 2000. Visceral obesity and metabolic syndrome. Obes. Rev. 1,47–56.Boulware, S.D., Tamborlane, W.V., Rennert, N.J., Gesundhelt, N., Sherwin, R.S., 1994. Com-parison of the metabolic effects of recombinant human insulin-like growth factor-1and insulin dose–response relationship in healthy young and middle-aged adults.J. Clin. Invest. 93, 1131–1139.Brundage, S.I., Kirilcuk, N.N., Lam, J.C., Spain, D.A., Zautke, N.A., 2008. Insulin increases therelease of proinflammatory mediators. J. Trauma 65, 367–372.Bryant, R.E., DesPrez, R.M., VanWay, M.H., Rogers, D.E., 1966. Studies on human leukocytemotility. I. Effects of alterations in pH, electrolyte concentration, and phagocytosis onleukocyte migration, adhesiveness, and aggregation. J. Exp. Med. 124, 483–499.Buckley, C.D., 2011.Why does chronic inflammation persist: an unexpected role for fibro-blasts. Immunol. Lett. 138, 12–14.Buckman, L.B., Hasty, A.H., Flaherty, D.K., Buckman, C.T., Thompson, M.M., Matlock, B.K.,Weller, K., Ellacott, K.L., 2014. Obesity induced by a high-fat diet is associated with in-creased immune cell entry into the,central nervous system. Brain Behav. Immun. 35,33–42.Businaro, R., Ippoliti, F., Ricci, S., Canitano, N., Fusso, A., 2012. Alzheimer's disease promo-tion by obesity: induced mechanisms-molecular links and perspectives. Curr.Gerontol. Geriatr. Res. 2012, 986823.Byars, J.A., Beglinger, L.J., Moser, D.J., Gonzalez-Alegre, P., Nopoulos, P., 2012. Substanceabuse may be a risk factor for earlier onset of Huntington disease. J. Neurol. 259,1824–1831.Cai, D., 2013. Neuroinflammation and neurodegeneration in overnutrition-induceddiseases. Trends Endocrinol. Metab. 24, 40–47.Cannella, B., Pitt, D., Capello, E., Raine, C.S., 2000. Insulin-like growth factor-1 fails to en-hance central nervous system myelin repair during autoimmune demyelination.Am. J. Pathol. 157, 933–943.Castilla-Cortazar, I., Guerra, L., Puche, J.E., Munoz, U., Barhoum, R., Escudero, E., Lavandera,J.L., 2014. An experimental model of partial insulin-like growth factor-1 deficiency inmice. J. Physiol. Biochem. 70, 129–139.Cereda, E., Cassani, E., Barichella, M., Caccialanza, R., Pezzoli, G., 2013. Anthropometric in-dices of fat distribution and cardiometabolic risk in Parkinson's disease. Nutr. Metab.Cardiovasc. Dis. 23, 264–271.Chen, C.C., Yang, J.C., 1991. Effects of short and long-lasting diabetes mellitus on mousebrain monoamines. Brain Res. 552, 175–179.Chen, D.B., Wang, L., Wang, P.H., 2000. Insulin-like growth factor I retards apoptoticsignaling induced by ethanol in cardiomyocytes. Life Sci. 67, 1683–1693.Chen, J., Guan, Z., Wang, L., Song, G., Ma, B., Wang, Y., 2014a. Meta-analysis: overweight,obesity and Parkinson's disease. Int. J. Endocrinol. 2014, 203930.Chen, T.J., Wang, D.C., Hung, H.S., Ho, H.F., 2014b. Insulin can induce expression of amemory-related synaptic protein through facilitating AMPA receptor endocytosis inrat cortical neurons. Cell. Mol. Life Sci. http://dx.doi.org/10.1007/s00018- 014-1620-5.Chiaretti, A., Pulitano, S., Barone, G., Ferrara, P., Romano, V., Capozzi, D., Riccardi, R., 2013.IL-1 beta and IL-6 upregulation in children with H1N1 influenza virus infection.Mediat. Inflamm. 2013, 495848.Clark, P.A., Clarke, W.L., Pedadda, S., Reiss, A., Langlois, C., Nieves-Rivera, F., Rogol, A.D.,1998. The effects of pubertal status and glycemic control on the growth hormone-IGF-1 axis in boys with insulin-dependent diabetes mellitus. J. Pediatr. Endocrinol.Metab. 11, 427–435.Cnop, M., Havel, P.J., Utzschneider, K.M., Carr, D.B., Sinha, M.K., Boyko, E.J., Retzlaff, B.M.,Knopp, R.H., Brunzell, J.D., Kahn, S.E., 2003. Relationship of adiponectin to body fatdistribution, insulin sensitivity and plasma lipoproteins: evidence for independentroles of age and sex. Diabetologia 46, 459–469.Colin, E., Regulier, E., Perrin, V., Durr, A., Brice, A., Aebischer, P., Deglon, N., Humbert, S.,Saudou, F., 2005. Akt is altered in an animal model of Huntington's disease and inpatients. Eur. J. Neurosci. 21, 1478–1488.Conejo, R., Lorenzo, M., 2001. Insulin signaling leading to proliferation, survival, andmembrane ruffling in c2c12 myoblasts. J. Cell. Physiol. 187, 96–108.Corpas, E., Harman, S.M., Blackman, M.R., 1993. Human growth hormone and humanaging. Endocr. Rev. 14, 20–39.Craft, S., Peskind, E., Schwartz, M.W., Schellenberg, G.D., Raskind, M., Porte Jr., D., 1998.Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship toseverity of dementia and apolipoprotein E genotype. Neurology 50, 164–168.Craft, S., Baker, L.D., Montine, T.J., Minoshima, S., Watson, G.S., Claxton, A., Arbuckle, M.,Callaghan, M., Tsai, E., Plymate, S.R., Green, P.S., Leverenz, J., Cross, D., Gerton, B.,2012. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitiveimpairment: a pilot clinical trial. Arch. Neurol. 69, 29–38.Crandall, E.A., Gillis, M.A., Fernstrom, J.D., 1981. Reduction in brain serotonin synthesisrate in streptozotocin-diabetic rats. Endocrinology 109, 310–312.Crocker, S.F., Costain, W.J., Robertson, H.A., 2006. DNA microarray analysis of striatal geneexpression in symptomatic transgenic Huntington's mice (R6/2) reveals neuroin-flammation and insulin associations. Brain Res. 1088, 176–186.Cummings, J.L., Benson, D.F., 1988. Psychological dysfunction accompanying subcorticaldementias. Annu. Rev. Med. 39, 53–61.Cunningham, C., 2013. Microglia and neurodegeneration: the role of systemic inflamma-tion. Glia 61, 71–90.Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L.,Gan, W.B., 2005. ATP mediates rapid microglial response to local brain injury in vivo.Nat. Neurosci. 8, 752–758.de la Monte, S.M., Wands, J.R., 2005. Review of insulin and insulin-like growth factorexpression, signaling, and malfunction in the central nervous system: relevance toAlzheimer's disease. J. Alzheimers Dis. 7, 45–61.Dehouck, M.P., Meresse, S., Delorme, P., Fruchart, J.C., Cecchelli, R., 1990. An easier, repro-ducible, and mass-production method to study the blood–brain barrier in vitro. J.Neurochem. 54, 1798–1801.http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0020http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0020http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0020http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0025http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0025http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0025http://dx.doi.org/10.1016/j.bbi.2014.03.012http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0040http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0040http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0040http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0035http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0035http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0035http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0045http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0045http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0050http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0050http://dx.doi.org/10.1016/j.euroneuro.2014.03.002http://dx.doi.org/10.1016/j.euroneuro.2014.03.002http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0070http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0075http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0075http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0085http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0085http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0090http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0090http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0095http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0095http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0110http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0110http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0110http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0115http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0115http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0120http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0120http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0125http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0125http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0125http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0135http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0135,http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0140http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0140http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0100http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0100http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0105http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0105http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0145http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0145http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0150http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0150http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0160http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0160http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0165http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0165http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0175http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0175http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0180http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0180http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0180http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0185http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0185http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1190http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1190http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1190http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0195http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0195http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0195http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0205http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0205http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0215http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0215http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0220http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0220http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0220http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0225http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0225http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0230http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0230http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0235http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0235http://dx.doi.org/10.1007/s00018- 