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.

Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.

Obesity is characterized by systemic low-grade inflammation in which adipose tissue, especially the omental depot, is thought to play a key role. We have previously shown that inflammation impairs 3T3-L1 preadipocyte cell line differentiation. To explore whether this interaction also takes place in vivo, the expression of several genes related to inflammation and adipocyte differentiation was assessed in human samples. Paired adipose tissue biopsies (from omental and subcutaneous depots) were obtained from 24 women: 6 lean normoglycemic and 18 obese volunteers with different glycemic states (normoglycemic, glucose-intolerant, or type 2 diabetic). The expression levels of CD14, IL-18, leptin, adiponectin, sterol regulatory element binding transcription factor 1 (SREBP1), peroxisome proliferator-activated receptor gamma (PPARγ), pre-B-cell colony enhancing factor 1 (PBEF1) (or visfatin), glycerol-3-phosphate dehydrogenase 1 (soluble) (GPD1), lipoprotein lipase (LPL), fatty acid binding protein 4, adipocyte (FABP4), and hypoxia-inducible factor 1α were determined by quantitative real-time PCR. CD14 and IL-18 were overexpressed in omental adipose tissue compared with the subcutaneous depot, irrespective of the subject's obesity or diabetes status. A significant decrease of LPL, GPD1, and leptin expression was observed in omental tissue, and an inverse correlation between expression of CD14 and IL-18 and that of PPARγ, LPL, and FABP4 was observed. The underexpression of omental lipogenic markers was more accentuated in the presence of glucose intolerance. Furthermore, adiponectin and SREBP1 expression was also significantly decreased in omental tissue of type 2 diabetic patients. PBEF1 and HIF1α expression remained comparable in all samples. Therefore, in humans, inflammation is increased in the omental depot, as evidenced by CD14 and IL-18 expression. In this localization, the inflammatory state is associated with a decreased expression of lipogenic markers, which is more pronounced in diabetic subjects.