More Metabolism!

To celebrate our Focus Issue, we asked a selection of researchers working on different aspects of metabolism what they are excited about and what is still to come. They discuss emerging concepts, unanswered questions, things to consider, and technologies that are enabling new discoveries, as well as developing and integrating approaches to drive the field forward.

Metabolic channeling: predictions, deductions, and evidence.

With the elucidation of myriad anabolic and catabolic enzyme-catalyzed cellular pathways crisscrossing each other, an obvious question arose: how could these networks operate with maximal catalytic efficiency and minimal interference? A logical answer was the postulate of metabolic channeling, which in its simplest embodiment assumes that the product generated by one enzyme passes directly to a second without diffusion into the surrounding medium. This tight coupling of activities might increase a pathway's metabolic flux and/or serve to sequester unstable/toxic/reactive intermediates as well as prevent their access to other networks. Here, we present evidence for this concept, commencing with enzymes that feature a physical molecular tunnel, to multi-enzyme complexes that retain pathway substrates through electrostatics or enclosures, and finally to metabolons that feature collections of enzymes assembled into clusters with variable stoichiometric composition. Lastly, we discuss the advantages of reversibly assembled metabolons in the context of the purinosome, the purine biosynthesis metabolon.

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Scaling of joint mass and metabolism fluctuations in in silico cell-laden spheroids.

Variations and fluctuations are characteristic features of biological systems and are also manifested in cell cultures. Here, we describe a computational pipeline for identifying the range of three-dimensional (3D) cell-aggregate sizes in which nonisometric scaling emerges in the presence of joint mass and metabolic rate fluctuations. The 3D cell-laden spheroids with size and single-cell metabolic rates described by probability density functions were randomly generated in silico. The distributions of the resulting metabolic rates of the spheroids were computed by modeling oxygen diffusion and reaction. Then, a method for estimating scaling exponents of correlated variables through statistically significant data collapse of joint probability distributions was developed. The method was used to identify a physiologically relevant range of spheroid sizes, where both nonisometric scaling and a minimum oxygen concentration (0.04 mol⋅m-3) is maintained. The in silico pipeline described enables the prediction of the number of experiments needed for an acceptable collapse and, thus, a consistent estimate of scaling parameters. Using the pipeline, we also show that scaling exponents may be significantly different in the presence of joint mass and metabolic-rate variations typically found in cells. Our study highlights the importance of incorporating fluctuations and variability in size and metabolic rates when estimating scaling exponents. It also suggests the need for taking into account their covariations for better understanding and interpreting experimental observations both in vitro and in vivo and brings insights for the design of more predictive and physiologically relevant in vitro models.

Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides.

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.

Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence.

Host-derived fatty acids are an important carbon source for pathogenic mycobacteria during infection. How mycobacterial cells regulate the catabolism of fatty acids to serve the pathogenicity, however, remains unknown. Here, we identified a TetR-family transcriptional factor, FdmR, as the key regulator of fatty acid catabolism in the pathogen Mycobacterium marinum by combining use of transcriptomics, chromatin immunoprecipitation followed by sequencing, dynamic 13C-based flux analysis, metabolomics, and lipidomics. An M. marinum mutant deficient in FdmR was severely attenuated in zebrafish larvae and adult zebrafish. The mutant showed defective growth but high substrate consumption on fatty acids. FdmR was identified as a long-chain acyl-coenzyme A (acyl-CoA)-responsive repressor of genes involved in fatty acid degradation and modification. We demonstrated that FdmR functions as a valve to direct the flux of exogenously derived fatty acids away from ß-oxidation toward lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. Moreover, we found that FdmR suppresses degradation of long-chain acyl-CoAs endogenously synthesized through the type I fatty acid synthase. By modulating the supply of long-chain acyl-CoAs for lipogenesis, FdmR controls the abundance and chain length of virulence-associated lipids and mycolates and plays an important role in the impermeability of the cell envelope. These results reveal that despite the fact that host-derived fatty acids are used as an important carbon source, overactive catabolism of fatty acids is detrimental to mycobacterial cell growth and pathogenicity. This study thus presents FdmR as a potentially attractive target for chemotherapy.

"Minimal metabolism": A key concept to investigate the origins and nature of biological systems.

The systems view on life and its emergence from complex chemistry has remarkably increased the scientific attention on metabolism in the last two decades. However, during this time there has not been much theoretical discussion on what constitutes a metabolism and what role it actually played in biogenesis. A critical and updated review on the topic is here offered, including some references to classical models from last century, but focusing more on current and future research. Metabolism is considered as intrinsically related to the living but not necessarily equivalent to it. More precisely, the idea of "minimal metabolism", in contrast to previous, top-down conceptions, is formulated as a heuristic construct, halfway between chemistry and biology. Thus, rather than providing a complete or final characterization of metabolism, our aim is to encourage further investigations on it, particularly in the context of life's origin, for which some concrete methodological suggestions are provided. Also see the video abstract here: https://youtu.be/DP7VMKk2qpA.

ABHD5 suppresses cancer cell anabolism through lipolysis-dependent activation of the AMPK/mTORC1 pathway.

ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest.

Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans.

Misalignment of the daily sleep-wake and fasting-feeding cycles with the endogenous circadian timing system is an inevitable consequence of night shift work and is associated with adverse metabolic health effects. However, a detailed characterisation of the effects of night shifts on 24-h rhythms in the metabolome is missing. We performed targeted metabolomic profiling on plasma samples collected every 2 h from healthy human subjects during two 24-h measurement periods at baseline and on the fourth day of a simulated night shift protocol, in which the habitual sleep-wake cycle was delayed by 10 h. Thirty-two out of the 130 detected metabolites showed a 24-h rhythm both at baseline and during the night shift condition. Among these, 75% were driven by sleep-wake and fasting-feeding cycles rather than by the endogenous circadian clock, showing an average phase delay of 8.8 h during the night shift condition. Hence, the majority of rhythmic metabolites were misaligned relative to the endogenous circadian system during the night shift condition. This could be a key mechanism involved in the increased prevalence of adverse metabolic health effects observed in shift workers. On the individual level, the response to the night shift protocol was highly diverse, with phase shifts of rhythmic metabolite profiles ranging from a 0.2-h advance in one subject to a 12-h delay in another subject, revealing an individual metabolomic signature of circadian misalignment. Our findings provide insight into the overall and individual responses of the metabolome to circadian misalignment associated with night schedules and may thereby contribute to the development of individually tailored strategies to minimise the metabolic impacts of shift work.

Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.

Human mitochondrial DNA (mtDNA) shows extensive within population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic,metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation,insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.

Effects of Increased Central Cholinergic Activity on the Metabolic Challenge Induced by Submaximal Exercise in Rats: Adrenomedullary Secretion Influences.

AIM: The aim of this study was to assess the influence of adrenomedullary secretion on the plasma glucose, lactate, and free fatty acids (FFAs) during running exercise in rats submitted to intracerebroventricular (i.c.v.) injection of physostigmine (PHY). PHY i.c.v. was used to activate the central cholinergic system. METHODS: Wistar rats were divided into sham-saline (sham-SAL), sham-PHY, adrenal medullectomy-SAL, and ADM-PHY groups. The plasma concentrations of glucose, lactate, and FFAs were determined immediately before and after i.c.v. injection of 20 µL of SAL or PHY at rest and during running exercise on a treadmill. RESULTS: The i.c.v. injection of PHY at rest increased plasma glucose in the sham group, but not in the ADM group. An increase in plasma glucose, lactate, and FFAs mobilization from adipose tissue was observed during physical exercise in the sham-SAL group; however, the increase in plasma glucose was greater with i.c.v. PHY. Moreover, the hyperglycemia induced by exercise and PHY in the ADM group were blunted by ADM, whereas FFA mobilization was unaffected. CONCLUSION: These results indicate that there is a dual metabolic control by which activation of the central cholinergic pathway increases plasma glucose but not FFA during rest and exercise, and that this hyperglycemic response is dependent on adrenomedullary secretion.

Associations between obesity, metabolic health, and the risk of breast cancer in East Asian women.

BACKGROUND: This study examined the associations between metabolic syndrome(MetS), obesity, their combination as a metabolic obesity phenotype, and the risk of breast cancer in East Asian postmenopausal women. METHODS: A total of 3,095,336 postmenopausal cancer-free women aged 40-79 years who underwent the National Health Insurance Service health examination between 2009 and 2010 were included. The incidence of invasive breast cancer was followed up until 2018. The presence of obesity (body mass index[BMI] ≥25 kg/m2), MetS, and each component of MetS was investigated. RESULTS: Obesity and MetS were associated with breast cancer risk, but when the effects of obesity and MetS were mutually adjusted, the associations were attenuated, especially for MetS. Only elevated fasting blood glucose levels and waist circumference increased the risk of breast cancer after adjusting for BMI. Compared to metabolically healthy normal-weight women, metabolically unhealthy normal-weight women, metabolically healthy obese, and metabolically unhealthy obese women had an increased risk of breast cancer. CONCLUSIONS: Obesity and MetS were independently associated with an increased risk of breast cancer in postmenopausal women, despite the relationship between MetS and breast cancer appearing to result from a partial association with BMI. Postmenopausal women should be encouraged to control their weight and metabolic health.

Assessing the role of amino acids in systemic inflammation and organ failure in patients with ACLF.

BACKGROUND & AIMS: Systemic inflammation and organ failure(s) are the hallmarks of acute-on-chronic liver failure (ACLF), yet their pathogenesis remains uncertain. Herein, we aimed to assess the role of amino acids in these processes in patients with ACLF. METHODS: The blood metabolomic database of the CANONIC study (comprising 137 metabolites, with 43% related to amino acids) - obtained in 181 patients with ACLF and 650 with acute decompensation without ACLF (AD) - was reanalyzed with a focus on amino acids, in particular 9 modules of co-regulated metabolites. We also compared blood metabolite levels between ACLF and AD. RESULTS: The main findings in ACLF were: i) Metabolite modules were increased in parallel with increased levels of markers of systemic inflammation and oxidative stress. ii) Seventy percent of proteinogenic amino acids were present and most were increased. iii) A metabolic network, comprising the amino acids aspartate, glutamate, the serine-glycine one-carbon metabolism (folate cycle), and methionine cycle, was activated, suggesting increased purine and pyrimidine nucleotide synthesis. iv) Cystathionine, L-cystine, glutamate and pyroglutamate, which are involved in the transsulfuration pathway (a methionine cycle branch) were increased, consistent with increased synthesis of the antioxidant glutathione. v) Intermediates of the catabolism of 5 out of the 6 ketogenic amino acids were increased. vi) The levels of spermidine (a polyamine inducer of autophagy with anti-inflammatory effects) were decreased. CONCLUSIONS: In ACLF, blood amino acids fueled protein and nucleotide synthesis required for the intense systemic inflammatory response. Ketogenic amino acids were extensively catabolized to produce energy substrates in peripheral organs, an effect that was insufficient because organs failed. Finally, the decrease in spermidine levels may cause a defect in autophagy contributing to the proinflammatory phenotype in ACLF. LAY SUMMARY: Systemic inflammation and organ failures are hallmarks of acute-on-chronic liver failure (ACLF). Herein, we aimed to characterize the role of amino acids in these processes. The blood metabolome of patients with acutely decompensated cirrhosis, and particularly those with ACLF, reveals evidence of intense skeletal muscle catabolism. Importantly, amino acids (along with glucose), are used for intense anabolic, energy-consuming metabolism in patients with ACLF, presumably to support de novo nucleotide and protein synthesis in the activated innate immune system.

Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses.

