RESUMO
Converging data support the role of chronic low-grade inflammation in depressive symptomatology in obesity. One mechanism likely to be involved relies on the effects of inflammation on tryptophan (TRP) metabolism. While recent data document alterations in the indole pathway of TRP metabolism in obesity, the relevance of this mechanism to obesity-related depressive symptoms has not been investigated. The aim of this preliminary study was to assess the association between plasma levels of TRP and indole metabolites and depressive symptoms in 44 subjects with severe or morbid obesity, free of clinically relevant neuropsychiatric disorders. The interaction effect of inflammation, reflected in serum high-sensitive C-reactive protein (hsCRP) levels, and indoles on depressive symptoms was also determined. Higher serum levels of hsCRP and lower concentrations of TRP and indoles, particularly indole-3-carboxaldehyde (IAld), correlated with more severe depressive symptoms. Interestingly, the effect of high hsCRP levels in predicting greater depressive symptoms was potentiated by low IAld levels. These results comfort the link between inflammation, the indole pathway of TRP metabolism, and obesity-related depressive symptoms.
Assuntos
Cinurenina , Triptofano , Proteína C-Reativa/metabolismo , Depressão/metabolismo , Humanos , Indóis , Inflamação/metabolismo , Cinurenina/metabolismo , Obesidade/complicações , Triptofano/metabolismoRESUMO
Long-chain (LC) n-3 polyunsaturated fatty acids (PUFAs) have drawn attention in the field of neuropsychiatric disorders, in particular depression. However, whether dietary supplementation with LC n-3 PUFA protects from the development of mood disorders is still a matter of debate. In the present study, we studied the effect of a two-month exposure to isocaloric diets containing n-3 PUFAs in the form of relatively short-chain (SC) (6% of rapeseed oil, enriched in α-linolenic acid (ALA)) or LC (6% of tuna oil, enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) PUFAs on behavior and synaptic plasticity of mice submitted or not to a chronic social defeat stress (CSDS), previously reported to alter emotional and social behavior, as well as synaptic plasticity in the nucleus accumbens (NAc). First, fatty acid content and lipid metabolism gene expression were measured in the NAc of mice fed a SC (control) or LC n-3 (supplemented) PUFA diet. Our results indicate that LC n-3 supplementation significantly increased some n-3 PUFAs, while decreasing some n-6 PUFAs. Then, in another cohort, control and n-3 PUFA-supplemented mice were subjected to CSDS, and social and emotional behaviors were assessed, together with long-term depression plasticity in accumbal medium spiny neurons. Overall, mice fed with n-3 PUFA supplementation displayed an emotional behavior profile and electrophysiological properties of medium spiny neurons which was distinct from the ones displayed by mice fed with the control diet, and this, independently of CSDS. Using the social interaction index to discriminate resilient and susceptible mice in the CSDS groups, n-3 supplementation promoted resiliency. Altogether, our results pinpoint that exposure to a diet rich in LC n-3 PUFA, as compared to a diet rich in SC n-3 PUFA, influences the NAc fatty acid profile. In addition, electrophysiological properties and emotional behavior were altered in LC n-3 PUFA mice, independently of CSDS. Our results bring new insights about the effect of LC n-3 PUFA on emotional behavior and synaptic plasticity.
