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淘豆网网友近日为您收集整理了关于Endotoxaemia resulting from decreased serotonin tranporter (5-HTT) function A reciprocal risk factor for depression and insulin resistance.pdf的文档，希望对您的工作和学习有所帮助。以下是文档介绍：Behavioural Brain Research 276 (–117Contents lists available at ScienceDirectBehavioural Brain Researchjournal homepage: ate/bbrReviewEndotoxaemia resulting from decreased serotonin tranporter (5-HTT)function: A reciprocal risk factor for depression and insulinresistance?Igor A. Pomytkina, Brandon H. Clineb,c,d, Daniel C. Anthonye, Harry W. Steinbuschf,Klaus-Peter Leschf,g, Tatyana Strekalovaf,h,i,aBuddha Biopharma Oy, Horsemakuja 10, FI-01300 Vantaa, RS, UMR6265, Université de Bourgogne, CSGA, 9E boulevard Jeanne d’Arc, 21000 Dijon, FrancecINRA, UMR1324, Université de Bourgogne, CSGA, 9E boulevard Jeanne d’Arc, 21000 Dijon, FrancedUniversité de Bourgogne, CSGA, 9E boulevard Jeanne d’Arc, 21000 Dijon, FranceeDepartment of Pharmacology, Oxford University, Manseld Road, OX1 3QT Oxford, UKfDepartment of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 40, NL 6229 ER herlandsgDivision of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University ofWuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, GermanyhInstitute of Physiologically pounds RAS, Severnii proesd 1, 142432 Chernogolovka, Moscow region, RussiaiInstitute for Hygiene and Tropical Medicine, New University of Lisbon, Rua da Junqueira, 96,
Lisboa, Portugalh i g h l i g h t s A hypothesis: low 5-HTT function results in increased intestinal permeability. This may result from elevated 5-HT3 receptor activity and lead to endotoxemia. Subsequent inammation can trigger factors of both depression and diabetes. Antidepressants and “cafeteria-type diet” might aggravate indicated effects. Low 5-HTT activity can be reciprocal risk factor for diabetes and depression.a r t i c l e i n f oArticle history:Received 22 February 2014Received in revised form 25 April epted 28 April 2014Available online 9 May 2014Keywords:DepressionInsulin resistanceEndotoxemiaInammation5-HTAntidepressanta b s t r a c tDepression and diabetes are serious diseases with an increasing global prevalence. Intriguingly, recentmeta-analyses have highlighted an asymmetrical relationship between the two conditions as depressedpatients were found to display a higher risk of developing type 2 diabetes than those individuals suffer-ing from diabetes are to e depressed. Based on recent ndings, we favor a hypothesis where bydecreased peripheral serotonin (5-HT) transporter (5-HTT) function is a reciprocal risk factor for the co-morbidity of depression and diabetes, as it can trigger inammatory ic mechanisms of bothconditions. Higher intestinal levels of 5-HT and 5-HT3 receptor stimulation lead to increased intestinalpermeability in 5-HTT decient mice, which is viewed one of the most relevant animal models of depres-sion. We hypothesize that this leakage of bacterial endotoxins can activate both central and peripheralToll-like receptor 4 (TLR4), which inhibits insulin signaling and IRS1/PI3K/Akt and thus, contribute tothe pathogenesis of diabetes and depression that are associated with this pathway. Antidepressant ther-apies, which also suppress intestinal 5-HTT, may have potentiating effects on the association betweendepression and diabetes. It is also of interest that high carbohydrate and fat intake (“cafeteria-type diet”)increases intestinal 5-HT leading to TLR4 activation. Thus, endotoxaemia and inammation owing toincreased intestinal 5-HT may underpin the depression and diabetes association, where the risk of thelatter pathology es particularly preeminent after the onset of depression and not vice versa. Theevidence presented here shows the further investigation into peripheral mechanisms that linked diabetesto depression is clearly warranted. 2014 Published by Elsevier B.V. Corresponding author at: Department of Neuroscience, Maastricht University Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands.Tel.: +00 31 43 38 84 110/+00 31 43 367 1097; fax: +00 31 43 .E-mail address: t.strekalova@maastrichtuniversity.nl (T. Strekalova).http://dx./10.1016/j.bbr./ 2014 Published by Elsevier B.V.112 I.A. Pomytkin et al. / Behavioural Brain Research 276 (–117Contents1. Epidemiology of depression, antidepressant therapies and insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122. Decreased gut 5-HTT function results in endotoxemia, inammation and altered insulin receptor signaling: Potentialmolecular implications in S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123. Dietary factor as mon element of low-grade inammation and endotoxemia during depression and insulin resistance . . . . . . . . . . . . . . . . . 