Kynurenic acid, an aryl hydrocarbon receptor ligand, is elevated in serum of Zucker fatty rats - Abstract and study findings

Q: What was the main goal of the study in Zucker fatty rats (ZFR)?

To determine whether the tryptophan–kynurenine metabolic pathway (TKP) shows deviations in ZFR by comparing serum concentrations of major TKP metabolites between ZFR (fa/fa) and lean rats.

Q: Which TKP metabolite showed the most significant change in ZFR serum?

Kynurenic acid (KYNA) was elevated by about 50% in ZFR serum compared with lean rats, with reported statistical significance (p<0.004; Mann–Whitney two-tailed test).

Q: How might increased KYNA relate to obesity or cognition in this model?

The results suggest elevated KYNA could contribute to obesity via activation of the aryl hydrocarbon receptor (AHR) and to cognitive impairment by antagonizing the N-methyl-d-aspartate receptor (NMDAR).

Sep 10, 2026

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Obesity is an increasingly urgent global problem, and the molecular basis remains incompletely defined. Dysregulation of the tryptophan–kynurenine metabolic pathway (TKP) has been implicated in obesity, yet TKP has not been examined in leptin-receptor-deficient Zucker fatty rats (ZFR, fa/fa). Using HPLC-MS, major TKP metabolites were quantified in serum from ZFR and lean rats, revealing higher kynurenic acid (KYNA) and a trend toward increased anthranilic acid (AA). Elevated KYNA may promote obesity via aryl hydrocarbon receptor activation and contribute to cognitive impairment through antagonism of N-methyl-d-aspartate receptor.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages3

Reading Time8 min

AccessFree to download

Abstract

Introduction

Methods

Serum sampling and metabolite analysis

Statistical analysis

Results

Initial phase of TKP

Intermediate phase of TKP

Final phase of TKP

Correspondence and publication details

Table 1. Kynurenines (serum) concentrations

Integrative Molecular Medicine | Research Article ISSN: 2056-6360 | | --- | | Kynurenic acid, an aryl hydrocarbon receptor ligand, is elevated in serum of Zucker fatty rats
Oxenkrug G1*, Cornicelli J2, van der Hart M3, RoeserJ3 and Summergrad P1
1Department of Psychiatry, Tufts University School of Medicine, Boston, USA 2Charles River, Inc., USA
3Brains On-Line, S. San Francisco, USA | | Abstract
Obesity is an increasingly urgent global problem. Molecular mechanisms of obesity have not been fully understood. Dysregulation of tryptophan (Trp)– kynurenine (Kyn) metabolic pathway (TKP) was suggested as one of the mechanism of obesity and described in obese subjects and animal models of obesity. However, to the best of our knowledge, TKP metabolism has not been studied in leptin-receptor-deficient Zucker fatty rats (ZFR) (fa/fa), the best-known and most widely used rat model of obesity. We therefore interested to find out if there are any deviations ofTKP in ZFR. Concentrations of major TKP metabolites were evaluated (HPLC-MS method) in serum of ZFR (fa/fa) and lean rats (FA/-). Concentrations ofkynurenic acid (KYNA) were 50% higher in ZFR that in lean rats (p<0.004, Mann-Whitney two-tailed test) . While elevation of anthranilic acid (AA) concentrations (33%), did not reach high level of statistical significance (p<0.04, one-tailed test) . Our data suggested that elevated KYNA serum concentrations might contribute to development of obesity via KYNA-induced activation of aryl hydrocarbon receptor (AHR) and to cognitive impairment in ZFR because of KYNA antagonism to N-methyl-d-aspartate receptor (NMDAR) . Elevated KYNA concentrations were reported in brains, cerebrospinal fluid and serum of schizophrenia patients. Therefore, up-regulated KYNA formation might contribute to high prevalence of obesity in schizophrenia patients. Present results warrant further studies ofKYNA and AA in other animal models of obesity. | Introduction Obesity is an increasingly urgent global problem. Molecular mechanisms of obesity have not been fully understood. Dysregulation of tryptophan (Trp)–kynurenine (Kyn) metabolic pathway (TKP) was suggested as one of the mechanisms to of obesity [1,2] . In mammals, TKP consists of three major phases: initial conversion of Trp into KYN (via N-formylKYN) catalyzed by inflammation-induced indoleamine- 2,3-dioxygenase 1 (IDO) or stress-activated Trp-2,3-dioxygenase 2 ( TDO); intermediate by Kyn conversion into 3-hydroxykynurenine (3-HK), kynurenic (KYNA) and anthranilic (AA) acids; and final phase production of NAD initiated by 3-HK conversion into 3-hydroxyAA (Figure 1) [3]. KYNA andAA are the end-products of KTPin astrocytes and adipocytes because Kyn-3-monooxygenase (KMO), a riboflavin (vitamin B2)-dependent enzyme, that catalyzes Kyn conversion into 3-HK, is not expressed in these tissues [4,5] . Activation of TKP initial phase was reported in animal models of obesity [6,7] and in obese human subjects [8-10] . Recent studies found different patterns of TKP dysregulation in obese mice and in human obesity and concluded that these mouse models [high-fat diet inducedobesity and the leptin-deficiency (ob/ob)] are inappropriate for studies ofTKP involvement in mechanisms of human obesity [11] . However, to the best of our knowledge, TKP metabolism has not been studied in leptin-receptor-deficient Zucker fatty rats (ZFR) (fa/fa), the bestknown and most widely used rat model of obesity. We were interested to find out if there are any deviations of TKP in ZFR by comparing serum concentrations of major TKP metabolites in ZFR (fa/fa) and lean rats (FA/-) . Methods Serum samples (drawn after 5 hrs of fasting) from male ZFR (fa/ fa) and lean (FA/-) rats (6 – 8 weeks of age) were provided by Charles River, Inc. and stored at −50°C until analysis. Trp, Kyn, KYNA, AA, 3-HK, and XA were analyzed by modified HPLC – MS method [12,13] . Statistical analysis Results are presented as mean ± standard error

FAQs

What was the main goal of the study in Zucker fatty rats (ZFR)?

To determine whether the tryptophan–kynurenine metabolic pathway (TKP) shows deviations in ZFR by comparing serum concentrations of major TKP metabolites between ZFR (fa/fa) and lean rats.

Which TKP metabolite showed the most significant change in ZFR serum?

Kynurenic acid (KYNA) was elevated by about 50% in ZFR serum compared with lean rats, with reported statistical significance (p<0.004; Mann–Whitney two-tailed test).

How might increased KYNA relate to obesity or cognition in this model?

The results suggest elevated KYNA could contribute to obesity via activation of the aryl hydrocarbon receptor (AHR) and to cognitive impairment by antagonizing the N-methyl-d-aspartate receptor (NMDAR).

Sep 10, 2026

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