Assuntos
Ácidos Graxos Ômega-3 , Núcleo Accumbens , Animais , Dieta , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Insaturados/metabolismo , Humanos , Camundongos , Núcleo Accumbens/metabolismoRESUMO
BACKGROUND: Early consumption of obesogenic diets, rich in saturated fat and added sugar, is associated with a plethora of biological dysfunctions, at both peripheral and brain levels. Obesity is also linked to decreased vitamin A bioavailability, an essential molecule for brain plasticity and memory function. METHODS: Here we investigated in mice whether dietary vitamin A supplementation (VAS) could prevent some of the metabolic, microbiota, neuronal and cognitive alterations induced by obesogenic, high-fat and high-sugar diet (HFSD) exposure from weaning to adulthood, i.e. covering periadolescent period. RESULTS: As expected, VAS was effective in enhancing peripheral vitamin A levels as well as hippocampal retinoic acid levels, the active metabolite of vitamin A, regardless of the diet. VAS attenuated HFSD-induced excessive weight gain, without affecting metabolic changes, and prevented alterations of gut microbiota α-diversity. In HFSD-fed mice, VAS prevented recognition memory deficits but had no effect on aversive memory enhancement. Interestingly, VAS alleviated both HFSD-induced higher neuronal activation and lower glucocorticoid receptor phosphorylation in the hippocampus after training. CONCLUSION: Dietary VAS was protective against the deleterious effects of early obesogenic diet consumption on hippocampal function, possibly through modulation of the gut-brain axis.
Assuntos
Cognição/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Vitamina A , Animais , Eixo Encéfalo-Intestino/efeitos dos fármacos , Hipocampo/química , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Vitamina A/administração & dosagem , Vitamina A/farmacologiaRESUMO
Metabolic syndrome represents a major risk factor for severe comorbidities such as cardiovascular diseases or diabetes. It is also associated with an increased prevalence of emotional and cognitive alterations that in turn aggravate the disease and related outcomes. Identifying therapeutic strategies able to improve those alterations is therefore a major socioeconomical and public health challenge. We previously reported that both hippocampal inflammatory processes and neuronal plasticity contribute to the development of emotional and cognitive alterations in db/db mice, an experimental model of metabolic syndrome that displays most of the classical features of the syndrome. In that context, nutritional interventions with known impact on those neurobiological processes appear as a promising alternative to limit the development of neurobiological comorbidities of metabolic syndrome. We therefore tested here whether n-3 polyunsaturated fatty acids (n-3 PUFAs) associated with a cocktail of antioxidants can protect against the development of behavioral alterations that accompany the metabolic syndrome. Thus, this study aimed: 1) to evaluate if a diet supplemented with the plant-derived n-3 PUFA α-linolenic acid (ALA) and antioxidants (provided by n-3 PUFAs-rich rapeseed oil fortified with a mix of naturally constituting antioxidant micronutrients, including coenzyme Q10, tocopherol, and the phenolic compound canolol) improved behavioral alterations in db/db mice, and 2) to decipher the biological mechanisms underlying this behavioral effect. Although the supplemented diet did not improve anxiety-like behavior and inflammatory abnormalities, it reversed hippocampus-dependent spatial memory deficits displayed by db/db mice in a water maze task. It concomitantly changed subunit composition of glutamatergic AMPA and NMDA receptors in the hippocampus that has been shown to modulate synaptic function related to spatial memory. These data suggest that changes in local neuronal plasticity may underlie cognitive improvements in db/db mice fed the supplemented diet. The current findings might therefore provide valuable data for introducing new nutritional strategies for the treatment of behavioral complications associated with MetS.
Assuntos
Transtornos Cognitivos/dietoterapia , Cognição/efeitos dos fármacos , Alimentos Fortificados , Síndrome Metabólica/dietoterapia , Micronutrientes/farmacologia , Óleo de Brassica napus/química , Óleo de Brassica napus/farmacologia , Animais , Transtornos Cognitivos/complicações , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , CamundongosRESUMO
Although the high prevalence of anxiety in obesity increasingly emerges as significant risk factor for related severe health complications, the underlying pathophysiological mechanisms remain poorly understood. Considering that chronic inflammation is a key component of obesity and is well known to impact brain function and emotional behavior, we hypothesized that it may similarly contribute to the development of obesity-related anxiety. This hypothesis was experimentally tested by measuring whether chronic food restriction, a procedure known to reduce inflammation, or chronic anti-inflammatory treatment with ibuprofen improved anxiety-like behavior and concomitantly decreased peripheral and/or hippocampal inflammation characterizing a model of severe obesity, the db/db mice. In both experiments, reduced anxiety-like behaviors in the open-field and/or elevated plus-maze were selectively associated with decreased hippocampal tumor necrosis factor-α (TNF-α) mRNA expression. Highlighting the causality of both events, chronic central infusion of the TNF-α blocker etanercept was then shown to be sufficient to improve anxiety-like behavior in db/db mice. Lastly, by measuring the impact of ex-vivo etanercept on hippocampal synaptic processes underlying anxiety-like behaviors, we showed that the anxiolytic effect of central TNF-α blockade likely involved modulation of synaptic transmission within the ventral hippocampus. Altogether, these results uphold the role of brain TNF-α in mediating obesity-related anxiety and provide important clues about how it may modulate brain function and behavior. They may therefore help to introduce novel therapeutic strategies to reduce anxiety associated with inflammatory conditions.