1144. Conclusions and future perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151. Epidemiology of depression, antidepressant therapiesand insulin resistanceA number of epidemiological studies have established a linkbetween insulin resistance and the prevalence of depression.Interestingly, recent meta-analytic studies have identied a sig-nicant positive cross-sectional association between depressionand peripheral insulin resistance in non-diabetic individuals [1–3].Despite heterogeneity in the methods used between the studies,the correlation wa however, no causative rela-tionships between depression and insulin resistance were exploredor speculated about in these analyses [4–9].Depression in patients with diabetes can result from the chronicpsychological and medical conditions associahowever, the occurrence of depression was found to precede theonset of diabetes [10–12], which apart from the behavioral fac-tors and changes in eating habits often panies depression[13,14]. Depression is more than three times mon amongpatients with type-1 diabetes [15,16] and almost twice monamong patients with type-2 diabetes [16–18] for the general popu-lation. Moreover, the severity plications caused by diabeteswas found to be higher among patients orbid depression[19–23]. Interestingly, a bi-directional positive correlation betweendiabetes and depression has been found to be asymmetrical (Fig. 1):patients with depression have an increased risk of ing dia-betic by 60% (95% CI 37–88%) [24], 65% (95% CI 2–166%) [25], and56% (95% CI 37–77%, p & 0.001) [26]; whereas a risk for depressionin diabetic patients is elevated only by 24% (95% CI 9–40%) [27] and25% (95% CI 10–44%, p = 0.001) [28]. Recently, a longitudinal studyin Taiwan has shown a 43%-increased risk of depression in diabeticindividuals (95% CI 16–77%) and a 102%-increased risk of diabetesin depressed patients (95% CI 80–127%) [29].mon medical condition the displays orbiditywith depression i one of the most recentmeta-analysis has discovered a 1.54-fold greater prevalence ofmetabolic syndrome in patients with major depression (95% CI1.27–1.97, p = 0.001) [30]. Recently, it was found that depressedFig. 1. Bi-directional association between diabetes and depression. Subjects with dia-betes have an increased risk for depression over the general population and viceversa.individuals have an increased risk of metabolic syndrome of 52%over the general population (95% CI 20–91%) and patients that arediagnosed with this syndrome have a 49% higher risk to developdepression than others (95% CI 19–89%) [31].On another hand, there is growing evidence suggesting thattreatment with antidepressant drugs from different classes andmechanisms-of-action is associated with an increased risk of dia-betes which might contribute to the increased incidence of insulinresistance in large cohorts of depressed patients [32–39]. One ofthese studies showed that long-term antidepressant medicationwith selective serotonin (5-HT) reuptake inhibitors (SSRIs) or tri-cyclic antidepressants increased the risk for type-2 diabetes inpatients with obesity, while elevated fasting glucose and impairedglucose tolerance was treatable with metformin [32,33]. Moreover,it was reported that a medication history of ≥200 dened dailydoses of conventional antidepressant therapies primarily basedon SSRIs and tricyclics increased the risk of diabetes in patientswith moderate or severe depression by 93% (95% CI 48–151%) and165% (95% CI 31–439%) over the rate found in the general pop-ulation, respectively [37]. Another publication has reported thatan 18-year long study has revealed the incidence of diabetes to be3.1-fold higher among antidepressant users than in non-users (95%CI 1.66–5.78, p & 0.0001) [38]. Notably, these results refer, ratherthan to individual drugs, to the class of antidepressants -bined pharmacotherapies that are most broadly used in clinic andprobably the most representable mon cases of depressivedisorder.Evidence suggest that not only antidepressants, but other drugsthat are widely used as an adjunctive therapy of depression, suchas antipsychotics, anxiolytics, and off-label medications, can affectinsulin resistance, body weight and increase risk of diabetes type2 [39–45]. While the effects of antidepressant drugs of variousclasses and of adjunctive therapies on metabolic measures andbody weight are quite variable among individual patients and,moreover, in some clinical cases (e.g., anorectic symptoms) weightgain is of therapeutic , overall, elevated insulin resistanceseems to represent an important issue with a pharmacotherapy oflarge cohorts of depressed patients [39].In summary, epidemiological studies have established a bi-directional association between depression, on one side, andmedical conditions dened by insulin resistance on the other side(Fig. 1). This relationship appears to be asymmetrical as most stud-ies show that depressed patients are at a considerably higher riskto e diabetic than diabetic individuals are prone to developdepression. As many data suggest, conventional antidepressantmedications of various nature, that includes SSRIs, tryciclics andadjunctive drugs, might be an additional factor which may notablycontribute to the increased risk of diabetes during depression.2. Decreased gut 5-HTT function results in endotoxemia,inammation and altered insulin receptor signaling:Potential molecular implications in SOne of mon features of depression and insulin resis-tance is regarded to be low-grade inammation [46–51]. Elevatedendotoxin levels and increased production of pro-inammatoryI.A. Pomytkin et al. / Behavioural Brain Research 276 (–117 113cytokines in the periphery was suggested to contribute to the devel-opment of both depression and diabetes [46,52,53]. As has beenreviewed recently, peripheral endotoxin triggers depressive-likebehavior in both humans and rodents through elevation of lev-els of pro-inammatory cytokines (e.g., IL-1 and TNF- ) in brainand subsequent modulation of 5-HT neural circuits that drivesbehavioral responses [54]. IL-1 and TNF- stimulate 5-HT re-uptake through an acute catalytic activation of neuronal 5-HTTactivity [55]. Peripheral immune system activation has been shownto increase 5-HT turnover in the prefrontal cortex and to alteremotional behavior [56]. Furthermore, recent studies implicatealtered 5-HT neurotransmission in mechanisms associated with theincreased production of pro-inammatory cytokines which havebeen contributed to the development of both depression and type-2diabetes [46,50]. While aberrant brain 5-HT signaling and inheriteddeciency of 5-HTT in subjects with a short variant of the 5-HTTgene-related polymorphic region (5-HTTLPR) were attributed tothe neurobiology of depression as a major pathogenic factor [57,58],ically dependent decits of 5-HTT function equally hamper5-HT signaling on a systemic level [59–61]. Decreased 5-HTT canevoke pathological changes in the periphery that may affect brainfunction implying an, as of yet, unexplored mechanism linking thepathogenesis of depression and insulin resistance.ically attributed decits of 5-HT impedes its activity inperipheral tissues, including the gut, where 95% of 5-HT is syn-thesized [60,62–66]. Enteric 5-HT is synthesized and stored inenterochromafn cells and released into the lumen, regulatingperistaltic reexes and gastrointestinal motility and acting as anendocrine hormone and growth factor. As in the brain, 5-HT uptakeby 5-HTT is a key mechanism controlling the availability of 5-HT inthe gastrointestinal tract [59,67,68]. Besides the intestine, 5-HTThas been detected in other peripheral tissues, including pancreas,vascular smooth muscle cells, liver, and
thelatter two are considered to be classical targets for insulin action[63,66,69–71].A study in 5-HTT knockout (KO) mice has revealed enhancedintestinal permeability and a leakage of bacterial endotoxin into theblood stream resulting from a reduction of tight-junction proteinsin the gut, which is an important source of circulating endotoxins[72,73]. These effects were shown to be mediated by excessive con-centrations of 5-HT activating the5-HT3 receptor [68,71], a widelydistributed5-HTreceptor in the gut [64]. Interestingly, 5-HT3 recep-tor up regulation in 5-HTT decient mice was earlier reported in anumber of brain regions as well [74]. In line with the above men-tioned ndings, experiments with ob/ob mutant mice showed thatantagonists of the 5-HT3 receptor can prevent endotoxin translo-cation into the portal blood and subsequently reduce inammationin the liver as well as accumulation of fat in these mice [67,75,76].The elevation of circulating endotoxin, referred to as “metabolicendotoxemia”, is considered to be an important pathogenic fea-ture that mon for obesity, insulin resistance, and type-2diabetes [52,53,73,75,77,78]. It was reported that circulating endo-toxin stimulates toll-like receptor 4 (TLR4) in the brain [79] andinduces insulin resistance in ans via the inhibitoryeffect of subsequently activated c-jun N-terminal kinase (JNK) onthe IRS1/PI3K/Akt pathway [51,80].In line with experiments on 5-HTT-decient mice, studies inrhesus monkeys (Macaca mulatta) have demonstrated that thes-variant of the serotonin transporter polymorphism (5HTTLPR)contributes to a risk for metabolic alterations during psychosocialstress, while l/l allele variant is a protective factor [81]. The stressresulted in a signicant raise of fasting serum insulin, a measure ofinsulin resistance, in adult female rhesus monkeys possessing theshort allele variant (l/s or s/s), while a decrease of fasting insulin inmonkeys with the l/l variant. Interestingly at baseline, the monkeyswith the s-variant had lower fasting serum insulin, adiposity meas-Fig. 2. Schematic representation of the likely mechanisms whereby 5-HT signaling inthe intestine may interfere with insulin receptor signaling and glucose metabolismin skeletal muscle and induce neuroinammation. (A) Antidepressant- or 5-HTTLPRpolymorphism-induced increase in 5-HT availability leads to activation of intesti-nal 5-HT3 receptor thereby enhancing intestinal permeability and inducing leakageof bacterial endotoxin (LPS) from gut microbiota into blood. Circulating LPS acti-vates Toll-like receptor 4 (TLR4) and thus c-Jun N-terminal kinase (JNK), which inturn phosphorylates insulin receptor substrate 1 (IRS1) at Ser307, thereby inhib-iting insulin receptor (IR) signaling via IRS1/PI3K/Akt pathway, which is criticalfor glucose disposal. (B) Diabetes or cafeteria-type diet-induced increase in 5-HTavailability leading to enhanced leakage of LPS into blood and subsequent centralneuroinammation evoking depression.ures and reduced 5HT release in response to provocative stimuli parison to their l/l counterparts [81]. Altogether, the animaldata described here allude to a hypothesis that 5HTTLPR poly-morphism in humans might result in similar effects related toendotoxemia, which could contribute to the mechanisms of sus-ceptibility/resilience to depression in s/s/ vs. l/l carriers of this gene.Metabolic endotoxemia might affect not only peripheral, butcentral IRS1/PI3K/Akt regulatory cascades as well, given that circu-lating endotoxin stimulates brain TLR4 receptor and triggers brainIL-1 and TNF- signaling [54,79] that results in a subsequentJNK activation. The latter molecular event leads to the inhibitionof IRS1/PI3K/Akt pathway [82]. A rapidly increasing body of evi-dence suggests that the PI3K/Akt signaling pathway in the braincan regulate molecular mechanisms of depression (Fig. 2). Also,the IRS1/PI3K/Akt pathway as a key mechanism in the regula-tion of glucose metabolism in insulin-sensitive peripheral tissues[80,82] and is also implicated in the general response to extracel-lular stress [83,84] and inammation [83,85,86]. Pro-inammatoryfactors activated by a stimulation of TLR4signaling [85] were shownto suppress this pathway. Antidepressants of distinct classes: e.g.,imipramine and uoxetine, as well as the mood stabilizer lithium[84,85,87–89] were demonstrated to elevate Akt activity. Inter-estingly, the stimulation of 5-HTreceptors leads to the activationof Akt and a subsequent inhibition of the transcriptional factorforkhead box O (FOXO) transcriptional activities [89]. The acti-vation of several key neurotransmitter receptors, a crucial roleof which antidepressant mechanisms are well established, wasshown to potentiate Akt activity, thus mediating these effects. Thiswas found to be the case for the 5-HTreceptors 5-HT1A [90] and5-HT1B [91,92], cannabinoid receptor, subtype 1, (CB1R) [93,94],brain-derived neurotropic factor (BDNF) receptor, TrkB [95–99]and insulin receptor [100,101]. For instance, the binding of BDNFto the TrkB receptor activates PI3K/Akt pathway that leads tothe phosphorylation of the N-terminal serine of glycogen syn-thase kinase-3 beta (GSK3 ) and a decrease of its activity [95,96].These effects were shown to be induced via the inactivation of theabove-mentioned molecules whose levels are positively correlatedwith a depressive-like phenotype, such as GSK3 [87,95,96], JNK[102,103] and FOXO3a [98] by phosphorylation.114 I.A. Pomytkin et al. / Behavioural Brain Research 276 (–117The role of some of these