Kynurenine metabolites are generated by tryptophan catabolism and regulate biological processes that include host-microbiome signaling, immune cell response, and neuronal excitability. Enzymes of the kynurenine pathway are expressed in different tissues and cell types throughout the body and are regulated by cues, including nutritional and inflammatory signals. As a consequence of this systemic metabolic integration, peripheral inflammation can contribute to accumulation of kynurenine in the brain, which has been associated with depression and schizophrenia. Conversely, kynurenine accumulation can be suppressed by activating kynurenine clearance in exercised skeletal muscle. The effect of exercise training on depression through modulation of the kynurenine pathway highlights an important mechanism of interorgan cross-talk mediated by these metabolites. Here, we discuss peripheral mechanisms of tryptophan-kynurenine metabolism and their effects on inflammatory, metabolic, oncologic, and psychiatric disorders.

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

Cell 159, 33-45; September 25, 2014) During the preparation of Figure 1 in the article above, we inadvertently included lines separating the lanes in the western blot shown in Figure 1E. In that panel, the Vinculin control for ARC should not display separating lines, as all samples were loaded on consecutive lanes. We would like to clarify that the legends of Figures 1 and 2 should have indicated that the separating lines demarcate bands that come from nonconsecutive lanes of the same gel. Finally, in the legend of Figure 1, we did not mention that the Vinculin loading control for ARC and CamKIIa shown in Figure 1E is the same, as these proteins were detected in the same membrane. The errors do not in any way affect the results or interpretation of the figure. We apologize for any confusion that these errors may have caused.

The role of tryptophan-kynurenine metabolism in psychiatric disease is well established, but remains less explored in peripheral tissues. Exercise training activates kynurenine biotransformation in skeletal muscle, which protects from neuroinflammation and leads to peripheral kynurenic acid accumulation. Here we show that kynurenic acid increases energy utilization by activating G protein-coupled receptor Gpr35, which stimulates lipid metabolism, thermogenic, and anti-inflammatory gene expression in adipose tissue. This suppresses weight gain in animals fed a high-fat diet and improves glucose tolerance. Kynurenic acid and Gpr35 enhance Pgc-1α1 expression and cellular respiration, and increase the levels of Rgs14 in adipocytes, which leads to enhanced beta-adrenergic receptor signaling. Conversely, genetic deletion of Gpr35 causes progressive weight gain and glucose intolerance, and sensitizes to the effects of high-fat diets. Finally, exercise-induced adipose tissue browning is compromised in Gpr35 knockout animals. This work uncovers kynurenine metabolism as a pathway with therapeutic potential to control energy homeostasis.

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin-17 (IL-17) have intrinsically distinct metabolic requirements. Whereas IFN-γ + γδ T cells were almost exclusively dependent on glycolysis, IL-17 + γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development, and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17 + γδ T cells selectively showed high lipid uptake and intracellular lipid storage, and were expanded in obesity, and in tumors of obese mice. Conversely, glucose supplementation enhanced the anti-tumor functions of IFN-γ + γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.

Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.

Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor ␥ coactivator-1 ␣ (PGC-1␣) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1␣1 expression, resistance exercise activates the expression of PGC-1␣2, -␣3, and -␣4. These three alternative PGC-1␣ isoforms lack the arginine/serine-rich (RS) and RNA recognition motifs characteristic of PGC-1␣1. Discrete functions for PGC-1␣1 and -␣4 have been described, but the biological role of PGC-1␣2 and -␣3 remains elusive. Here we show that different PGC-1␣ variants can affect target gene splicing through diverse mechanisms, including alternative promoter usage. By analyzing the exon structure of the target transcripts for each PGC-1␣ isoform, we were able to identify a large number of previously unknown PGC-1␣2 and -␣3 target genes and pathways in skeletal muscle. In particular, PGC-1␣2 seems to mediate a decrease in the levels of cholesterol synthesis genes. Our results suggest that the conservation of the N-terminal activation and repression domains (and not the RS/RNA recognition motif) is what determines the gene programs and splicing options modulated by each PGC-1␣ isoform. By using skeletal muscle-specific transgenic mice for PGC-1␣1 and -␣4, we could validate, in vivo, splicing events observed in in vitro studies. These results show that alternative PGC-1␣ variants can affect target gene expression both quantitatively and qualitatively and identify novel biological pathways under the control of this system of coactivators.