Assuntos
Ansiedade/metabolismo , Obesidade/psicologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ansiolíticos/farmacologia , Transtornos de Ansiedade/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Etanercepte/farmacologia , Hipocampo/metabolismo , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The cerebral innate immune system is able to modulate brain functioning and cognitive processes. During activation of the cerebral innate immune system, inflammatory factors produced by microglia, such as cytokines and adenosine triphosphate (ATP), have been directly linked to modulation of glutamatergic system on one hand and learning and memory functions on the other hand. However, the cellular mechanisms by which microglial activation modulates cognitive processes are still unclear. Here, we used taste memory tasks, highly dependent on glutamatergic transmission in the insular cortex, to investigate the behavioral and cellular impacts of an inflammation restricted to this cortical area in rats. We first show that intrainsular infusion of the endotoxin lipopolysaccharide induces a local inflammation and increases glutamatergic AMPA, but not NMDA, receptor expression at the synaptic level. This cortical inflammation also enhances associative, but not incidental, taste memory through increase of glutamatergic AMPA receptor trafficking. Moreover, we demonstrate that ATP, but not proinflammatory cytokines, is responsible for inflammation-induced enhancement of both associative taste memory and AMPA receptor expression in insular cortex. In conclusion, we propose that inflammation restricted to the insular cortex enhances associative taste memory through a purinergic-dependent increase of glutamatergic AMPA receptor expression at the synapse.
Assuntos
Aprendizagem por Associação/fisiologia , Encefalite/fisiopatologia , Memória/fisiologia , Microglia/metabolismo , Purinérgicos , Transmissão Sináptica/fisiologia , Paladar/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Corticosterona/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/sangue , Encefalite/induzido quimicamente , Ácido Glutâmico/metabolismo , Lipopolissacarídeos/farmacologia , Cloreto de Lítio/farmacologia , Masculino , Memória/efeitos dos fármacos , Microglia/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Paladar/efeitos dos fármacosRESUMO
Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra-dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra-dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects.
Assuntos
Atenção/fisiologia , Função Executiva/fisiologia , Inflamação , Obesidade/fisiopatologia , Obesidade/psicologia , Adulto , Proteína C-Reativa/metabolismo , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: The postnatal period is a critical time window during which inflammatory events have significant and enduring effects on the brain, and as a consequence, induce alterations of emotional behavior and/or cognition later in life. However, the long-term effect of neonatal inflammation on behavior during adolescence, a sensitive period for the development of neurodevelopmental psychiatric disorders, has been little studied. In this study, we examined whether an early-life inflammatory challenge could alter emotional behaviors and spatial memory at adolescence and adulthood and whether stress axis activity, inflammatory response and neurogenesis were affected. METHODS: Lipopolysaccharide (LPS, 100 µg/kg) was administered to mice on postnatal day (PND) 14 and cytokine expression was measured in the plasma and in brain structures 3 hours later. Anxiety-like and depressive-like behavior (measured in the novelty-suppressed feeding test and the forced swim test, respectively) and spatial memory (Y-maze test) were measured at adolescence (PND30) and adulthood (PND90). Hypothalamic-pituitary-adrenal (HPA) axis activity (plasma corticosterone and glucocorticoid receptors in the hippocampus and prefrontal cortex) was measured at adulthood. In addition, the impact of a novel adult LPS challenge (100 µ/kg) was measured on spatial memory (Y-maze test), neurogenesis (doublecortin-positive cell numbers in the hippocampus) and plasma cytokine expression. RESULTS: First, we show in PND14 pups that a peripheral administration of LPS induced the expression of pro- and anti-inflammatory cytokines in the plasma and brain structures that were studied 3 hours after administration. Anxiety-like behavior was altered in adolescent, but not in adult, mice, whereas depressive-like behavior was spared at adolescence and increased at adulthood. This was accompanied by a decreased phosphorylation of the glucocorticoid receptor in the prefrontal cortex, with no effect on corticosterone levels. Second, neonatal LPS treatment had no effect on spatial memory in adolescence and adulthood. However, a second challenge of LPS in adulthood impaired spatial memory performance and neurogenesis and increased circulating levels of CCL2. CONCLUSIONS: Our study shows for the first time, in mice, that a peripheral LPS treatment at PND14 differentially alters emotional behaviors, but not spatial memory, at adolescence and adulthood. The behavioral effect of LPS at PND14 could be attributed to HPA axis deregulation and neurogenesis impairment.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiopatologia , Inflamação/complicações , Neurogênese/fisiologia , Memória Espacial/fisiologia , Animais , Animais Recém-Nascidos , Western Blotting , Encéfalo/patologia , Feminino , Sistema Hipotálamo-Hipofisário/fisiopatologia , Imuno-Histoquímica , Inflamação/patologia , Inflamação/fisiopatologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In addition to metabolic and cardiovascular disorders, obesity pandemic is associated with chronic low-grade inflammation as well as adverse cognitive outcomes. However, the existence of critical periods of development that differ in terms of sensitivity to the effects of diet-induced obesity remains unexplored. Using short exposure to a high-fat diet (HFD) exerting no effects when given to adult mice, we recently found impairment of hippocampal-dependent memory and plasticity after similar HFD exposure encompassing adolescence (from weaning to adulthood) showing the vulnerability of the juvenile period (Boitard et al., 2012). Given that inflammatory processes modulate hippocampal functions, we evaluated in rats whether the detrimental effect of juvenile HFD (jHFD) on hippocampal-dependent memory is associated with over-expression of hippocampal pro-inflammatory cytokines. jHFD exposure impaired long-term spatial reference memory in the Morris water maze without affecting acquisition or short-term memory. This suggests an effect on consolidation processes. Moreover, jHFD consumption delayed spatial reversal learning. jHFD intake did neither affect basal expression of pro-inflammatory cytokines at the periphery nor in the brain, but potentiated the enhancement of Interleukin-1-beta and Tumor Necrosis Factor-alpha expression specifically in the hippocampus after a peripheral immune challenge with lipopolysaccharide. Interestingly, whereas the same duration of HFD intake at adulthood induced similar weight gain and metabolic alterations as jHFD intake, it did neither affect spatial performance (long-term memory or reversal learning) nor lipopolysaccharide-induced cytokine expression in the hippocampus. Finally, spatial reversal learning enhanced Interleukin-1-beta in the hippocampus, but not in the frontal cortex and the hypothalamus, of jHFD-fed rats. These results indicate that juvenile HFD intake promotes exaggerated pro-inflammatory cytokines expression in the hippocampus which is likely to contribute to spatial memory impairment.
