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1.
Cell ; 185(23): 4280-4297.e12, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36323316

RESUMEN

The gut microbiome has an important role in infant health and development. We characterized the fecal microbiome and metabolome of 222 young children in Dhaka, Bangladesh during the first two years of life. A distinct Bifidobacterium longum clade expanded with introduction of solid foods and harbored enzymes for utilizing both breast milk and solid food substrates. The clade was highly prevalent in Bangladesh, present globally (at lower prevalence), and correlated with many other gut taxa and metabolites, indicating an important role in gut ecology. We also found that the B. longum clades and associated metabolites were implicated in childhood diarrhea and early growth, including positive associations between growth measures and B. longum subsp. infantis, indolelactate and N-acetylglutamate. Our data demonstrate geographic, cultural, seasonal, and ecological heterogeneity that should be accounted for when identifying microbiome factors implicated in and potentially benefiting infant development.


Asunto(s)
Bifidobacterium longum , Lactante , Niño , Femenino , Humanos , Preescolar , Bifidobacterium longum/metabolismo , Bifidobacterium/metabolismo , Destete , Oligosacáridos/metabolismo , Bangladesh , Leche Humana , Heces/microbiología
2.
Cell ; 184(16): 4168-4185.e21, 2021 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-34216539

RESUMEN

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.


Asunto(s)
Autoinmunidad/inmunología , Modelos Biológicos , Células Th17/inmunología , Acetiltransferasas/metabolismo , Adenosina Trifosfato/metabolismo , Aerobiosis/efectos de los fármacos , Algoritmos , Animales , Autoinmunidad/efectos de los fármacos , Cromatina/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Citocinas/metabolismo , Eflornitina/farmacología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Epigenoma , Ácidos Grasos/metabolismo , Glucólisis/efectos de los fármacos , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones Endogámicos C57BL , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Oxidación-Reducción/efectos de los fármacos , Putrescina/metabolismo , Análisis de la Célula Individual , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/efectos de los fármacos , Transcriptoma/genética
3.
Cell ; 170(1): 199-212.e20, 2017 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-28666119

RESUMEN

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.


Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Basigina/metabolismo , Membrana Celular/metabolismo , Cromosomas Humanos Par 17/metabolismo , Técnicas de Silenciamiento del Gen , Haplotipos , Hepatocitos/metabolismo , Heterocigoto , Código de Histonas , Humanos , Hígado/metabolismo , Modelos Moleculares , Transportadores de Ácidos Monocarboxílicos/química
4.
Cell ; 164(5): 884-95, 2016 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-26919427

RESUMEN

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.


Asunto(s)
Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Precondicionamiento Isquémico , Ácidos Cetoglutáricos/metabolismo , Animales , Isquemia/prevención & control , Ácido Quinurénico/metabolismo , Hígado/metabolismo , Ratones , Modelos Animales , Daño por Reperfusión Miocárdica/prevención & control , Parabiosis
5.
Cell ; 167(1): 171-186.e15, 2016 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-27641501

RESUMEN

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.


Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Terapia Molecular Dirigida , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Diferenciación Celular , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Ensayos Analíticos de Alto Rendimiento , Proteínas de Homeodominio/genética , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Células Mieloides/patología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Pirimidinas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/aislamiento & purificación , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Nature ; 596(7873): 576-582, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34381210

RESUMEN

Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.


Asunto(s)
Ciclo Celular , Linaje de la Célula , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antioxidantes/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Células Clonales/patología , Código de Barras del ADN Taxonómico , Ácidos Grasos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Lentivirus/genética , Recurrencia Local de Neoplasia/genética , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Oncogénicas/antagonistas & inhibidores , Oxidación-Reducción , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Transcripción Genética/efectos de los fármacos
8.
Nature ; 560(7716): 102-106, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30022159