RATIONALE: A hallmark of chronic inflammatory disorders is persistence of proinflammatory macrophages in diseased tissues. In atherosclerosis, this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood. OBJECTIVE: To investigate mechanisms linking dyslipidemia, oxidative stress, and macrophage activation through modulation of immunometabolism and to explore therapeutic potential targeting specific metabolic pathways. METHODS AND RESULTS: Using a combination of biochemical, immunologic, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxidized LDL (low-density lipoprotein). Mitochondrial-specific inhibition of superoxide inhibited oxidized LDL-induced NF-κB (nuclear factor-κB) activation and inflammatory cytokine generation. RNA sequencing, flow cytometry, 3H-labeled palmitic acid uptake, lipidomic analysis, confocal and electron microscopy imaging, and functional energetics revealed that oxidized LDL upregulated effectors of long-chain fatty acid uptake and mitochondrial import, while downregulating fatty acid oxidation and inhibiting ATP5A (ATP synthase F1 subunit alpha)-an electron transport chain component. The combined effect is long-chain fatty acid accumulation, alteration of mitochondrial structure and function, repurposing of the electron transport chain to superoxide production, and NF-κB activation. Apoe null mice challenged with high-fat diet showed similar metabolic changes in circulating Ly6C+ monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial reactive oxygen species were positively correlated with CD36 expression in aortic lesional macrophages. CONCLUSIONS: These findings reveal that oxidized LDL/CD36 signaling in macrophages links dysregulated fatty acid metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.

Elementary Growth Modes provide a molecular description of cellular self-fabrication.

In this paper we try to describe all possible molecular states (phenotypes) for a cell that fabricates itself at a constant rate, given its enzyme kinetics and the stoichiometry of all reactions. For this, we must understand the process of cellular growth: steady-state self-fabrication requires a cell to synthesize all of its components, including metabolites, enzymes and ribosomes, in proportions that match its own composition. Simultaneously, the concentrations of these components affect the rates of metabolism and biosynthesis, and hence the growth rate. We here derive a theory that describes all phenotypes that solve this circular problem. All phenotypes can be described as a combination of minimal building blocks, which we call Elementary Growth Modes (EGMs). EGMs can be used as the theoretical basis for all models that explicitly model self-fabrication, such as the currently popular Metabolism and Expression models. We then use our theory to make concrete biological predictions. We find that natural selection for maximal growth rate drives microorganisms to states of minimal phenotypic complexity: only one EGM will be active when growth rate is maximised. The phenotype of a cell is only extended with one more EGM whenever growth becomes limited by an additional biophysical constraint, such as a limited solvent capacity of a cellular compartment. The theory presented here extends recent results on Elementary Flux Modes: the minimal building blocks of cellular growth models that lack the self-fabrication aspect. Our theory starts from basic biochemical and evolutionary considerations, and describes unicellular life, both in growth-promoting and in stress-inducing environments, in terms of EGMs.

Intracellular metabolic reprogramming mediated by micro-RNAs in differentiating and proliferating cells under non-diseased conditions.

Intracellular metabolic reprogramming is a critical process the cells carry out to increase biomass, energy fulfillment and genome replication. Cells reprogram their demands from internal catabolic or anabolic activities in coordination with multiple genes and microRNAs which further control the critical processes of differentiation and proliferation. The microRNAs reprogram the metabolism involving mitochondria, the nucleus and the biochemical processes utilizing glucose, amino acids, lipids, and nucleic acids resulting in ATP production. The processes of glycolysis, tricarboxylic acid cycle, or oxidative phosphorylation are also mediated by micro-RNAs maintaining cells and organs in a non-diseased state. Several reports have shown practical applications of metabolic reprogramming for clinical utility to assess various diseases, mostly studying cancer and immune-related disorders. Cells under diseased conditions utilize glycolysis for abnormal growth or proliferation, respectively, affecting mitochondrial paucity and biogenesis. Similar metabolic processes also affect gene expressions and transcriptional regulation for carrying out biochemical reactions. Metabolic reprogramming is equally vital for regulating cell environment to maintain organs and tissues in non-diseased states. This review offers in depth insights and analysis of how miRNAs regulate metabolic reprogramming in four major types of cells undergoing differentiation and proliferation, i.e., immune cells, neuronal cells, skeletal satellite cells, and cardiomyocytes under a non-diseased state. Further, the work systematically summarizes and elaborates regulation of genetic switches by microRNAs through predominantly through cellular reprogramming and metabolic processes for the first time. The observations will lead to a better understanding of disease initiation during the differentiation and proliferation stages of cells, as well as fresh approaches to studying clinical onset of linked metabolic diseases targeting metabolic processes.