Assuntos
Citocinas/sangue , Dieta Hiperlipídica/efeitos adversos , Encefalite/imunologia , Hipocampo/imunologia , Memória/fisiologia , Animais , Encéfalo/imunologia , Ingestão de Alimentos , Masculino , Aprendizagem em Labirinto/fisiologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Obesidade/imunologia , Obesidade/fisiopatologia , Ratos , Ratos Wistar , Memória Espacial/fisiologiaRESUMO
Activation of the immune system elicits several behavioral changes collectively called sickness. Among the behavioral changes, systemic infections induce an increase in time spent in nonrapid-eye-movement (NREM) sleep and an increase of slow wave activity (or "sleep pressure"). Using an inducible, astrocyte-specific transgenic dominant negative SNARE (dnSNARE) mouse line we recently demonstrated that gliotransmission plays an important role in sleep homeostasis through an adenosine receptor 1 (A1R)-sensitive pathway. It has been hypothesized that systemic infection, mimicked by peripheral administration of lipopolysaccharide (LPS), increases sleeping behavior in part through upregulation of central adenosine levels. Moreover, as a source of immunologically relevant factors, astrocytes play a pivotal role in the central nervous system immune and inflammatory responses. However, little is known about the role of astrocytes in the CNS response to a peripheral immune challenge. We hypothesize that LPS impacts sleep homeostasis through the modulation of astrocyte-derived adenosine accumulation. We therefore used dnSNARE mice to determine whether astrocytes contribute to the increased sleep pressure under immune challenge and whether this is a result of changes in adenosine signaling. We demonstrate that dnSNARE-mediated gliotransmission is required for the ability of LPS to elevate sleep pressure as measured by the power of slow wave activity during NREM sleep. Moreover, in agreement with a role of astrocyte-derived adenosine in modulating sleep homeostasis, we find that intracerebroventricular infusion of the A1R antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) mimics this dnSNARE phenotype. Taken together, our data demonstrate that astrocytic adenosine acting through A1 receptors contributes to the modulation of sleep pressure by LPS.
Assuntos
Adenosina/fisiologia , Astrócitos/patologia , Sono/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Eletroencefalografia/métodos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor A1 de Adenosina/fisiologia , Proteínas SNARE/biossíntese , Proteínas SNARE/genética , Sono/efeitos dos fármacosRESUMO
Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Ácidos Graxos Ômega-3 , Feminino , Masculino , Animais , Camundongos , Transtorno Autístico/induzido quimicamente , Transtorno do Espectro Autista/induzido quimicamente , Ácido Valproico/efeitos adversos , Dieta , Ácidos Graxos Insaturados , Ácidos Graxos Ômega-3/farmacologia , Suplementos NutricionaisRESUMO
Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Sobrepeso/etiologia , Fatores Etários , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Corticosterona/sangue , Giro Denteado/química , Giro Denteado/patologia , Aprendizagem por Discriminação/efeitos dos fármacos , Proteínas do Domínio Duplacortina , Ingestão de Energia/efeitos dos fármacos , Hipocampo/patologia , Técnicas Imunoenzimáticas , Leptina/sangue , Lipídeos/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/análise , Proteínas do Tecido Nervoso/análise , Neuropeptídeos/análise , Sobrepeso/sangue , Comportamento Espacial/efeitos dos fármacosRESUMO
Fatigue is frequent in patients with diabetes and this symptom appears to be more prominent in type 2 rather than type 1 diabetic subjects. Chronic inflammation represents one characteristic of type 2 diabetes that may contribute to fatigue symptoms. This possibility was assessed in a sample of 20 type 2 diabetic patients relatively to a group of 20 type 1 diabetic subjects. Specific dimensions of fatigue, including general fatigue, physical fatigue, reduced activity, mental fatigue and reduced motivation, were assessed using the Multidimensional-Fatigue-Inventory (MFI). Biological assays comprised the measurement of serum inflammatory markers [high-sensitive C-reactive-protein (hsCRP), high-sensitive interleukin-6 (hsIL-6), high-sensitive tumor-necrosis-factor-α (hsTNF-α) and neopterin]. Clinical parameters including indexes of adiposity were collected. In comparison to type 1 diabetic subjects, patients with type 2 diabetes exhibited higher fatigue scores, notably in the dimensions of general fatigue, physical fatigue and reduced activity, together with greater levels of inflammatory markers