RESUMEN

Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease1. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation2-4. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid cycle intermediate succinate is a metabolic signature of adipose tissue thermogenesis upon activation by exposure to cold. Succinate accumulation occurs independently of adrenergic signalling, and is sufficient to elevate thermogenic respiration in brown adipocytes. Selective accumulation of succinate may be driven by a capacity of brown adipocytes to sequester elevated circulating succinate. Furthermore, brown adipose tissue thermogenesis can be initiated by systemic administration of succinate in mice. Succinate from the extracellular milieu is rapidly metabolized by brown adipocytes, and its oxidation by succinate dehydrogenase is required for activation of thermogenesis. We identify a mechanism whereby succinate dehydrogenase-mediated oxidation of succinate initiates production of reactive oxygen species, and drives thermogenic respiration, whereas inhibition of succinate dehydrogenase supresses thermogenesis. Finally, we show that pharmacological elevation of circulating succinate drives UCP1-dependent thermogenesis by brown adipose tissue in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis, using succinate as a systemically-derived thermogenic molecule.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Ácido Succínico/metabolismo , Termogénesis/fisiología , Adipocitos/efectos de los fármacos , Adipocitos/enzimología , Adipocitos/metabolismo , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/enzimología , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/enzimología , Tejido Adiposo Blanco/metabolismo , Animales , Femenino , Masculino , Metabolómica , Ratones , Obesidad/metabolismo , Obesidad/prevención & control , Oxidación-Reducción/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Succinato Deshidrogenasa/metabolismo , Ácido Succínico/farmacología , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1/metabolismo
9.
Nature ; 532(7597): 112-6, 2016 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-27027295

RESUMEN

Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.


Asunto(s)
Cisteína/química , Metabolismo Energético , Canales Iónicos/química , Canales Iónicos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Termogénesis , Tejido Adiposo Pardo/química , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Animales , Respiración de la Célula , Cisteína/genética , Cisteína/metabolismo , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Canales Iónicos/deficiencia , Canales Iónicos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oxidación-Reducción , Compuestos de Sulfhidrilo/metabolismo , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1
10.
Circulation ; 142(20): 1905-1924, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-32927962

RESUMEN

BACKGROUND: Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans. METHODS: Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411). RESULTS: We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; P=1.5×10-55; dimethylguanidino valeric acid [DMGV], -18%; P=5.8×10-18) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10-67), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10-169), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10-38), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo2). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (P≤0.003 for both). CONCLUSIONS: In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.


Asunto(s)
Índice de Masa Corporal , Enfermedades Cardiovasculares , Ejercicio Físico , Metaboloma , Metabolómica , Adulto , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/terapia , Femenino , Humanos , Masculino , Massachusetts , Persona de Mediana Edad , Estudios Prospectivos
11.
Proc Natl Acad Sci U S A ; 115(27): E6283-E6290, 2018 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-29915083

RESUMEN

Renal oncocytomas are benign tumors characterized by a marked accumulation of mitochondria. We report a combined exome, transcriptome, and metabolome analysis of these tumors. Joint analysis of the nuclear and mitochondrial (mtDNA) genomes reveals loss-of-function mtDNA mutations occurring at high variant allele fractions, consistent with positive selection, in genes encoding complex I as the most frequent genetic events. A subset of these tumors also exhibits chromosome 1 loss and/or cyclin D1 overexpression, suggesting they follow complex I loss. Transcriptome data revealed that many pathways previously reported to be altered in renal oncocytoma were simply differentially expressed in the tumor's cell of origin, the distal nephron, compared with other nephron segments. Using a heuristic approach to account for cell-of-origin bias we uncovered strong expression alterations in the gamma-glutamyl cycle, including glutathione synthesis (increased GCLC) and glutathione degradation. Moreover, the most striking changes in metabolite profiling were elevations in oxidized and reduced glutathione as well as γ-glutamyl-cysteine and cysteinyl-glycine, dipeptide intermediates in glutathione biosynthesis, and recycling, respectively. Biosynthesis of glutathione appears adaptive as blockade of GCLC impairs viability in cells cultured with a complex I inhibitor. Our data suggest that loss-of-function mutations in complex I are a candidate driver event in renal oncocytoma that is followed by frequent loss of chromosome 1, cyclin D1 overexpression, and adaptive up-regulation of glutathione biosynthesis.


Asunto(s)
Adenoma Oxifílico , Complejo I de Transporte de Electrón/deficiencia , Glutatión , Neoplasias Renales , Mitocondrias , Proteínas de Neoplasias/deficiencia , Adenoma Oxifílico/genética , Adenoma Oxifílico/metabolismo , Adenoma Oxifílico/patología , Supervivencia Celular/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Femenino , Perfilación de la Expresión Génica , Glutatión/genética , Glutatión/metabolismo , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología
12.
Mol Cell ; 48(6): 900-13, 2012 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-23142079

RESUMEN

Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1α acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.


Asunto(s)
Gluconeogénesis , Hepatocitos/metabolismo , Sirtuinas/fisiología , Transactivadores/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Animales , Glucemia , Línea Celular , Activación Enzimática , Expresión Génica , Gluconeogénesis/genética , Hepatocitos/enzimología , Humanos , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Obesos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fosforilación , Procesamiento Proteico-Postraduccional , Sirtuina 1/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismo , Factores de Transcripción
13.
Proc Natl Acad Sci U S A ; 114(22): E4472-E4481, 2017 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-28507131

RESUMEN

Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf. LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet- and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.


Asunto(s)
Glucemia/metabolismo , Microbioma Gastrointestinal/fisiología , Índice Glucémico/fisiología , Degeneración Macular/metabolismo , Retina/metabolismo , Animales , Productos Finales de Glicación Avanzada/metabolismo , Metaboloma/fisiología , Metabolómica , Ratones
14.
Circulation ; 137(8): 841-853, 2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29459470

RESUMEN

BACKGROUND: Although metabolomic profiling offers promise for the prediction of coronary heart disease (CHD), and metabolic risk factors are more strongly associated with CHD in women than men, limited data are available for women. METHODS: We applied a liquid chromatography-tandem mass spectrometry metabolomics platform to measure 371 metabolites in a discovery set of postmenopausal women (472 incident CHD cases, 472 controls) with validation in an independent set of postmenopausal women (312 incident CHD cases, 315 controls). RESULTS: Eight metabolites, primarily oxidized lipids, were significantly dysregulated in cases after the adjustment for matching and CHD risk factors in both the discovery and validation data sets. One oxidized phospholipid, C34:2 hydroxy-phosphatidylcholine, remained associated with CHD after further adjustment for other validated metabolites. Subjects with C34:2 hydroxy-phosphatidylcholine levels in the highest quartile had a 4.7-fold increase in CHD odds in comparison with the lowest quartile; C34:2 hydroxy-phosphatidylcholine also significantly improved the area under the curve (P<0.01) for CHD. The C34:2 hydroxy-phosphatidylcholine findings were replicated in a third replication data set of 980 men and women (230 cardiovascular events) with a stronger association observed in women. CONCLUSIONS: These data replicate known metabolite predictors, identify novel markers, and support the relationship between lipid oxidation and subsequent CHD.


Asunto(s)
Enfermedad Coronaria/sangre , Enfermedad Coronaria/epidemiología , Metabolómica , Fosfatidilcolinas/sangre , Anciano , Cromatografía Liquida , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Espectrometría de Masas en Tándem
15.
Cardiovasc Diabetol ; 18(1): 151, 2019 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-31722714

RESUMEN

BACKGROUND: The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. METHODS: Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography-tandem mass spectrometry, at baseline and after 1-year of intervention. RESULTS: In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05-1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. CONCLUSIONS: Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.