Do Telomeres Influence Pace-of-Life-Strategies in Response to Environmental Conditions Over a Lifetime and Between Generations?

The complexity of the physiological phenotype currently prevents us from identifying an integrative measure to assess how the internal state and environmental conditions modify life-history strategies. In this article, it is proposed that shorter telomeres should lead to a faster pace-of-life where investment in self-maintenance is decreased as a means of saving energy for reproduction, but at the cost of somatic durability. Inversely, longer telomeres would favor an increased investment in soma maintenance and thus a longer reproductive lifespan (i.e., slower pace-of-life). Under this hypothesis, telomere dynamics could be such an integrative mediator, which will assemble the information about oxidative stress levels, inflammation status and stress reactivity, and relate this information to the potential lifespan of the organism and its pace-of-life strategy. The signaling function of telomere dynamics can also reach over generations, a phenomenon in which the telomere lengths of gametes would provide a channel through which offspring would receive information about their environment early in their development, hence increasing the possibilities for developmental plasticity.

Effects of a One-week Vacation with Various Activity Programs on Metabolism and Adipokines.

This study was conducted as part of a larger study of East Tyrolean health tourism, and investigates the effects of an active seven-day vacation on metabolic parameters and adipokines. Fifty-two healthy vacationers participated in two types of vacation activities (golf vs. Nordic walking or e-biking [nw&eb]). In the former group, 30 subjects played golf for a mean duration of 33.5 h per week; in the NW&EB group, 22 persons performed Nordic walking or e-biking for a mean duration of 14.2 h per week. Metabolic parameters and adipokines, such as leptin, adiponectin, GF-21, irisin, omentin-1, betatrophin, and resistin, were measured one day before and one day after the stay. After one week, only the NW&EB group experienced a significant decrease of 1.0 kg in body weight. Significant changes in HDL-C, FGF-21, irisin, and omentin-1 were seen in the golf group; and in triglycerides, HbA1c, leptin and adiponectin in the NW&EB group. No significant changes in betatrophin or resistin were registered in either group. A seven-day vacation with an activity program for several hours per week causes favorable changes in metabolic parameters and adipokines known to be involved in the pathophysiology of the metabolic syndrome. The changes differed in their magnitude and significance, depending on the type of activity.

Metabolic Shifts as the Hallmark of Most Common Diseases: The Quest for the Underlying Unity.

A hyper-specialization characterizes modern medicine with the consequence of classifying the various diseases of the body into unrelated categories. Such a broad diversification of medicine goes in the opposite direction of physics, which eagerly looks for unification. We argue that unification should also apply to medicine. In accordance with the second principle of thermodynamics, the cell must release its entropy either in the form of heat (catabolism) or biomass (anabolism). There is a decreased flow of entropy outside the body due to an age-related reduction in mitochondrial entropy yield resulting in increased release of entropy in the form of biomass. This shift toward anabolism has been known in oncology as Warburg-effect. The shift toward anabolism has been reported in most diseases. This quest for a single framework is reinforced by the fact that inflammation (also called the immune response) is involved in nearly every disease. This strongly suggests that despite their apparent disparity, there is an underlying unity in the diseases. This also offers guidelines for the repurposing of old drugs.

The kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain.

Tryptophan catabolism through the kynurenine pathway generates a variety of bioactive metabolites. Physical exercise can modulate kynurenine pathway metabolism in skeletal muscle and thus change the concentrations of select compounds in peripheral tissues and in the central nervous system. Here we review recent advances in our understanding of how exercise alters tryptophan-kynurenine metabolism in muscle and its subsequent local and distal effects. We propose that the effects of kynurenine pathway metabolites on skeletal muscle, adipose tissue, immune system, and the brain suggest that some of these compounds could qualify as exercise-induced myokines. Indeed, some of the more recently discovered biological activities for kynurenines include many of the best-known benefits of exercise: improved energy homeostasis, promotion of an anti-inflammatory environment, and neuroprotection. Finally, by considering the tissue expression of the different membrane and cytosolic receptors for kynurenines, we discuss known and potential biological activities for these tryptophan metabolites.