that correlated with indexes of adiposity. Regression analyses controlling for diabetes duration, insulin treatment status, glycemic control and fasting status, indicated that levels of inflammatory markers, in particular hsIL-6, hsCRP and neopterin, were associated with MFI fatigue dimensions in type 2 diabetic patients. Mediation analyses revealed that adiposity did not significantly account for the relationship of inflammatory markers with fatigue scores albeit coefficient regressions decreased somewhat when this variable was controlled for in regression models. These findings indicate that systemic low-grade inflammation relates to fatigue symptoms in patients with type 2 diabetes and suggest the involvement of inflammatory processes in the pathophysiology of diabetes-related fatigue.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Fadiga/etiologia , Inflamação/metabolismo , Adiposidade/fisiologia , Adulto , Idoso , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fadiga/diagnóstico , Fadiga/metabolismo , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
Converging epidemiological studies suggest that dietary essential n-3 polyunsaturated fatty acid (PUFA) are likely to be involved in the pathogenesis of mood and cognitive disorders linked to aging. The question arises as to whether the decreased prevalence of these symptoms in the elderly with high n-3 PUFA consumption is also associated with improved central inflammation, i.e. cytokine activation, in the brain. To answer this, we measured memory performance and emotional behavior as well as cytokine synthesis and PUFA level in the spleen and the cortex of adult and aged mice submitted to a diet with an adequate supply of n-3 PUFA in form of α-linolenic acid (α-LNA) or a n-3 deficient diet. Our results show that docosahexaenoic acid (DHA), the main n-3 PUFA in the brain, was higher in the spleen and cortex of n-3 adequate mice relative to n-3 deficient mice and this difference was maintained throughout life. Interestingly, high level of brain DHA was associated with a decrease in depressive-like symptoms throughout aging. On the opposite, spatial memory was maintained in adult but not in aged n-3 adequate mice relative to n-3 deficient mice. Furthermore, increased interleukin-6 (IL-6) and decreased IL-10 expression were found in the cortex of aged mice independently of the diets. All together, our results suggest that n-3 PUFA dietary supply in the form of α-LNA is sufficient to protect from deficits in emotional behavior but not from memory disruption and brain proinflammatory cytokine expression linked to age.
Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Citocinas/biossíntese , Depressão/prevenção & controle , Dieta , Ácidos Graxos Ômega-3/farmacologia , Memória de Curto Prazo/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Emoções/fisiologia , Ácidos Graxos Insaturados/sangue , Feminino , Interleucina-10/biossíntese , Interleucina-10/sangue , Interleucina-6/biossíntese , Interleucina-6/sangue , Fígado/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fosfolipídeos/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
Background: Neuroinflammation is a key feature shared by most, if not all, neuropathologies. It involves complex biological processes that act as a protective mechanism to fight against the injurious stimuli, but it can lead to tissue damage if self-perpetuating. In this context, microglia, the main cellular actor of neuroinflammation in the brain, are seen as a double-edged sword. By phagocyting neuronal debris, these cells can not only provide tissue repair but can also contribute to neuronal damage by releasing harmful substances, including inflammatory cytokines. The mechanisms guiding these apparent opposing actions are poorly known. The endocannabinoid system modulates the release of inflammatory factors such as cytokines and could represent a functional link between microglia and neuroinflammatory processes. According to transcriptomic databases and in vitro studies, microglia, the main source of cytokines in pathological conditions, express the cannabinoid type 1 receptor (CB1R). Methods: We thus developed a conditional mouse model of CB1R deletion specifically in microglia, which was subjected to an immune challenge (peripheral lipopolysaccharide injection). Results: Our results reveal that microglial CB1R differentially controls sickness behavior in males and females. Conclusion: These findings add to the comprehension of neuroinflammatory processes and might be of great interest for future studies aimed at developing therapeutic strategies for brain disorders with higher prevalence in men.
