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@mail :  marie.favennec@good.ibl.fr      tél. :  0320871049

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Titre de la communication :
Dysregulation of tryptophan metabolism in human obesity
Auteurs (et leurs adresses) de la communication :
M. Favennec(1), B. Hennart(2), A. Leloire(1), G. Guillemin(3); G. Chinetti(4), D. Allorge(2), F. Pattou(5), P. Froguel(1) & O. Poulain-Godefroy(1) 1 CNRS UMR 8199; 2 EA4483; 3 Macquarie University, Sydney; 4 INSERM U1011; 5 INSERM U859
Résumé de la communication :
Obesity is a major recognized risk factor for insulin-resistance and type 2 diabetes. We have recently demonstrated that indoleamine-2,3-dioxygenase (IDO1), the enzyme that converts tryptophan to kynurenine through the kynurenine pathway (KP), is over-expressed in the liver and adipose tissues of obese patients likely due to an excessive inflammatory response. Several metabolites from the KP called collectively kynurenines were shown to interact with pancreatic beta cell physiology. Our hypothesis is that obesity could play a key role in diabetes elicitation via the activation of the KP. Our objective was to characterize the dysregulation of the different components of this pathway in diabetic patients.
Concentrations of the metabolites kynurenines were measured in sera using mass spectrometry-based methods. Expression of genes encoding enzymes of the KP and genes of adipocyte differentiation and some inflammatory markers were evaluated by qRT-PCR in paired-adipose tissues (omental and subcutaneous) of obese normoglycemic and diabetic patients. To assess the role of different cell types, the expression of KP genes was also evaluated in human primary adipocytes and human macrophages.
Kynurenines concentrations in sera are not significantly different between diabetic and normoglycemic patients. Nevertheless, kynurenine, quinolinic acid (the last metabolite of the KP) and the ratio of kynurenine to tryptophan, are correlated with BMI. All the enzymes of the KP are expressed in omental and subcutaneous adipose tissue of obese but there is no significant difference between obese normoglycemic and diabetic patients. The expression of some enzymes such as IDO1 and QPRT (the last enzyme of the KP) is higher in omental adipose tissue than in subcutaneous adipose tissue. A key enzyme of this pathway, kynurenine monooxygenase (KMO) is expressed in macrophages and not in adipocytes and is correlated in adipose tissues with CD68 a well known marker of macrophages.
In adipose tissue of obese patients, we have observed a global activation of the KP, which could be responsible for the circulating metabolite disequilibrium linked to BMI. Obesity induced inflammation seems to be the major player in this dysregulation 1) by inducing an over-expression of several enzymes 2) through the infiltration of macrophages that can lead to the generation of xanthurenic acid, produced by KMO. Since xanthurenic acid was shown to have diabetogenic effects, we will further explore its direct effect on adipocytes and on beta-cell models. We did not demonstrate any significant differences in circulating kynurenines levels between normoglycemic and diabetic patients but we used sera collected from fasting patients. We cannot exclude that a tryptophan load in normoglycemic and diabetic patients could have revealed differences between the two groups.