molecular factors in affective disor-ders, including depression, is now well established. For example,for GSK3 -related signaling it was found that GSK3 is increasedand Akt is diminished in the brain of suicide victims who suf-fered from major depression [104]. In support of this notion, ourrecent studies have shown that mice with an individual predis-position to behavioral despair or stress-induced anhedonia haveelevated gene expression and protein levels of GSK3 in the pre-frontal cortex (Strekalova and Markova, in preparation). As it wasmentioned, the activation of TLR4 was found to stimulate JNK [102]that, via a subsequent phosphorylation of the 14-3-3 protein, aregulator for the re-localization of molecules from the nucleus tothe cytoplasm [103], enhances production of FOXO3a which is anewly discovered factor in the pathogenesis of depression [105].FOXO3a is highly expressed
it is known toactivate the genes related to the apoptotic processes and to inhibitglucose metabolism by regulating glucose-6-phosphatase (G6P) anenzyme that convertsglucose-6-phosphate to glucose. Noticeably,mice with ic oblation of FOXO3a are resilient to the induc-tion of learned helplessness [105] and stress effects of forced swimand tail suspension tests [89]. As it was shown by the forced swimtest in mice, the pro-depressant effects of FOXO3a are mediatedby the inactivation of Akt kinase via its phosphorylation result-ing to a subsequent activation of GSK3 [95,96,105]. The FOXO3aoverexpression was found to pany high levels of anxiety-like behavior in mice. Selective stimulation of 5-HT release andblockade of its reuptake by d-fenuramine, or chronic but not acutedosing with imipramine, enhances PI3K/Akt signaling, resulting inthe inactivation of FOXO3a in several brain regions [89,98,99]. Inreturn, stress exposure induces a transient inactivation of Akt anda prolonged activation of FOXO3a and GSK3 in the cerebral cortex[105].Another mechanism of central JNK activation by excessiveconcentrations of 5-HT can be proposed based on the recently iden-tied peripheral regulation of serotonin receptors. 5-HT was shownto activate JNK via a direct stimulation of 5-HT1B/1D, 5-HT2A, and5-HT2B receptors in smooth muscle cells. However, whether thismechanism occurs in the brain, was not investigated and thereforeit is unclear whether it is of relevance for the above-described cellu-lar and molecular mechanisms of depression and insulin resistance[106].3. Dietary factor as mon element of low-gradeinammation and endotoxemia during depression andinsulin resistanceAs many antidepressants promote food intake, and particularlythat of food consisting primarily of fat and carbohydrates [6–9],these altered dietary preferences may additionally contribute toa systemic decrease of 5-HTT functionin depressed patients, asexcessive ingestion of fat or fructose was shown to inhibit 5-HTT and increase extracellular 5-HT in the gut [67,107]. Glucosestimulates 5-HT release from the enterochromafn cells in a dose-dependent manner [59,62,108] which can additionally increaseextracellular 5-HT levels resulting in over-stimulation of intesti-nal 5-HT3 receptors and leakage of endotoxins during depressivestates. Chronic intake of another carbohydrate, fructose, has beenidentied as a risk factor for insulin resistance, obesity, and liversteatosis [8]. Importantly, 5-HTT inactivation in mice causes insulinresistance and hepatic steatosis independent of food intake [38]while chronic glucose intake dramatically increases the effects of5-HTT deciency [60]. Signicantly increased endotoxin levels, inportal plasma of 5-HTT KO mice, was induced via the intake of a30% glucose solution. In mutant mice enriched with decient 5-HTT function, exposure to sweetened water increased intestinalpermeability, TNF- mRNA expression in the liver, and umulation and hepatosteatosis [67].Consumption of a high-saturated fat or a high-carbohydratediet has been shown to elevate circulating endotoxins [77,78].Endotoxin administration to healthy individuals was reported toincrease plasma levels of TNF- , IL-1 , IL-6, IL-10 and cortisol, aswell as elevate the measures of trait and state anxiety evaluatedwith the Sate-Trait-Anxiety Inventory (STAI-S and STAI-T), as wellas induce self-reported worsening of mood [109].We also show that, for nave C57BL6 mice, a three-week expo-sure to a diet enriched with cholesterol (0.2%) results in a 4-5-foldoverexpression of TL4R in a number of brain regions which panied with reduced