014-1620-5http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0245http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0245http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0250http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0250http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0250http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0255http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0255http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0255http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0260http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0260http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0265http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0265http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0270http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0270http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0275http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0275http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0280http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0280http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0285http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0285http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0290http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0290http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0290http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0295http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0295http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0300http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0300http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0305http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0305http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0310http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0310http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0310http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0315http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0315http://refhub.elsevier.com/S0165-5728(14)00175-1/rf031518 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Delafontaine, P., Song, Y.H., Li, Y., 2004. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler. Thromb. Vasc. Biol. 24,435–444.Delcommenne, M., Tan, C., Gray, V., Rue, L., Woodgett, J., Dedhar, S., 1998.Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3and protein kinase B/Akt by the integrin-linked kinase. Proc. Natl. Acad. Sci. U. S. A.95, 11211–11216.Denis, P.A., 2013. Alzheimer's disease: a gas model. The NADPH oxidase-nitric oxidesystem as an antibubble biomachinery. Med. Hypotheses 81, 976–987.Doyle, S.L., Donohoe, C.L., Lysaght, J., Reynolds, J.V., 2012. Visceral obesity, metabolicsyndrome, insulin resistance and cancer. Proc. Nutr. Soc. 71, 181–189.Drake, C., Boutin, H., Jones, M.S., Denes, A., McColl, B.W., Selvarajah, J.R., Hulme, S.,Georgiou, R.F., Hinz, R., Gerhard, A., Vail, A., Prenant, C., Julyan, P., Maroy, R., Brown,G., Smigova, A., Herholz, K., Kassiou, M., Crossman, D., Francis, S., Proctor, S.D.,Russell, J.C., Hopkins, S.J., Tyrrell, P.J., Rothwell, N.J., Allan, S.M., 2011. Brain inflamma-tion is induced by co-morbidities and risk factors for stroke. Brain Behav. Immun. 25,1113–1122.Duarte, A.I., Petit, G.H., Ranganathan, S., Li, J.Y., Oliveira, C.R., Brundin, P., Bjorkqvist, M.,Rego, A.C., 2011. IGF-1 protects against diabetic features in an in vivo model ofHuntington's disease. Exp. Neurol. 231, 314–319.Duarte, A.I., Moreira, P.I., Oliveira, C.R., 2012. Insulin in central nervous system: more thanjust a peripheral hormone. J. Aging Res. 2012, 384017.Duff, G.W., Durum, S.K., 1982. Fever and immunoregulation: hyperthermia, interleukins 1and 2, and T-cell proliferation. Yale J. Biol. Med. 55, 437–442.Ebert, A.D., Beres, A.J., Barber, A.E., Svendsen, C.N., 2008. Human neural progenitor cellsover-expressing IGF-1 protect dopamine neurons and restore function in a ratmodel of Parkinson's disease. Exp. Neurol. 209, 213–223.Elias, M.F., Elias, P.K., Sullivan, L.M., Wolf, P.A., D'Agostino, R.B., 2003. Lower cognitivefunction in the presence of obesity and hypertension: the Framinham Heart Study.Int. J. Obes. Relat. Metab. Disord. 27, 260–268.Elias, M.F., Elias, P.K., Sullivan, L.M.,Wolf, P.A., D'Agostino, R.B., 2005. Obesity, diabetes andcognitive deficit: the Framingham Heart Study. Neurobiol. Aging 26S, S11–S16.Erickson, M.A., Dohi, K., Banks, W.A., 2012. Neuroinflammation: a common pathway inCNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation 19,121–130.Fain, J.N., Del Mar, N.A., Meade, C.A., Reiner, A., Goldowitz, D., 2001. Abnormalities in thefunctioning of adipocytes from R6/2 mice that are transgenic for Huntington's diseasemutation. Hum. Mol. Genet. 10, 145–152.Farb, M.G., Bigornia, S., Mott, M., Tanriverdi, K., Morin, K.M., Freedman, J.E., Joseph, L.,Hess, D.T., Apovian, C.M., Vita, J.A., Gokce, N., 2011. Reduced,adipose tissue inflamma-tion represents an intermediate cardiometabolic phenotype in obesity. J. Am. Coll.Cardiol. 58, 232–237.Folco, E.J., Rocha, V.Z., Lopez-Ilasca, M., Libby, P., 2009. Adiponectin inhibits pro- inflam-matory signaling in human macrophages independent of interleukin- 10. J. Biol.Chem. 284, 25569–25575.Frank-Cannon, T.C., Alto, L.T., McAlpine, F.E., Tansey, M.G., 2009. Does neuroinflammationfan the flame in neurodegenerative diseases? Mol. Neurodegener. 4, 47.Fujita, M., Ieguchi, K., Cedano-Prieto, D.M., Fong, A., Wilkerson, C., Chen, J.Q., Wu, M., Lo, S.H., Cheung, A.T., Wilson, M.D., Cardiff, R.D., Borowsky, A.D., Takada, Y.K., Takada, Y.,2013. An integrin binding-defective mutant of insulin-like growth factor-1 (R36E/R37E IGF1) acts as a dominant-negative antagonist of the IGF1 receptor (IGF1R)and suppresses tumorigenesis but still binds to IGF1R. J. Biol. Chem. 288,19593–19603.Gao, H.M., Kotzbauer, P.T., Uryu, K., Leight, S., Trojanowski, J.Q., Lee, V.M., 2008. Neuroin-flammation and oxidation/nitration of alpha-synuclein linked to dopaminergicneurodegeneration. J. Neurosci. 28, 7687–7698.Gao, Y., Ottaway, N., Schriever, S.C., Legutko, B., Garcia-Caceres, C., de la Fuente, E.,Mergen, C., Bour, S., Thaler, J.P., Seeley, R.J., Filosa, J., Stern, J.E., Perez-Tilve, D.,Schwartz, M.W., Tschop, M.H., Yi, C.X., 2014. Hormones and diet, but not bodyweight,control hypothalamic microglial activity. Glia 62, 17–25.Ghosh, S., May, M.J., Kopp, E.B., 1998. Nf-kappa B and Rel proteins: evolutionarilyconserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260.Gilette-Guyonnet, S., Nourhashemi, F., Andrieu, S., de Glisezinski, I., Ousset, P.J., Riviere, D.,Albarede, J.L., Vellas, B., 2000. Weight loss in Alzheimer disease. Am. J. Clin. Nutr. 71,637S–642S.Glendorf, T., Stidsen, C.E., Norrman, M., Nishimura, E., Sorensen, A.R., Kjeldsen, T., 2011.Engineering of insulin receptor isoform-selective insulin analogues. PLoS One 6,e20288.Goll, Y., Bekenstein, U., Barbash, S., Greenberg, D.S., Zangen, R., Shoham, S., Soreq, H., 2013.Sustained Alzheimer's amyloid pathology in myeloid differentiation protein-88-deficient APPswe/PS1 mice. Neurodegener. Dis. 13, 58–60.Gonzales, M.M., Tarumi, T., Eagan, D.E., Tanaka, H., Vaghasia, M., Haley, A.P., 2012. Indirecteffects of elevated body mass index on memory performance through alteredcerebral metabolite concentrations. Psychosom. Med. 74, 691–698.Gregor, M.F., Hotamisligil, G.S., 2011. Inflammatory mechanisms in obesity. Annu. Rev.Immunol. 29, 415–445.Guest, P.C., Schwarz, E., Krishnamurthy, D., Harris, L.W., Leweke, F.M., Rothermundt, M.,van Beveren, N.J.M., Spain, M., Barnes, A., Steiner, J., Rahmoune, H., Bahn, S., 2011. Al-tered levels of circulating insulin and other neuroendocrine hormones associatedwith the onset of schizophrenia. Psychoneuroendocrinology 36, 1092–1096.Gustafson, D.R., Rothenberg, E., Blennow, K., Steen, B., Skoog, I., 2003. An 18-year follow-up of overweight and risk of Alzheimer's disease. Arch. Intern. Med. 163, 1524–1528.Gustafson, D.R., Backman, K., Joa, E., Waern, M., Ostling, S., Guo, X., Skoog, I., 2012.37 years of body mass index and dementia: observations from the prospectivepopulation study of women in Gothenburg, Sweden. J. Alzheimers Dis. 28, 163–167.Ha, A.D., Fung, V.S., 2012. Huntington's disease. Curr. Opin. Neurol. 