Constitutive loss of kynurenine-3-monooxygenase changes circulating kynurenine metabolites without affecting systemic energy metabolism.

Abstract

Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites of the kynurenine pathway of tryptophan degradation with opposing biological activities in the central nervous system. In the periphery, KYNA is known to positively affect metabolic health, whereas the effects of QUIN remain less explored. Interestingly, metabolic stressors, including exercise and obesity, differentially change the balance between circulating KYNA and QUIN. Here, we hypothesized that chronically elevated levels of circulating KYNA and reduced levels of QUIN would manifest as differences in whole body energy metabolism. To test this, we used a mouse model lacking the enzyme kynurenine 3-monooxygenase (KMO), thus shunting kynurenine away from QUIN synthesis and toward KYNA production. KMO-deficient and wild-type littermate male and female mice were evaluated under chow and high-fat diets. Comprehensive kynurenine pathway metabolite profiling in plasma showed that the loss of KMO elicits robust changes in circulating levels of kynurenine metabolites. This included a 45-fold increase in kynurenine, a 26-fold increase in KYNA, and a 99% decrease in QUIN levels, depending on the diet. However, despite these changes, loss of KMO did not significantly impact whole body energy metabolism or change the transcriptomic profile of subcutaneous adipose tissue on either diet. With KMO inhibitors being considered therapeutic candidates for various disorders, this work shows that chronic systemic KMO inhibition does not have widespread metabolic effects. Our data also indicate that the beneficial effects of KYNA on metabolism may depend on its acute, intermittent elevation in circulation, akin to transient exercise-induced signals that mediate improved metabolic health.NEW & NOTEWORTHY The kynurenine pathway of tryptophan degradation is influenced by metabolic stressors: exercise raises circulating KYNA levels, while obesity is linked to increased QUIN. We investigated whether a mouse model lacking KMO-leading to increased circulating KYNA and decreased QUIN-would exhibit changes in energy metabolism. We found that energy metabolism was largely unaffected despite robust changes in circulating kynurenine metabolites, suggesting that systemic KMO inhibition may not have widespread metabolic effects.