time spent in anxiety-related areasof dark/light and elevated O-maze apparatuses, and behavioraldespair in the forced swim test (Strekalova and Anthony, in prepa-ration).Importantly, as generalized anxiety and other anxiety-relatedconditions, in many cases, are associated with the 5-HTPLR phe-notype [58,110] and are routinely treated with pharmacotherapiesthat are largely shared with conventional antidepressant therapy[107]; these conditions may likely implicate the above-describedmolecular mechanisms related to the putative phenomenon ofendotoxemia in the brain and periphery, constituting an ic factor of this syndrome. Besides, elevated anxiety iswell documented to change eating behavior and lead to increasedcaloric intake [13] that, again, may implicate the above-ic factors that are characteristic of major depression, inthe etiopathology of anxiety disorder.4. Conclusions and future perspectiveThus, endotoxemia related to decreased intestinal 5-HTsignaling due to 5-HTTLPR polymorphism, conventional antide-pressant pharmacotherapy and “cafeteria-type diet” may underliea reciprocal risk factor for depression and insulin resistance viacentral and peripheral mechanisms of inammation/insulin recep-tor signaling (Fig. 3). Taken together, summarized here literaturefurther suggest the spectrum nature of neuropsychiatric syn-dromes and ic relationship between various disordereddomains, such as symptoms of major depression, diabetes, insulinresistance, anxiety, obesity and pro-inammatory changes thatemphasizes the importance of integrated cross-domain concept asa good empowering approach for translational biological psychia-try [110,111].Given the multiple lines of evidence reviewed here concerningthe consequences of peripheral 5-HTT deciency and its poten-tial role in a central mechanism that involves specically theIRS1/PI3K/Akt pathway, it is of critical relevance to study theseobservations in more detail. Until now, it has not been well inves-tigated whether or not central insulin resistance is linked tothe 5-HTTLPR or ic inactivation of 5-HTT in mice, althoughsome clinical studies have suggested this link [112], it wouldbe of considerable interest to carry out such studies in animalmodels. In particular, diet-induced activation of TL4R was pre-cluded by 5-HT3 receptor antagonist in 5-HTT decient mice butit was not investigated whether or not endotoxemia occurs in thismodel of depressive-like behavior. Furthermore, besides the above-described ic and dietary factors, chronic treatment withantidepressants induces systemic hypofunction of 5-HTT [64,65].Whether this results in increased levels of intestinal5-HT and endo-toxemia was however not reported and would be of essentialclinical and fundamental importance to be elucidated. As such, cen-tral downstream factors of decient 5-HTT function were shownto contribute to the ic mechanisms of depression. Thusperipheral elements may substantially contribute to its etiopathol-ogy and require experimental consideration.I.A. Pomytkin et al. / Behavioural Brain Research 276 (–117 115Fig. 3. Schematic representation of functions of IRS1/PI3K/Akt pathway in the mechanisms of glucose metabolism and depression. The regulation of glucose metabolism anddepression by IRS1/PI3K/Akt pathway is mediated by TLR4, FOXO, BDNF, GSK3 and cytokines. (abbreviations: see Fig. 2).AcknowledgmentsThe authors’ work reported in this review was supported bythe munity (EC: AGGRESSOTYPE FP7-HEALTH-2013-INNOVATION-1, N ).References[1] Kan C, Silva N, Golden SH, Rajala U, Timonen M, Stahl D, et al. A systematicreview and meta-analysis of the association between depression and insulinresistance. Diabetes Care –9.[2] Cline BH, Steinbusch HW, Malin D, Revishchin AV, Pavlova GV, CespuglioR, et al. The neuronal insulin sensitizer dicholine inate reduces stress-induced depressive traits and memory decit: possible role of insulin-likegrowth factor 2. BMC Neurosci .[3] Pyykkonen AJ, Raikkonen K, Tuomi T, Eriksson JG, Groop L, Isomaa B. Depres-sive symptoms, antidepressant medication use, and insulin resistance: thePPP-Botnia Study. 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Behavioural Brain Research 276 (–117Contents lists available at ScienceDirectBehavioural Brain Researchjournal homepage: ate/bbrReviewEndotoxaemia resulting from decreased serotonin tranporter (5-HTT)function: A reciprocal risk factor for depression and insulinresistance?Igor A. Pomytkina,...
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