Asunto(s)
Ácido 2-Aminoadípico/sangre , Enfermedades Cardiovasculares/sangre , Diabetes Mellitus Tipo 2/sangre , Lisina/sangre , Ácidos Pipecólicos/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Dieta Mediterránea , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevención Primaria , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Conducta de Reducción del Riesgo , Factores de Tiempo , Resultado del Tratamiento
17.
Am J Nephrol ; 43(5): 366-74, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27172772

RESUMEN

BACKGROUND: Whereas several longitudinal metabolomics studies have been conducted in individuals with normal estimated glomerular filtration rate (eGFR) at baseline, disease progression among individuals with established chronic kidney disease (CKD) has not been rigorously examined. METHODS: We performed a nested case-control study of rapid CKD progression in the Chronic Renal Insufficiency Cohort Study, profiling baseline plasma from 200 individuals each with eGFR slope <-3 ml/min/1.73 m2/year (cases) or between -1 and +1 ml/min/1.73 m2/year (controls), matched on baseline eGFR and proteinuria. To directly assess how the kidney modulates circulating metabolites, we profiled plasma from the aorta and renal vein of 25 hospital-based individuals. RESULTS: At baseline, cases and controls had a mean eGFR of 41.7 ± 13.3 and 45.0 ± 14.5 ml/min/1.73 m2, respectively. Ten plasma metabolites were nominally associated with CKD progression in logistic regression models adjusted for age, sex, race/ethnicity, hypertension, systolic and diastolic blood pressure, diabetes, eGFR and proteinuria; no metabolite achieved the Bonferroni-adjusted significance threshold (p < 0.0003). In a cross-sectional analysis, all 6 of the metabolites that were higher in cases than controls were significantly associated with eGFR at baseline. By contrast, threonine, methionine and arginine were lower in cases than in controls and had no association with baseline eGFR. Furthermore, in the hospital-based cohort that underwent renal arteriovenous sampling, these 3 metabolites were net released from the kidney. Combining these metabolites into a panel of markers further strengthened their association with CKD progression. CONCLUSION: Our results motivate interest in arginine, methionine and threonine as potential indicators of renal metabolic function and markers of renal prognosis.


Asunto(s)
Insuficiencia Renal Crónica/metabolismo , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Metaboloma , Metabolómica , Persona de Mediana Edad
18.
Mol Genet Metab ; 114(1): 73-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25497115

RESUMEN

Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure.


Asunto(s)
Glucosa/metabolismo , Metaboloma , Benzoato de Sodio/administración & dosificación , Benzoato de Sodio/metabolismo , Adolescente , Adulto , Anticonvulsivantes/sangre , Glucemia/metabolismo , Estudios Cruzados , Dieta , Femenino , Conservantes de Alimentos/administración & dosificación , Conservantes de Alimentos/metabolismo , Glucagón/sangre , Glicina/análogos & derivados , Glicina/sangre , Hipuratos/sangre , Homeostasis , Humanos , Insulina/sangre , Masculino , Sobrepeso , Adulto Joven , ortoaminobenzoatos/sangre
19.
J Am Soc Nephrol ; 24(8): 1330-8, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23687356

RESUMEN

Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P≤0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR.


Asunto(s)
Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/epidemiología , Metabolómica/métodos , Anciano , Biomarcadores/sangre , Cromatografía Liquida , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Fallo Renal Crónico/sangre , Pruebas de Función Renal , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo
20.
bioRxiv ; 2024 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-38798570

RESUMEN

Parkinson's disease (PD) is the second most common neurodegenerative disorder and lacks disease-modifying therapies. We developed a Drosophila model for identifying novel glial-based therapeutic targets for PD. Human alpha-synuclein is expressed in neurons and individual genes are independently knocked down in glia. We performed a forward genetic screen, knocking down the entire Drosophila kinome in glia in alpha-synuclein expressing flies. Among the top hits were five genes (Ak1, Ak6, Adk1, Adk2, and awd) involved in adenosine metabolism. Knockdown of each gene improved locomotor dysfunction, rescued neurodegeneration, and increased brain adenosine levels. We determined that the mechanism of neuroprotection involves adenosine itself, as opposed to a downstream metabolite. We dove deeper into the mechanism for one gene, Ak1, finding rescue of dopaminergic neuron loss, alpha-synuclein aggregation, and bioenergetic dysfunction after glial Ak1 knockdown. We performed metabolomics in Drosophila and in human PD patients, allowing us to comprehensively characterize changes in purine metabolism and identify potential biomarkers of dysfunctional adenosine metabolism in people. These experiments support glial adenosine as a novel therapeutic target in PD.

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