Assuntos
Canabinoides , Encefalite , Animais , Masculino , Camundongos , Microglia , Doenças Neuroinflamatórias , Receptores de Canabinoides/genéticaRESUMO
Background: Obesity is a condition with a complex pathophysiology characterized by both chronic low-grade inflammation and changes in the gut microbial ecosystem. These alterations can affect the metabolism of tryptophan (TRP), an essential amino acid and precursor of serotonin (5-HT), kynurenine (KYN), and indoles. This study aimed to investigate alterations in KYN and microbiota-mediated indole routes of TRP metabolism in obese subjects relatively to non-obese controls and to determine their relationship with systemic inflammation. Methods: Eighty-five obese adults (avg. BMI = 40.48) and 42 non-obese control individuals (avg. BMI = 24.03) were recruited. Plasma levels of TRP catabolites were assessed using Ultra High Performance Liquid Chromatography-ElectroSpray-Ionization-Tandem Mass Spectrometry. High-sensitive C-reactive protein (hsCRP) and high-sensitive interleukin 6 (hsIL-6) were measured in the serum as markers of systemic inflammation using enzyme-linked immunosorbent assay. Results: Both KYN and microbiota-mediated indole routes of TRP metabolism were altered in obese subjects, as reflected in higher KYN/TRP ratio and lower 5-HT and indoles levels, relatively to non-obese controls. HsIL-6 and hsCRP were increased in obesity and were overall associated with TRP metabolic pathways alterations. Conclusion: These results indicate for the first time that KYN and indole TRP metabolic pathways are concomitantly altered in obese subjects and highlight their respective associations with obesity-related systemic inflammation.
Assuntos
Inflamação/metabolismo , Cinurenina/metabolismo , Redes e Vias Metabólicas/imunologia , Obesidade/metabolismo , Triptofano/metabolismo , Adulto , Feminino , Humanos , Inflamação/imunologia , Masculino , Obesidade/imunologiaRESUMO
Despite extensive research, the origin of Alzheimer's disease (AD) remains unknown. The role of infectious pathogens has recently emerged. Epidemiological studies have shown that Helicobacter pylori infection increases the risk of developing AD. We hypothesized that H. pylori-induced gastritis may be associated with a systemic inflammation and finally neuroinflammation. C57BL/6 mice were infected with H. pylori (nâ=â15) or Helicobacter felis (nâ=â13) or left uninfected (nâ=â9) during 18 months. Gastritis, amyloid deposition, astroglial and microglial cell area, and systemic and brain cytokines were assessed. The infection (H. felis> H. pylori) induced a severe gastritis and an increased neuroinflammation but without brain amyloid deposition or systemic inflammation.
Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/microbiologia , Encefalite/etiologia , Gastrite/complicações , Gastrite/microbiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Inflamação/complicações , Inflamação/microbiologia , Animais , Astrócitos/patologia , Química Encefálica , Citocinas/metabolismo , Helicobacter felis , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Placa Amiloide/patologiaRESUMO
BACKGROUND AND AIMS: The gut microbiota produces metabolites that are an integral part of the metabolome and, as such, of the host physiology. Changes in gut microbiota metabolism could therefore contribute to pathophysiological processes. We showed previously that a chronic and moderate overproduction of indole from tryptophan in male individuals of the highly stress-sensitive F344 rat strain induced anxiety-like and helplessness behaviors. The aim of the present study was to extend the scope of these findings by investigating whether emotional behaviors of male mice that are moderately stress-sensitive but chronically exposed to environmental stressors would also be affected by indole. METHODS: We colonized germ-free male C3H/HeN mice with a wild-type indole-producing Escherichia coli strain, or with the non-indole producing mutant. Gnotobiotic mice were subjected to an unpredictable chronic mild stress procedure, then to a set of tests aimed at assessing anxiety-like (novelty and elevated plus maze tests) and depression-like behaviors (coat state, splash, nesting, tail suspension and sucrose tests). Results of the individual tests were aggregated into a common z-score to estimate the overall emotional response to chronic mild stress and chronic indole production. We also carried out biochemical and molecular