Marie Favennec1,2,3,4,5, Benjamin Hennart2,5,6, Robert Caiazzo2,4,5,7, Audrey Leloire1,2,3,4, Loïc Yengo1,2,3,4, Marie Verbanck1,2,3,4, Abdelilah Arredouani8, Michel Marre9, Marie Pigeyre2,4,5,7, Alban Bessede10, Gilles J Guillemin11, Giulia Chinetti2,3,4,12, Bart Staels2,3,4,12, François Pattou2,4,5,7, Beverley Balkau13, Delphine Allorge2,5,6, Philippe Froguel1,2,3,4,5,14, Odile Poulain-Godefroy1,2,3,4. 1. CNRS UMR 8199, Lille, France. 2. University of Lille, Lille, France. 3. Institut Pasteur De Lille, Lille, France. 4. European Genomic Institute for Diabetes (EGID), Lille, France. 5. CHRU De Lille, Lille, France. 6. EA4483, Lille, France. 7. INSERM UMR 1190, Lille, France. 8. Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar. 9. INSERM U872, Paris, France. 10. Immusmol, Pessac, France. 11. Neuroinflammation Group, Macquarie University, Sydney, New South Wales, Australia. 12. INSERM UMR 1011, Lille, France. 13. INSERM UMRS 1018, Villejuif, France. 14. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
Abstract
OBJECTIVE: This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. METHODS: Tryptophan and KP metabolite levels were measured in serum of individuals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly sampled) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. RESULTS: In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10(-19) ) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10(-4) ). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). CONCLUSIONS: In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.
OBJECTIVE: This study characterized the kynurenine pathway (KP) in humanobesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. METHODS:Tryptophan and KP metabolite levels were measured in serum of individuals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly sampled) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. RESULTS: In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10(-19) ) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10(-4) ). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). CONCLUSIONS: In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.
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