The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.
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.
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|CHRU De Lille, Lille, France.
Marie
M
Favennec
University of Lille, Lille, France.|CHRU De Lille, Lille, France.|EA4483, Lille, France.
Benjamin
B
Hennart
University of Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|CHRU De Lille, Lille, France.|INSERM UMR 1190, Lille, France.
Robert
R
Caiazzo
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.
Audrey
A
Leloire
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.
Loïc
L
Yengo
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.
Marie
M
Verbanck
Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar.
Abdelilah
A
Arredouani
INSERM U872, Paris, France.
Michel
M
Marre
University of Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|CHRU De Lille, Lille, France.|INSERM UMR 1190, Lille, France.
Marie
M
Pigeyre
Immusmol, Pessac, France.
Alban
A
Bessede
Neuroinflammation Group, Macquarie University, Sydney, New South Wales, Australia.
Gilles J
GJ
Guillemin
University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|INSERM UMR 1011, Lille, France.
Giulia
G
Chinetti
University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|INSERM UMR 1011, Lille, France.
Bart
B
Staels
University of Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|CHRU De Lille, Lille, France.|INSERM UMR 1190, Lille, France.
François
F
Pattou
INSERM UMRS 1018, Villejuif, France.
Beverley
B
Balkau
University of Lille, Lille, France.|CHRU De Lille, Lille, France.|EA4483, Lille, France.
Delphine
D
Allorge
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.|CHRU De Lille, Lille, France.|Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
Philippe
P
Froguel
CNRS UMR 8199, Lille, France.|University of Lille, Lille, France.|Institut Pasteur De Lille, Lille, France.|European Genomic Institute for Diabetes (EGID), Lille, France.
Odile
O
Poulain-Godefroy
D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000097:blood*; D050601:Kynurenine 3-Monooxygenase / Q000097:blood*; D009765:Obesity / Q000378:metabolism*
D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase