The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation

Favennec, Marie; Hennart, Benjamin; Caïazzo, Robert; Leloire, Audrey; Yengo, Loïc; Verbanck, Marie; Arredouani, Abdelilah; Marre, Michel; Pigeyre, Marie; Bessede, Alban; Guillemin, Gilles J.; Chinetti-Gbaguidi, Giulia; Staels, Bart; Pattou, François; Balkau, Beverley; Allorge, Delphine; Froguel, Philippe; Poulain‐Godefroy, Odile

doi:10.1002/oby.21199

Cited by 202 publications

(189 citation statements)

References 40 publications

(45 reference statements)

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“…[32] It is therefore plausible that the associations we observed does not only reflect a specific effect on neurodegeneration. Metabolites from the KP have been associated with other diseases that could subsequently modulate risk of dementia, such as obesity, [45] acute coronary events [46] and stroke [47] although the effect size we observed was not reduced by adjustment for vascular risk factors, suggesting the observed effect was not chiefly due to vascular injury. Finally, as tryptophan metabolism is conserved across species and tightly regulated, metabolites from the KP could be involved more broadly in the aging processes.…”

Section: Discussionmentioning

confidence: 76%

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Chouraki

Preis

Yang

et al. 2017

Alzheimer's & Dementia

104

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INTRODUCTION The identification of novel biomarkers associated with Alzheimer’s disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. METHODS Plasma levels of 217 metabolites were assessed in 2067 dementia-free Framingham Offspring Cohort participants (mean age=55.9±9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. RESULTS Ninety-three participants developed incident dementia (mean follow-up=15.6±5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (HR=1.40; 95%CI=[1.15–1.70]; p=8.08×10–4). Glutamic acid (HR=1.38; 95%CI=[1.11–1.72]), taurine (HR=0.74; 95%CI=[0.60–0.92]) and hypoxanthine (HR=0.74; 95%CI=[0.60–0.92]) levels also showed suggestive associations with dementia risk. DISCUSSION We identified four biologically plausible, candidate plasma biomarkers for dementia. Association of anthranilic acid implicates the kynurenine pathway, which modulates glutamate excitotoxicity. The associations with hypoxanthine and taurine strengthen evidence that uric acid and taurine may be neuroprotective.

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Section: Discussionmentioning

confidence: 76%

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Chouraki

Preis

Yang

et al. 2017

Alzheimer's & Dementia

104

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“…The mechanisms of such association are not clear. Dysregulation of Trp-Kyn pathway in obesity was suggested [3,6] and supported by clinical and experimental data [27–29]. It is noteworthy that in Drosophila HSD induces not only IR/T2D but obesity as well [11].…”

Section: Discussionmentioning

confidence: 88%

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

Navrotskaya¹,

Oxenkrug²,

Vorobyova³

et al. 2015

Integr Obesity Diabetes

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Exposure to high sugar diet (HSD) serves as an experimental model of insulin resistance (IR) and type 2 diabetes (T2D) in mammals and insects. Peripheral IR induced by HSD delays emergence of pupae from larvae and decreases body weight of Drosophila imago. Understanding of mechanisms of IR/T2D is essential for refining T2D prevention and treatment strategies. Dysregulation of tryptophan (TRP) – kynurenine (KYN) pathway was suggested as one of the mechanisms of IR development. Rate-limiting enzyme of TRP – KYN pathway in Drosophila is TRP 2,3-dioxygenase (TDO), an evolutionary conserved ortholog of human TDO. In insects TDO is encoded by vermilion gene. TDO is not active in vermilion mutants. In order to evaluate the possible impact of deficient formation of KYN from TRP on the inducement of IR by HSD, we compared the effect of HSD in wild type (Oregon) and vermilion mutants of Drosophila melanogaster by assessing the time of white pupae emergence from larva and body weight of imago. Delay of emergence of pupae from larvae induced by high sucrose diet was less pronounced in vermilion (1.4 days) than in Oregon flies (3.3 days) in comparison with flies maintained on standard diet. Exposure to high sucrose diet decreased body weight of Oregon (but not vermilion) imago. Attenuation of high sucrose diet–induced IR/T2D in vermilion flies might depend on deficiency of TRP – KYN pathway. Besides IR/T2D, HSD induces obesity in Drosophila. Future studies of HSD-induced obesity and IR/T2D in TDO deficient vermilion mutants of Drosophila might help to understand the mechanisms of high association between IR/T2D and obesity. Modulation of TRP – KYN metabolism might be utilized for prevention and treatment of IR/T2D.

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“…In fact, inflammation-associated increases in kynurenine pathway levels are commonly observed in obesity. Whether this metabolic disturbance is a risk factor for several obesity-associated disorders including diabetes, neuronal dysfunction, or metabolic syndrome remains to be determined [37]. In addition, QA has been reported to be involved in the pathogenesis of different neurological disorders such as Alzheimer's disease, dementia, hepatic encephalopathy and Huntington's disease itself [38].…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

et al. 2016

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Different factors may contribute to the development of neurodegenerative diseases. Among them, metabolic syndrome (MS), which has reached epidemic proportions, has emerged as a potential element that may be involved in neurodegeneration. Furthermore, studies have shown the importance of the sirtuin family in neuronal survival and MS, which opens the possibility of new pharmacological targets. This study investigates the influence of sirtuin metabolic pathways by examining the functional capacities of glucose-induced obesity in an excitotoxic state induced by a quinolinic acid (QA) animal model. Mice were divided into two groups that received different diets for 8 weeks: one group received a regular diet, and the other group received a high-fat diet (HF) to induce MS. The animals were submitted to a stereotaxic surgery and subdivided into four groups: Standard (ST), Standard-QA (ST-QA), HF and HF-QA. The QA groups were given a 250 nL quinolinic acid injection in the right striatum and PBS was injected in the other groups. Obese mice presented with a weight gain of 40 % more than the ST group beyond acquiring an insulin resistance. QA induced motor impairment and neurodegeneration in both ST-QA and HF-QA, although no difference was observed between these groups. The HF-QA group showed a reduction in adiposity when compared with the groups that received PBS. Therefore, the HF-QA group demonstrated a commitment-dependent metabolic pathway. The results suggest that an obesogenic diet does not aggravate the neurodegeneration induced by QA. However, the excitotoxicity induced by QA promotes a sirtuin pathway impairment that contributes to metabolic changes.

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The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation

Abstract: In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.

Cited by 202 publications

References 40 publications

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

Attenuation of high sucrose diet–induced insulin resistance in tryptophan 2,3-dioxygenase deficient Drosophila melanogaster vermilion mutants

Neurodegeneration Alters Metabolic Profile and Sirt 1 Signaling in High-Fat-Induced Obese Mice

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