25, 491–498.Hallschmid, M., Schultes, B., 2009. Central nervous insulin resistance: a promisingtarget in the treatment of metabolic and cognitive disorders? Diabetologia 52,2264–2269.Hansen, B.F., Glendorf, T., Hegelund, A.C., Lundby, A., Lutzen, A., Slaaby, R., Stidsen, C.E.,2012. Molecular characterization of long-acting insulin analogues in comparisonwith human insulin, IGF-1 and insulin x10. PLoS One 7, e34274.Hanson, C.D., Clarke, C., 2013. Is expressed emotion related to estimates of abilitymade byolder people with cognitive impairments and their partners? Aging Ment. Health 17,535–543.Harfenist, E.J., Craig, L.C., 1952. The molecular weight of insulin. J. Am. Chem. Soc. 74,3087–3089.Hauw, J.J., Verny, M., Delaere, P., Cervera, P., He, Y., Duyckaerts, C., 1990. Constantneurofibrillary changes in the neocortex in progressive supranuclear palsy. Basicdifferences with Alzheimer's disease and aging. Neurosci. Lett. 119, 182–186.He, J., Usui, I., Ishizuka, K., Kanatani, Y., Hiratani, K., Iwata, M., Bukhari, A., Haruta, T.,Sasaoka, T., Kobayashi, M., 2006. Interleukin-1alpha inhibits insulin signalingwith phosphorylating insulin receptor substrate-1 on serine residues in 3 T3–L1adipocytes. Mol. Endocrinol. 20, 114–124.Holmes, C., Cunningham, C., Zotova, E., Wooldford, J., Dean, C., Kerr, S., Culliford, D., Perry,V.H., 2009. Systemic inflammation and disease progression in Alzheimer disease.Neurology 73, 768–774.Hotamisligil, G.S., Shargill, N.S., Spiegelman, B.M., 1993. Adipose expression of tumor necrosisfactor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91.Hotamisligil, G.S., Peraldi, P., Budavari, A., Ellis, R., White, M.F., Spiegelman, B.M., 1996.IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha-and obesity-induced insulin resistance. Science 271, 665–668.Hsiao, H.Y., Chern, Y., 2010. Targeting glial cells to elucidate the pathogenesis ofHuntington's disease. Mol. Neurobiol. 41, 248–255.Hsiao, H.Y., Chen, Y.C., Chen, H.M., Tu, P.H., Chern, Y., 2013. A critical role of astrocyte-mediated nuclear factor-kappaB-dependent inflammation in Huntington's disease.Hum. Mol. Genet. 22, 1826–1842.Hsuchou, H., Kastin, A.J., Pan, W., 2012. Blood-borne metabolic factors in obesity exacer-bate injury-induced gliosis. J. Mol. Neurosci. 47, 267–277.Hu, G., Jousilahti, P., Nissinen, A., Antikainen, R., Kivipelto, M., Tuomilehto, J., 2006. Bodymass index and the risk of Parkinson disease. Neurology 67, 1955–1959.Hu, G., Jousilahti, P., Bidel, S., Antikainen, R., Tuomilehto, J., 2007. Type 2 diabetes and therisk of Parkinson's disease. Diabetes Care 30, 842–847.Huang, T.J., Price, S.A., Chilton, L., Calcutt, N.A., Tomlinson, D.R., Verkhratsky, A.,Fernyhough, P., 2003. Insulin prevents depolarization of the mitochondria innermembrane in sensory neurons of type 1 diabetic rats in the presence of sustained hy-perglycemia. Diabetes 52, 2129–2136.Hubert, H.B., Feinleib, M., McNamara, P.M., Castelli, W.P., 1983. Obesity as an independentrisk factor for cardiovascular disease: a 26-year follow-up of participants in theFramingham Heart Study. Circulation 67, 968–977.Humbert, S., Bryson, E.A., Cordelieres, F.P., Connors, N.C., Datta, S.R., Finkbeiner, S.,Greenberg, M.E., Saudou, F., 2002. The IGF-1/Akt pathway is neuroprotective inHuntington's disease and involves huntingtin phosphorylation by Akt. Dev. Cell 2,831–837.Hurst, S.M., Wilkinson, T.S., McLoughlin, R.M., Jones, S., Horiuchi, S., Yamamoto, N.,Rose-John, S., Fuller, G.M., Topley, N., Jones, S.A., 2001. IL-6 and its soluble receptororchestrate a temporal switch in the pattern of leukocyte recruitment seen duringacute inflammation. Immunity 14, 705–714.Iida, K.T., Shimano, H., Kawakami, Y., Sone, H., Toyoshima, H., Suzuki, S., Asano, T., Okuda,Y., Yamada, N., 2001. Insulin up-regulates tumor necrosis factor-alpha production inmacrophages through an extracellular-regulated kinase-dependent pathway. J. Biol.Chem. 276, 32531–32537.Jafferali, S., Dumont, Y., Sotty, F., Robitaille, Y., Quirion, R., Kar, S., 2000. Insulin-like growthfactor-1 and its receptor in the frontal cortex, hippocampus, and cerebellum ofnormal human and Alzheimer disease brains. Synapse 38, 450–459.Jessen, K.R., 2004. Glial cells. Int. J. Biochem. Cell Biol. 36, 1861–1867.Kaiyala, K.J., Prigeon, R.L., Kahn, S.E., Woods, S.C., Schwartz, M.W., 2000. Obesity inducedby a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes49, 1525–1533.Karabulut, S., Duranyildiz,,D., Tas, F., Gezer, U., Akyuz, F., Serilmex, M., Ozgur, E., Yasasever,C.T., Vatansever, S., Aykan, N.F., 2014. Clinical significance of serum circulatinginsulin-like growth factor-1 (IGF-1) mRNA in hepatocellular carcinoma. Tumor Biol.35, 2729–2739.Kern, P.A., Ranganathan, S., Li, C., Wood, L., Ranganathan, G., 2001a. Adipose tissue tumornecrosis factor and interleukin-6 expression in human obesity and insulin resistance.Am. J. Physiol. Endocrinol. Metab. 280, E745–E751.Kern, W., Peters, A., Fruehwald-Schultes, B., Deininger, E., Born, J., Fehm, H.L., 2001b. Im-proving influence of insulin on cognitive functions in humans. Neuroendocrinology74, 270–280.Klegeris, A., Pelech, S.L., Giasson, B.I., Maguire, J., Zhang, H., McGeer, E.G., McGeer, P.L.,2008. Alpha-synuclein activates stress signaling protein kinases in THP-1 cells andmicroglia. Neurobiol. Aging 29, 739–752.Koga, S., Kojima, A., Kuwabara, S., Yoshiyama, Y., 2014. Immunohistochemical analysis oftau phosphorylation and astroglial activation with enhanced leptin receptor expres-sion in diet-induced obesity mouse hippocampus. Neurosci. Lett. http://dx.doi.org/10.1016/j.neulet.2014.04.028.Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel,R., Bluethmann, H., Kohler, G., 1994. Impaired immune and acute-phase responses ininterleukin-6-deficient mice. Nature 368, 339–342.Kurth, T., Gaziano, J.M., Berger, K., Kase, C.S., Rexrode, K.M., Cook, N.R., Buring, J.E.,Manson, J.E., 2002. Body mass index and the risk of stroke in men. Arch. Intern.Med. 162, 2557–2562.http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0320http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0320http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0320http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0325http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0325http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0325http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0330http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0330http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0335http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0335http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0340http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0340http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0340http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0350http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0350http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0345http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0345http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0355http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0355http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0360http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0360http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0360http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0365http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0365http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0365http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0370http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0370http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0375http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0375http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0375http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0380http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0380http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0380http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0385http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0385http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0385http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0390http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0390http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0390http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0395http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0395http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0400http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0400http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0400http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0400http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0405http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0405http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0405http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0410http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0410http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0415http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0415http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0420http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0420http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0425http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0425http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0430http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0430http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0435http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0435http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0435http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0440http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