analyses in gut mucosa, plasma, brain hippocampus and striatum, and adrenal glands, to examine biological correlates that are usually associated with stress, anxiety and depression. RESULTS: Chronic mild stress caused coat state degradation and anhedonia in both indole-producing and non-indole producing mice, but it did not influence behaviors in the other tests. Chronic indole production did not influence mice behavior when tests were considered individually, but it increased the overall emotionality z-score, specifically in mice under chronic mild stress. Interestingly, in the same mice, indole induced a dramatic increase of the expression of the adrenomedullary Pnmt gene, which is involved in catecholamine biosynthesis. By contrast, systemic tryptophan bioavailability, brain serotonin and dopamine levels and turnover, as well as expression of gut and brain genes involved in cytokine production and tryptophan metabolism along the serotonin and kynurenine pathways, remained similar in all mice. CONCLUSIONS: Chronic indole production by the gut microbiota increased the vulnerability of male mice to the adverse effects of chronic mild stress on emotional behaviors. It also targeted catecholamine biosynthetic pathway of the adrenal medulla, which plays a pivotal role in body's physiological adaptation to stressful events. Future studies will aim to investigate the action mechanisms responsible for these effects.
Assuntos
Medula Suprarrenal/efeitos dos fármacos , Emoções/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Indóis/farmacologia , Estresse Psicológico , Medula Suprarrenal/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Doença Crônica , Indóis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Estresse Psicológico/metabolismo , Estresse Psicológico/microbiologia , Estresse Psicológico/patologia , Estresse Psicológico/psicologia , Fatores de TempoRESUMO
BACKGROUND/OBJECTIVES: While excessive food consumption represents a key factor in the development of obesity, the underlying mechanisms are still unclear. Ghrelin, a gut-brain hormone involved in the regulation of appetite, is impaired in obesity. In addition to its role in eating behavior, this hormone was shown to affect brain regions controlling reward, including the striatum and prefrontal cortex, and there is strong evidence of impaired reward processing in obesity. The present study investigated the possibility that disrupted reward-related brain activity in obesity relates to ghrelin deficiency. SUBJECTS/METHODS: Fifteen severely obese subjects (BMIâ¯>â¯35â¯kg/m2) and fifteen healthy non-obese control subjects (BMIâ¯<â¯30â¯kg/m2) were recruited. A guessing-task paradigm, previously shown to activate the ventral striatum, was used to assess reward-related brain neural activity by functional magnetic resonance imaging (fMRI). Fasting blood samples were collected for the measurement of circulating ghrelin. RESULTS: Significant activations in the ventral striatum, ventromedial prefrontal cortex and extrastriate visual cortex were elicited by the fMRI task in both obese and control subjects. In addition, greater reward-related activations were present in the dorsolateral prefrontal cortex, and precuneus/posterior cingulate of obese subjects compared to controls. Obese subjects exhibited longer choice times after repeated reward and lower circulating ghrelin levels than lean controls. Reduced ghrelin levels significantly predicted slower post-reward choices and reward-related hyperactivity in dorsolateral prefrontal cortices in obese subjects. CONCLUSION: This study provides evidence of association between circulating ghrelin and reward-related brain activity in obesity and encourages further exploration of the role of ghrelin system in altered eating behavior in obesity.
Assuntos
Mapeamento Encefálico , Grelina/sangue , Obesidade Mórbida/sangue , Obesidade Mórbida/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Recompensa , Adulto , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Desempenho Psicomotor/fisiologia , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/fisiopatologia , Córtex Visual/diagnóstico por imagem , Córtex Visual/fisiopatologiaRESUMO
Pseudomonas stutzeri, a gram-negative bacterium, is a common inhabitant of soil and water. We report an unusual case of a relapse of infective endocarditis due to P. stutzeri 4 years after the initial episode. The identity of the strains was proven by genomic analysis.