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.
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•Skeletal muscle-PGC-1α1 transgenic mice are resilient to stress-induced depression•PGC-1α1 induces skeletal muscle kynurenine aminotransferase (KAT) expression•Skeletal muscle PGC-1α1 controls plasma and brain kynurenine/kynurenic acid balance•Exercise training activates PGC-1α1:PPARα/δ:KAT in mouse and human skeletal muscle
Exercise training activates the PGC-1α1/PPARα/Δ pathway, increasing skeletal muscle expression of kynurenine aminotransferases that convert kynurenine to kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing the kynurenine burden protects the brain from stress-induced changes associated with depression.
PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We ...have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.
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► Three PGC-1α variants are generated by alternative promoter use and splicing ► PGC-1α4 induces skeletal muscle hypertrophy ► PGC-1α4 muscle-specific transgenics have increased muscle mass and strength ► PGC-1α4 transgenic mice are resistant to cancer-induced cachexia
A splice variant of PGC-1α promotes increased muscle mass and strength, improves exercise performance, and provides resistance to cancer-induced cachexia.
Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery ...tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.
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.
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•Kynurenic acid increases energy expenditure by activating Gpr35•Gpr35 activation improves energy metabolism and inflammation in mice fed a high-fat diet•Kynurenic acid enhances adipocyte beta-adrenergic receptor signaling through Rgs14•Gpr35 knockout compromises exercise-induced adipose tissue browning
Kynurenine is a neurotoxic metabolite detoxified to kynurenic acid by exercised skeletal muscle. Now, Agudelo et al. show that the rise in circulating kynurenic acid activates Gpr35 in adipose tissue and increases energy expenditure. This improves the metabolic consequences of high-fat diet feeding in mice. Gpr35 deletion causes progressive weight gain.
Exercised cytokines promote endurance Correia, Jorge C; Ruas, Jorge L
Science (American Association for the Advancement of Science),
05/2020, Letnik:
368, Številka:
6490
Journal Article
Recenzirano
Muscle tissue secretory response to exercise promotes beneficial metabolism
Exercise is important for human health. Many of the beneficial effects of exercise come from the activation of metabolism ...to drive muscle contraction, which mobilizes and utilizes fuel stores and promotes healthy systemic energy homeostasis. Conversely, sedentary behaviors are linked to higher incidence of diseases such as diabetes and cardiovascular disorders, but also neurodegeneration and certain types of cancer (
1
). For these reasons, identifying the molecular mediators of the benefits of exercise could provide new therapeutic tools to fight many chronic diseases. On page 488 of this issue, Knudsen
et al.
(
2
) report that the cytokine interleukin-13 (IL-13) is produced in mouse skeletal muscle tissue and increases with exercise. This cytokine is necessary for the metabolic adaptation to exercise and enhances endurance and systemic metabolism in mice.
Proteins of the peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 (PGC-1) family of transcriptional coactivators coordinate physiological adaptations in many tissues, usually in ...response to demands for higher nutrient and energy supply. Of the founding members of the family,
PGC-1α
(also known as
PPARGC1A
) is the most highly regulated gene, using multiple promoters and alternative splicing to produce a growing number of coactivator variants.
PGC-1α
promoters are selectively active in distinct tissues in response to specific stimuli. To date, more than ten novel PGC-1α isoforms have been reported to be expressed from a novel promoter (PGC-1α-b, PGC-1α-c), to undergo alternative splicing (NT-PGC-1α) or both (PGC-1α2, PGC-1α3, PGC-1α4). The resulting proteins display differential regulation and tissue distribution and, most importantly, exert specific biological functions. In this review we discuss the structural and functional characteristics of the novel PGC-1α isoforms, aiming to provide an integrative view of this constantly expanding system of transcriptional coactivators.
The kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism is dysregulated in inflammation-driven pathologies including oncological and brain diseases e.g., multiple sclerosis (MS), depression ...and thus is a promising therapeutic target. Both pathological and compensatory mechanisms underlie disease-associated KP activation. There is growing evidence for bioenergetic roles of certain KP metabolites such as kynurenic acid (KA), or quinolinic acid (QA) as an NAD+ precursor, which may explain its frequently observed ‘pathological’ overactivation. Disease- and tissue-specific aspects, negative feedback on inflammatory signals, and the balance of downstream metabolites are likely to be decisive factors in the interpretation of an imbalanced KP. Therapeutic strategies should consider the compensatory actions and bioenergetic roles of KP metabolites to successfully design future theragnostic approaches aimed at attenuating disease progression.
The kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation is consistently imbalanced in chronic inflammatory diseases but mediates partly pathological and partly compensatory mechanisms in disease progression.Therapeutic drugs designed to modulate key KP enzymes, such as indoleamine 2,3-dioxygenase-1 (IDO-1) or KYN aminotransferases (KATs), have entered clinical trials in patients with various oncological diseases and schizophrenia.Interleukin-4-induced-1 is an enzyme recently discovered to regulate the generation of TRP-derived endogenous aryl hydrocarbon receptor (AhR) ligands and represents a potential new therapeutic target, especially in oncological and neurodegenerative diseases.Increased KP metabolism may represent a mechanism to regenerate levels of the pyridine nucleotide NAD+, which is essential to the continued viability of cells.
The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing ...specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.
The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.
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.
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