0440http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0445http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0445http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0445http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0450http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0450http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0455http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0455http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0460http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0465http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0465http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0465http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0470http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0470http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0475http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0475http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0475http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0480http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0480http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0485http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0485http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0485http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0490http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0490http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0490http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0495http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0495http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0505http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0505http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0500http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0500http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0515http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0515http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0510http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0510http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0510http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0520http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0520http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0530http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0530http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0525http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0525http://refhub.elsevier.com/S0165-5728(14)00175-1/rf9000http://refhub.elsevier.com/S0165-5728(14)00175-1/rf9000http://refhub.elsevier.com/S0165-5728(14)00175-1/rf9000http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0535http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0535http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0535http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0540http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0540http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0540http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0545http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0545http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0545,http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0550http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0550http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0550http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0555http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0555http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0555http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1195http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1200http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0565http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0565http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0565http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0570http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0570http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0570http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0575http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0575http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0575http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0580http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0580http://dx.doi.org/10.1016/j.neulet.2014.04.028http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0590http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0590http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0595http://refhub.elsevier.com/S0165-5728(14)00175-1/rf059519L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Kwon, H., Pessin, J.E., 2013. Adipokines mediate inflammation and insulin resistance.Front. Endocrinol. 4, 71.Lacau-Mengido, I.M., Mejia, M.E., Diaz-Torga, G.S., Gonzalez Iglesias, A., Formia, N.,Libertun, C., Becu-Villalobos, D., 2000. Endocrine studies in ivermectin- treatedheifers from birth to puberty. J. Anim. Sci. 78, 817–824.Lalic, N.M., Maric, J., Svetel, M., Jotic, A., Stefanova, E., Lalic, K., Dragasevic, N., Milicic, T.,Lukic, L., Kostic, V.S., 2008. Glucose homeostasis in Huntington disease: abnormalitiesin insulin sensitivity and early-phase insulin secretion. Arch. Neurol. 65, 476–480.Landi, S., Ciucci, F., Maffei, L., Berardi, N., Cenni, M.C., 2009. Setting the pace for retinal de-velopment: environmental enrichment acts through insulin-like growth factor I andbrain-derived neurotrophic factor. J. Neurosci. 29, 10809–10819.Laroux, F.S., 2004. Mechanisms of inflammation: the good, the bad and the ugly. Front.Biosci. 9, 3156–3162.Laskin, D.L., 2009. Macrophages and inflammatory mediators in chemical toxicity: a battleof forces. Chem. Res. Toxicol. 22, 1376–1385.Lawrence, M.C., McKern, N.M., Ward, C.W., 2007. Insulin receptor structure and its impli-cations for the IGF-1 receptor. Curr. Opin. Struct. Biol. 17, 699–705.Levin, B.E., 2000. Glucose-regulated dopamine release from substantia nigra neurons.Brain Res. 874, 158–164.Li, L., Holscher, C., 2007. Common pathological processes in Alzheimer disease and type 2diabetes: a review. Brain Res. Rev. 56, 384–402.Lin, S., Fan, L.W., Rhodes, P.G., Cai, Z., 2009. Intranasal administration of IGF-1 attenuateshypoxic–ischemic brain injury in neonatal rats. Exp. Neurol. 217, 361–370.Little, J.P., Madeira, J.M., Klegeris, A., 2012. The saturated fatty acid palmitate induceshuman monocytic cell toxicity toward neuronal cells: exploring a possible link be-tween obesity-related metabolic impairments and neuroinflammation. J. AlzheimersDis. 30 (Suppl. 2), S179–S183.Liu, X., Linnington, C., Webster, H. de F., Lassmann, S., Yao, D.-L., Hudson, L.D., Wekerle, H.,Kreutzberg, G.W., 1997. Insulin-like growth factor-1 treatment reduces immune cellresponses in acute non-demyelinative experimental autoimmune encephaolmyelitis.J. Neurosci. Res. 47, 531–538.Liu, T., Gao, Y.J., Ji, R.R., 2012. Emerging role of toll-like receptors in the control of pain anditch. Neurosci. Bull. 28, 131–144.Lopresti, A.L., Drummond, P.D., 2013. Obesity and psychiatric disorders: commonalities indysregulated biological pathways and their implications for treatment. Prog.Neuropsychopharmacol. Biol. Psychiatry 45C, 92–99.Lull, M.E., Block, M.L., 2010. Microglial activation and chronic neurodegeneration.Neurotherapeutics 7, 354–365.Lundh, S.H., Soylu, R., Petersen, A., 2012. Expression of mutant huntingtin in leptinreceptor-expressing neurons does not control the metabolic and psychiatric pheno-type of the BACDH mouse. PLoS One 7, e51168.Ma, X.H., Zhong, P., Gu, Z., Feng, J., Yan, Z., 2003. Muscarinic potentiation of GABA(A) re-ceptor currents is gated by insulin signaling in the prefrontal cortex. J. Neurosci. 23,1159–1168.Magnus, T., Chan, A., Grauer, O., Toyka, K.V., Gold, R., 2001. Microglial phagocytosis of ap-optotic inflammatory T cells leads to down-regulation of microglial immune activa-tion. J. Immunol. 167, 5004–5010.Mahlknecht, P., Poewe,W., 2013. Is there a need to redefine Parkinson's disease? J. NeuralTransm. 120 (Suppl. 1), S9–S17.Mallea-Gil, M.S., Ballarino, M.C., Spiraquis, A., Iriarte, M., Kura, M., Gimenez, S., Oneto, A.,Guitelman, M., Machado, R., Miguel, C.M., 2012. IGF-1 levels in different stages ofliver steatosis and its association with metabolic syndrome. Acta Gastroenterol.Latinoam. 42, 20–26.Mandrekar-Colucci, S., Landreth, G.E., 2010. Microglia and inflammation in Alzheimer'sdisease. CNS Neurol. Disord. Drug Targets 9, 156–167.Marcovecchio, M.L., Chiarelli, F., 2013. Obesity and growth during childhood and puberty.World Rev. Nutr. Diet. 106, 135–141.Marder, K., Zhao, H., Eberly, S., Tanner, C.M., Oakes, D., Shoulson, I., 2009. Dietary intake inadults at risk for Huntington disease: analysis of PHAROS research participants. Neu-rology 73, 385–392.Marder, K., Gu, Y., Eberly, S., Tanner, C.M., Scarmeas, N., Oakes, D., Shoulson, I., 2013.Relationship of Mediterranean diet and caloric intake to phenoconversion inHuntington disease. JAMA Neurol. 70, 1382–1388.Marques, O., Outeiro, T.F., 2012. Alpha-synuclein: from secretion to dysfunction anddeath. Cell Death Dis. 3, e350.Marvin, V., Montero-Julian, F.A., Gres, S., Boulay, V., Bongrand, P., Farnarier, C., Kaplanski,G., 2001. The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as anintermediate between acute and chronic inflammation: an experimental model in-volving thrombin. J. Immunol. 167, 3435–3442.Mastick, C.C., Brady, M.J., Printen, J.A., Ribon, V., Saltiel, A.R., 1998. Spatial determinants ofspecificity in insulin action. Mol. Cell. Biochem. 182, 65–71.Mathis, D., 2013. Immunological goings-on in visceral adipose tissue. Cell Metab. 17,851–859.McMorris, F.A., Smith, T.M., DeSalvo, S., Furlanetto, R.W., 1986. Insulin-like growth factor1/somatomedin C: a potent inducer of oligodendrocyte development. Neurobiology83, 822–826.Meijer, K., de Vries, M., Al-Lahham, S., Bruinenberg, M., Weening, D., Dijkstra, M.,Kloosterhuis, N., van der Leij, R.J., van der Want, H., Kroesen, B.J., Vonk, R., Rezaee,F., 2011. Human primary adipocytes exhibit immune cell function: adipocytesprime inflammation independent of macrophages. PLoS One 6, e17154.Milanski, M., Degasperi, G., Coope, A., Morari, J., Denis, R., Dintra, D.E., Tsukumo, D.M.L.,Anhe, G., Amaral, M.E., Takahashi, H.K., Curi, R., Oliveira, H.C., Carvalheira, J.B.C.,Bordin, S., Saad, M.J., Velloso, L.A., 2009. Saturated fatty acids produce an inflam-matory response predominantly through the activation of TLR4 signaling in thehypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29,359–370.Mitschelen, M., Yan, H., Farley, J.A., Warrington, J.P., Han, S., Herenu, C.B., Csiszar, A.,Ungvari, Z., Bailey-Downs, L.C., Bass, C.E., Sonntag, E., 2011. Long-term deficiencyof circulating and hippocampal insulin-like growth factor 1 induces depressivebehavior in adult mice: a potential model of geriatric depression. Neuroscience185, 50–60.Moloney, A.M., Griffin, R.J., Timmons, S., O'Connor, R., Ravid, R., O'Neill, C., 2010. Defects in,IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possibleresistance to IGF-1 and insulin signalling. Neurobiol. Aging 31, 224–243.Moroo, I., Yamada, T., Makino, H., Tooyama, I., McGeer, P.L., McGeer, E.G., Hirayama, K.,1994. Loss of insulin receptor immunoreactivity from the substantia nigra parscompacta neurons in Parkinson's disease. Acta Neuropathol. 87, 343–348.Morris, J.K., Bomhoff, G.L., Stanford, J.A., Geiger, P.C., 2010. Neurodegeneration in an ani-mal model of Parkinson's disease is exacerbated by a high-fat diet. Am. J. Physiol.Regul. Integr. Comp. Physiol. 299, R1082–R1090.Morris, J.K., Bomhoff, G.L., Gorres, B.K., Davis, V.A., Kim, J., Lee, P.P., Brooks,W.M., Gerhardt,G.A., Geiger, P.C., Stanford, J.A., 2011. Insulin resistance impairs nigrostriatal dopa-mine function. Exp. Neurol. 231, 171–180.Mozell, R.L., McMorris, F.A., 1991. Insulin-like growth factor 1 stimulates oligodenrocytedevelopment and myelination in rat brain aggregate cultures. J. Neurosci. Res. 30,382–390.Naugler, W.E., Karin, M., 2008. The wolf in sheep's clothing: the role of interleukin- 6 inimmunity, inflammation and cancer. Trends Mol. Med. 14, 109–119.Nemoto, T., Yanagita, T., Kanai, T., Wada, A., 2009. Drug development targeting the glyco-gen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: therole of GSK-3beta in themaintenance of steady-state levels of insulin receptor signal-ing molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells. J. Pharmacol.Sci. 109, 157–161.Nomura, F., Kawai, T., Nakanishi, K., Akira, S., 2000. Nf-kappaB activation throughIKK-i-dependent I-TRAF/TANK phosphorylation. Genes Cells 5, 191–202.Nov, O., Shapiro, H., Ovadia, H., Tarnovscki, T., Dvir, I., Shemesh, E., Kovsan, J., Shelef, I.,Carmi, Y., Voronov, E., Apte, R.N., Lewis, E., Haim, Y., Konrad, D., Bashan, N., Rudich,A., 2013. Interleukin-1beta regulates fat-liver crosstalk in obesity by auto-paracrinemodulation of adipose tissue inflammation and expandability. PLoS One 8, e53626.Olli, K., Lahtinen, S., Rautonen, N., Tiihonen, K., 2013. Betaine reduces the expression of in-flammatory adipokines caused by hypoxia in human adipocytes. Br. J. Nutr. 109,43–49.Orre, M., Kamphuis, W., Dooves, S., Kooijman, L., Chan, E.T., Kirk, C.J., Dimayuga Smith, V.,Koot, S., Mamber, C., Jansen, A.H., Ovaa, H., Hol, E.M., 2013. Reactive glia show in-creased immunoproteasome activity in Alzheimer's disease. Brain 136, 1415–1431.Pais, T.F., Figueiredo, C., Peixoto, R., Braz, M.H., Chatterjee, S., 2008. Necrotic neurons en-hance microglial neurotoxicity through induction of glutaminase by a MYD88-dependent pathway. J. Neuroinflammation 5, 43.Palacios, N., Gao, X., McCullough, M.L., Jacobs, E.J., Patel, A.V., Mayo, T., Schwarzschild, M.A.,Ascherio, A., 2011. Obesity, diabetes, and risk of Parkinson's disease. Mov. Disord. 26,2253–2259.Park, H.K., Ahima, R.S., 2013. Resistin in rodents and humans. Diabetes Metab. J. 37,404–414.Paslakis, G., Blum,W.F., Deuschle, M., 2012. Intranasal insulin-like growth factor 1 (IGF-1)as a plausible future treatment of depression. Med. Hypotheses 79, 222–225.Pellecchia, M.T., Santangelo, G., Picillo, M., Pivonello, R., Longo, K., Pivonello, C., Vitale, C.,Amboni, M., De Rosa, A., Moccia, M., Erro, R., De Michele, G., Santoro, L., Colao, A.,Barone, P., 2014. Insulin-like growth factor-1 predicts cognitive functions at 2-yearfollow-up in early, drug-naive Parkinson's disease. Eur. J. Neurol. 21, 802–807.Pitt, J., Thorner, M., Brautigan, D., Larner, J., Klein, W.L., 2013. Protection against thesynaptic targeting and toxicity of Alzheimer's-associated Abeta oligomers by insulinmimetic chiro-inositols. FASEB J. 27, 199–207.Podoll, K., Caspary, P., Lange, H.W., Noth, J., 1988. Language functions in Huntington'sdisease. Brain 111, 1475–1503.Podolsky, S., Leopold, N.A., 1977. Abnormal glucose tolerance and arginine tolerance testsin Huntington's disease. Gerontology 23, 55–63.Polonsky, K.S., Given, B.D., Van Cauter, E., 1988. Twenty-four-hour profiles and pul-satile patterns of insulin secretion in normal and obese subjects. J. Clin. Invest.81, 442–448.Prodam, F., Filigheddu, N., 2014. Ghrelin gene products in acute and chronic inflamma-tion. Arch. Immunol. Ther. Exp. http://dx.doi.org/10.1007/s00005-014-0287-9.Puglielli, L., 2008. Aging of the brain, neurotrophin signaling, and Alzheimer's disease: isIGF1-R the common culprit? Neurobiol. Aging 29, 795–811.Purdon, S.E., Mohr, E., Ilivitsky, V., Jones, B.D., 1994. Huntington's disease: pathogenesis,diagnosis and treatment. J. Psychiatry Neurosci. 19, 359–367.Qin, L., Liu, Y., Hong, J.S., Crews, F.T., 2013. NADPH oxidase and aging drive microglial ac-tivation, oxidative stress, and dopaminergic neurodegeneration following systemicLPS administration. Glia 61, 855–868.Rangone, H., Poizat, G., Troncoso, J., Ross, C.A., MacDonald, M.E., Saudou, F., Humbert, S.,2004. The serum- and glucocorticoid-induced kinase SKG inhibits mutanthuntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur. J.Neurosci. 19, 273–279.Rollero, A., Murialdo, G., Fonzi, S., Garrone, S., Gianelli, M.V., Gazzerro, E., Barreca, A.,Polleri, A., 1998. Relationship between cognitive function, growth hormone andinsulin-like growth factor 1 plasma levels in aged subjects. Neuropsychobiology 38,73–79.Rothlind, J.C., Bylsma, F.W., Peyser, C., Folstein, S.E., Brandt, J., 1993. Cognitive and motorcorrelates of everyday functioning in early Huntington's disease. J. Nerv. Ment. Dis.181, 194–199.Rubin, L.L., Hall, D.E., Porter, S., Barbu, K., Cannon, C., Horner, H.C., Janatpour, M., Liaw,C.W., Manning, K., Morales, J., et al., 1991. A cell culture model of the blood–brainbarrier. J. Cell Biol. 115, 1725–1735.http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0600http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0600http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0605http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0605http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0610http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0610http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0615http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0615http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0615http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0620http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0620http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0625http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0625http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0630http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0630http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0635http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0635http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0640http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0640http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0645http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0645http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0650http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0650http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0650http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0650http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1205http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1205http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1205http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0655http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0655http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0665http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0665http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0665http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0670http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0670http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0675http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0675http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0675http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0680,http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0680http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0680http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0685http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0685http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0685http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0690http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0690http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0695http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0695http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0695http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0700http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0700http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0705http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0705http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0710http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0710http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0710http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0715http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0715http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0720http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0720http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0725http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0725http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0725http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0730http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0730http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0735http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0735http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0740http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0740http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0740http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0745http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0745http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0750http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0750http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0750http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0750http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0755http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0755http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0755http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0755http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0760http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0760http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0760http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0765http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0765http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0775http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0775http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0775http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0770http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0770http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0780http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0780http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0780http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0785http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0785http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0790http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0790http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0790http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0790http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0790http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0795http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0795http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0800http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0800http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0805http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0805http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0805http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0810http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0810http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0815http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0815http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0815http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0820http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0820http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0830http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0830http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0825http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0825http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0835http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0835http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0840http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0840http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0840http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0845http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0845http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0850http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0850http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0855http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0855http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0855http://dx.doi.org/10.1007/s00005-014-0287-9http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0865http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0865http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0870http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0870http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0875http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0875http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0875http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0880http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0880http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0880http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0885http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0885http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0885http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0890http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0890http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0890http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0895http://refhub.elsevier.com/S0165-5728(14)00175-1/rf089520 L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Ruiz-Nunez, B., Pruimboom, L., Dijck-Brouwer, D.A., Muskiet, F.A., 2013. Lifestyle and nu-tritional imbalances associated with western diseases: causes and consequences ofchronic systemic low-grade inflammation in an evolutionary context. J. Nutr.Biochem. 24, 1183–1201.Russell-Jones, D.L., Rates, A.T., Umpleby, A.M., Hennessy, T.R., Bowes, S.B., Hopkins, K.D.,Jackson, N., Kelly, J., Shonjaee-Moradie, F., Jones, R.H., Sonksen, P.H., 1995. A compar-ison of the effects of IGF-1 and insulin on glucosemetabolism, fat metabolism and thecardiovascular system in normal human volunteers. Eur. J. Clin. Investig. 25, 403–411.Sahan, M., Sebe, A., Acikalin, A., Akpinar, O., Koc, F., Ay, M.O., Gulen, M., Topal, M., Satar, S.,2013. Acute-phase reactants and cytokines in ischemic stroke: do they have any rela-tionship with short-term mortality? Eur. Rev. Med. Pharmacol. Sci. 17, 2773–2777.Salminen, A., Ojala, J., Kauppinen, A., Kaarniranta, K., Suuronen, T., 2009. Inflammation inAlzheimer's disease: amyloid-beta oligomers trigger innate immunity defence viapattern recognition receptors. Prog. Neurobiol. 87, 181–194.Santiago, J.A., Potashkin, J.A., 2013. Shared dysregulated pathways lead to Parkinson's dis-ease and diabetes. Trends Mol. Med. 19, 176–186.Sathe, K., Maetzler, W., Lang, J.D., Mounsey, R.B., Fleckenstein, C., Martin, H.L., Schulte, C.,Mustafa, S., Synofzik, M., Vukovic, Z., Itohara, S., Berg, D., Teismann, P., 2012. S100B isincreased in Parkinson's disease and ablation protects against MPTP-induced toxicitythrough the RAGE and TNF-alpha pathway. Brain 135, 3336–3347.Scherer, P.E., William, S., Fogliano, M., Baldini, G., Lodish, H.F., 1995. A novel serum proteinsimilar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749.Schulingkamp, R.J., Pagano, T.C.,,Hung, D., Raffa, R.B., 2000. Insulin receptors and insulinaction in the brain: review and clinical implications. Neurosci. Biobehav. Rev. 24,855–872.Shomaker, L.B., Tanofsky-Kraff, M., Young-Hyman, D., Han, J.C., Yanoff, L.B., Brady, S.M.,Yanovski, S.Z., Yanovski, J.A., 2010. Psychological symptoms and insulin sensitivityin adolescents. Pediatr. Diabetes 11, 417–423.Simard, A.R., Soulet, D., Gowing, G., Julien, J.P., Rivest, S., 2006. Bone marrow- derivedmicroglia play a critical role in restricting senile plaque formation in Alzheimer'sdisease. Neuron 49, 489–502.Simons, P.J., van den Pangaart, P.S., Aerts, J.M., Boon, L., 2007. Pro-inflammatorydelipidizing cytokines reduce adiponectin secretion from human adipocytes withoutaffecting adiponectin oligomerization. J. Endocrinol. 192, 289–299.Smith, J.A., Das, A., Ray, S.K., Banik, N.L., 2012. Role of pro-inflammatory cytokinesreleased from microglia in neurodegenerative diseases. Brain Res. Bull. 87, 10–20.Soczynska, J.K., Kennedy, S.H., Woldeyohannes, H.O., Liauw, S.S., Alsuwaidan, M., Yim, C.Y.,McIntyre, R.S., 2011. Mood disorders and obesity: understanding inflammation as apathophysiological nexus. NeuroMolecular Med. 13, 93–116.Solas, M., Aisa, B., Tordera, R.M., Mugueta, M.C., Ramirez, M.J., 2013. Stress contributes tothe development of central insulin resistance during aging: implications forAlzheimer's disease. Biochim. Biophys. Acta 1832, 2332–2339.Solinas, G., Karin, M., 2010. JNK1 and IKKbeta: molecular links between obesity andmetabolic dysfunction. FASEB J. 24, 2596–2611.Soulet, D., Cicchetti, F., 2011. The role of immunity in Huntington's disease. Mol. Psychiatry16, 889–902.Speed, N.K., Matthies, H.J., Kennedy, J.P., Vaughan, R.A., Javitch, J.A., Russo, S.J., Lindsley,C.W., Niswender, K., Galli, A., 2010. Akt-dependent and isoform-specific regulation ofdopamine transporter cell surface expression. Chem. Neurosci. 1, 476–481.Spranger, J., Verma, S., Gohring, I., Bobbert, T., Seifert, J., Sindler, A.L., Pfeiffer, A., Hileman,S.M., Tschop, M., Banks, W.A., 2006. Adiponectin does not cross the blood-brain bar-rier but modifies cytokine expression of brain endothelial cells. Diabetes 55, 141–147.Stein, L.J., Dorsa, D.M., Baskin, D.G., Figlewicz, D.P., Porte Jr., D., Woods, S.C., 1987. Reducedeffect of experimental peripheral hyperinsulinemia to elevate cerebrospinal fluidinsulin concentrations of obese Zucker rats. Endocrinology 121, 1611–1615.Stenlof, K., Wernstedt, I., Fjallman, T., Wallenius, V., Wallenius, K., Jansson, J.O., 2003.Interleukin-6 levels in the central nervous system are negatively correlated with fatmass in overweight/obese subjects. J. Clin. Endocrinol. Metab. 88, 4379–4383.Stienstra, R., Tack, C.J., Kanneganti, T.D., Joosten, L.A., Netea, M.G., 2012. Theinflammasome puts obesity in the danger zone. Cell Metab. 15, 10–18.Strack, V., Hennige, A.M., Krutzfeldt, J., Bossenmaier, B., Klein, H.H., Kellerer, M., Lammers,R., Haring, H.U., 2000. Serine residues 994 and 1023/25 are important for insulin re-ceptor kinase inhibition by protein kinase C isoforms beta2 and theta. Diabetologia43, 443–449.Strieter, R.M., Kasahara, K., Allen, R., Showell, H.J., Standiford, T.J., Kunkel, S.L., 1990.Human neutrophils exhibit disparate chemotactic factor gene expression. Biochem.Biophys. Res. Commun. 173, 725–730.Suganami, T., Nishida, J., Ogawa, Y., 2005. A paracrine loop between adipocytes andmacrophages aggravates inflammatory changes: role of free fatty acids and tumornecrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 25, 2062–2068.Sun, Y.X., Minthon, L., Wallmark, A., Warkentin, S., Blennow, K., Janciauskiene, S., 2003.Inflammatory markers in matched plasma and cerebrospinal fluid from patientswith Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 16, 136–144.Takahashi, M., Yamada, T., Tooyama, I., Moroo, I., Kimura, H., Yamamoto, T., Okada, H.,1996. Insulin receptor mRNA in the substantia nigra in Parkinson's disease. Neurosci.Lett. 204, 201–204.Talbot, K., Wang, H.Y., Kazi, H., Han, L.Y., Bakshi, K.P., Stucky, A., Fuino, R.L., Kawaguchi,K.R., Samoyedny, A.J., Wilson, R.S., Arvanitakis, Z., Schneider, J.A., Wolf, B.A., Bennett,D.A., Trojanowski, J.Q., Arnold, S.E., 2012. Demonstrated brain insulin resistance inAlzheimer's disease patients is associated with IGF- 1 resistance, IRS-1 dysregulation,and cognitive decline. J. Clin. Invest. 122, 1316–1338.Tambuyzer, B.R., Ponsaerts, P., Nouwen, E.J., 2009. Microglia: gatekeepers of centralnervous system immunology. J. Leukoc. Biol. 85, 352–370.Timonen, M., Laakso, M., Jokelainen, J., Rajala, U., Meyer-Rochow, V.B., Keinanen-Kiukaanniemi, S., 2005. Insulin resistance and depression: cross sectional study. Br.Med. J. 330, 17–18.Trager, U., Tabrizi, S.J., 2013. Peripheral inflammation in neurodegeneration. J. Mol. Med.91, 673–681.Trejo, J.L., Carro, E., Garcia-Galloway, E., Torres-Aleman, I., 2004. Role of insulin-likegrowth factor I signaling in neurodegenerative diseases. J. Mol. Med. 82, 156–162.Troncoso, R., Vicencio, J.M., Parra, V., Nemchenko, A., Kawashima, Y., Del Campo, A., Toro,B., Battiprolu, P.K., Aranguiz, P., Chiong, M., Yakar, S., Gillette, T.G., Hill, J.A., Abel, E.D.,Leroith, D., Lavandero, S., 2012. Energy-preserving effects of IGF- 1 antagonizestarvation-induced cardiac autophagy. Cardiovasc. Res. 93, 320–329.Trumper, K., Trumper, A., Trusheim, H., Arnold, R., Goke, B., Horsch, D., 2000. Integrativemitogenic role of protein kinase B/Akt in beta-cells. Ann. N. Y. Acad. Sci. 921,242–250.Tyagi, E., Fiorelli, T., Norden, M., Padmanabhan, J., 2013. Alpha 1-antichymotrypsin, an in-flammatory protein overexpressed in the brains of patients with Alzheimer's disease,induces tau hyperphosphorylation through C-Jun N- terminal kinase activation. Int. J.Alzheimers Dis. 2013, 606083.Urso, B., Cope, D.L., Kalloo-Hosein, H.E., Hayward, A.C., Whitehead, J.P., O'Rahilly, S., Siddle,K., 1999. Differences in signaling properties of the cytoplasmic domains of the insulinreceptor and insulin-like growth factor receptor in 3 T3-L1 adipocytes. J. Biol. Chem.274, 30864–30873.Uysal, K.T., Wiesbrock, S.M., Marino, M.W., Hotamisligil, G.S., 1997. Protection fromobesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389,610–614.Vagelatos, N.T., Eslick, G.D., 2013. Type 2 diabetes as a risk factor for Alzheimer's disease:the confounders, interactions, and neuropathology associated with this relationship.Epidemiol. Rev. 35, 152–160.Venkatasubramanian, G., Chittiprol, S., Neelakantachar, N., Naveen, M.N., Thirhall, J.,Gangadhar, B.N., Shetty, K.T., 2007. Insulin and insulin-like growth factor-1 abnor-malities in antipsychotic-naïve schizophrenia. Am. J. Psychiatry 164, 1557–1560.Wagle, S.R., Ingebretsen Jr., W.R., Sampson, L., 1975. Studies on gluconeogenesis, proteinsynthesis and cyclic AMP levels in isolated hepatocytes from alloxan diabetic rats.Diabetologia 11, 411–417.Waldstein, S.R., Katzel, L.I., 2006. Interactive relations of central versus total obesity andblood pressure to cognitive function. Int. J. Obes. 30, 201–207.Wan, Q., Xiong, Z.G., Man, H.Y., Ackerley, C.A., Braunton, J., Lu, W.Y., Becker, L.E.,MacDonald, J.F., Wang, Y.T., 1997. Recruitment of functional GABA(A) receptors topostsynaptic domains by insulin. Nature 388, 686–690.Wang, G.J., Volkow, N.D., Logan, J., Pappas, N.R., Wong, C.T., Zhu, W., Netusil, N., Fowler, J.S.,2001. Brain dopamine and obesity. Lancet 357, 354–357.Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante Jr., A.W., 2003.Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest.112, 1796–1808.Werner, H., Raizada, M.K., Mudd, L.M., Foyt, H.L., Simpson, I.A., Roberts Jr., C.T., LeRoith, D.,1989. Regulation of rat brain/HepG2 glucose transporter gene expression by insulinand insulin-like growth factor-I in primary cultures of neuronal and glial cells.,Endo-crinology 125, 314–320.Wexler, N.S., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Shackell, E., Marder, K.,Penchaszadeh, G., Roberts, S.A., Gayan, J., Brocklebank, D., Cherny, S.S., Cardon, L.R.,Gray, J., Dlouhy, S.R., Wiktorski, S., Hodes, M.E., Conneally, P.M., Penney, J.B.,Gusella, J., Cha, J.H., Irizarry, M., Rosas, D., Hersch, S., Hollingsworth, Z., MacDonald,M., Young, A.B., Andresen, J.M., Housman, D.E., De Young, M.M., Bonilla, E., Stillings,T., Negrette, A., Snodgrass, S.R., Martinez-Jaurrieta, M.D., Ramos-Arroyo, M.A.,Bickham, J., Ramos, J.S., Marshall, F., Shoulson, I., Rey, G.J., Feigin, A., Arnheim, N.,Acevedo-Cruz, A., Acosta, L., Alvir, J., Fischbeck, K., Thompson, L.M., Young, A., Dure,L., O'Brien, C.J., Paulsen, J., Brickman, A., Krch, D., Peery, S., Hogarth, P., Higgins Jr.,D.S., Landwehrmeyer, B., 2004. Venezuelan kindreds reveal that genetic and environ-mental factors modulate Huntington's disease age of onset. Proc. Natl. Acad. Sci. U. S. A.101, 3498–3503.Whitmer, R.A., Gunderson, E.P., Quesenberry Jr., C.P., Zhou, J., Yaffe, K., 2007. Body massindex inmidlife and risk of Alzheimer disease and vascular dementia. Curr. AlzheimerRes. 4, 103–109.Wilczak, N., De Keyser, J., 1997. Insulin-like growth factor-1 receptors in normalappearing white matter and chronic plaques in multiple sclerosis. Brain Res. 772,243–246.Williams, J.M., Owens, W.A., Turner, G.H., Saunders, C., Dipace, C., Blakely, R.D., France, C.P.,Gore, J.C., Daws, L.C., Avison, M.J., Gali, A., 2010. Hypoinsulinemia regulatesamphetamine-induces reverse transport of dopamine. PLoS Biol. 5, e274.World Health Organization, Alzheimer's Disease International, 2012. Dementia: a publichealth priority. http://www.who.int/mental_health/publications/dementia_report_2012/en/.Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., Sole, J., Nichols, A., Ross, J.S.,Tartaglia, L.A., Chen, H., 2003. Chronic inflammation in fat plays a crucial role in thedevelopment of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830.Yamamoto, A., Cremona, M.L., Rothman, J.E., 2006. Autophagy-mediated clearance ofhuntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172,719–731.Yamash*ta, I., Katamine, S., Moriuchi, R., Nakamura, Y., Miyamoto, T., Eguchi, K., Nagataki,S., 1994. Transactivation of the human interleukin-6 gene by human T-lymphotropicvirus type 1 Tax protein. Blood 84, 1573–1578.Yoon, S., Seger, R., 2006. The extracellular signal-regulated kinase: multiple substratesregulate diverse cellular functions. Growth Factors 24, 21–44.Yu, D., Watanabe, H., Shibuya, H., Miura, M., 2003. Redundancy of radioresistant signalingpathways originating from insulin-like growth factor 1 receptor. J. Biol. Chem. 278,6702–6709.Zapf, A., Hsu, D., Olefsky, J.M., 1994. Comparison of the intracellular itineraries of insulin-like growth factor-1 and insulin and their receptors in Rat-1 fibroblasts. Endocrinol-ogy 134, 2445–2452.http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0900http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0900http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0900http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0900http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0905http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0905http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0905http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0910http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0910http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0915http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0915http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0915http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0920http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0920http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0925http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0925http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0925http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0930http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0930http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0935http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0935http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0935http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0940http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0940http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0945http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0945http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0945http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0950http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0950http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0950http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0955http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0955http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0960http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0960http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0965http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0965http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0965http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0970http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0970http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0975http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0975http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0980http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0980http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0985http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0985http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0990http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0990http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0990http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0995http://refhub.elsevier.com/S0165-5728(14)00175-1/rf0995http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1000http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1000http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1005http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1005http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1005http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1010http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1010http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1015http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1015http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1015http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1020http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1020http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1025http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1025http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1030http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1030http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1030http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1035http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1035http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1040http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1040http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1045http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1045http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1050http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1050http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1055http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1055http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1060http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1065http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1070http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1070http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1070http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1075http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1075http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1075,http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1080http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1085http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1085http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1090http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1090http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1090http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1095http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1095http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1100http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1100http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1105http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1115http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1115http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1120http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1120http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1120http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1210http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1130http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1135http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1135http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1135http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1110http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1110http://www.who.int/mental_health/publications/dementia_report_2012/en/http://www.who.int/mental_health/publications/dementia_report_2012/en/http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1140http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1140http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1145http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1145http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1145http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1150http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1150http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1155http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1160http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1160http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1160http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1165http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1165http://refhub.elsevier.com/S0165-5728(14)00175-1/rf116521L.J. Spielman et al. / Journal of Neuroimmunology 273 (2014) 8–21Zetterstrom, M., Sundgren-Andersson, A.K., Ostlund, P., Bartfai, T., 1998. Delineation of theproinflammatory cytokine cascade in fever induction. Ann. N. Y. Acad. Sci. 856, 48–52.Zhang, W., Wang, T., Pei, Z., Miller, D.S., Wu, X., Block, M.L., Wilson, B., Zhang, W., Zhou, Y.,Hong, J.S., Zhang, J., 2005. Aggregated alpha-synuclein activates microglia: a processleading to disease progression in Parkinson's disease. FASEB J. 19, 533–542.Zhang, L., Dasuri, K., Fernandez-Kim, S.O., Bruce-Keller, A.J., Freeman, L.R., Pepping, J.K.,Beckett, T.L., Murphy, M.P., Keller, J.N., 2013. Prolonged diet induced obesity has min-imal effects towards brain pathology in mouse model of cerebral amyloidangiopathy: implications for studying obesity-brain interactions in mice. Biochim.Biophys. Acta 1832, 1456–1462.http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1170http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1180http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1180http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1175http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1175http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1175http://refhub.elsevier.com/S0165-5728(14)00175-1/rf1175Inflammation and insulin/IGF-�1 resistance as the possible link between obesity and neurodegeneration1. Introduction2. Inflammatory response2.1. Inflammation in the periphery2.2. Chronic inflammation2.3. Neuroinflammation2.4. Glial cell activation in obesity3. Epidemiological evidence linking obesity and neurodegenerative diseases3.1. Epidemiological evidence linking obesity and Alzheimer's disease3.2. Epidemiological evidence linking obesity and Parkinson's disease3.3. Epidemiological evidence linking obesity and Huntington's disease4. Pathophysiological mechanisms of inflammation in adipose tissue5. Pathophysiological mechanisms of insulin/IGF-1 in obesity5.1. Insulin in the periphery5.2. IGF-1 in the periphery5.3. Insulin in the brain5.4. IGF-1 in the brain6. Pathophysiological mechanisms of insulin/IGF-1 signaling in neurodegenerative diseases6.1. Obesity, insulin/IGF-1 resistance and Alzheimer's disease6.2. Obesity, insulin/IGF-1 resistance and Parkinson's disease6.3. Obesity, insulin/IGF-1 resistance and Huntington's disease7. ConclusionsAcknowledgementsReferences