RESUMEN
BACKGROUND: Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. METHODS: In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). RESULTS: In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. CONCLUSIONS: Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. TRIAL REGISTRATION: NCT01425580.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Incretinas/uso terapéutico , Lípidos/sangre , Liraglutida/uso terapéutico , Metaboloma , Metabolómica , Compuestos de Sulfonilurea/uso terapéutico , Anciano , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Incretinas/efectos adversos , Lipidómica , Liraglutida/efectos adversos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Espectrometría de Masa por Ionización de Electrospray , Compuestos de Sulfonilurea/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.
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Genómica , Medicina de Precisión , Atención a la Salud , Enfermedad , HumanosRESUMEN
The identification of an early biomarker of psychotic disorder is important as early treatment is associated with improved patient outcome. Metabolomic and lipidomic approaches in combination with multivariate statistical analysis were applied to identify plasma alterations in children (age 11) (38 cases vs 67 controls) and adolescents (age 18) (36 cases vs 117 controls) preceeding or coincident with the development of psychotic disorder (PD) at age 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC). Overall, 179 lipids were identified at age 11, with 32 found to be significantly altered between the control and PD groups. Following correction for multiple comparisons, 8 of these lipids remained significant (lysophosphatidlycholines (LPCs) LPC(18:1), LPC(18:2), LPC(20:3); phosphatidlycholines (PCs) PC(32:2; PC(34:2), PC(36:4), PC(0-34-3) and sphingomyelin (SM) SM(d18:1/24:0)), all of which were elevated in the PD group. At age 18, 23 lipids were significantly different between the control and PD groups, although none remained significant following correction for multiple comparisons. In conclusion, the findings indicate that the lipidome is altered in the blood during childhood, long before the development of psychotic disorder. LPCs in particular are elevated in those who develop PD, indicating inflammatory abnormalities and altered phospholipid metabolism. These findings were not found at age 18, suggesting there may be ongoing alterations in the pathophysiological processes from prodrome to onset of PD.
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Trastornos Psicóticos/sangre , Trastornos Psicóticos/diagnóstico , Adolescente , Biomarcadores/sangre , Niño , Humanos , Lípidos/sangre , Estudios Longitudinales , Metabolómica , Análisis Multivariante , Trastornos Psicóticos/metabolismoRESUMEN
Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "ying/yang" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.
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Glicerofosfolípidos/metabolismo , Enfermedades Metabólicas/metabolismo , Esfingolípidos/metabolismo , Animales , Membrana Celular/metabolismo , Humanos , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/patología , Transducción de SeñalRESUMEN
Psychotic patients are at high risk for developing obesity, metabolic syndrome and type 2 diabetes. These metabolic co-morbidities are hypothesized to be related to both treatment side effects as well as to metabolic changes occurring during the psychosis. Earlier metabolomics studies have shown that blood metabolite levels are predictive of insulin resistance and type 2 diabetes in the general population as well as sensitive to the effects of antipsychotics. In this study, we aimed to identify the metabolite profiles predicting future weight gain and other metabolic abnormalities in psychotic patients. We applied comprehensive metabolomics to investigate serum metabolite profiles in a prospective study setting in 36 first-episode psychosis patients during the first year of the antipsychotic treatment and 19 controls. While corroborating several earlier findings when comparing cases and controls and the effects of the antipsychotic medication, we also found that prospective weight gain in psychotic patients was associated with increased levels of triacylglycerols with low carbon number and double-bond count at baseline, that is, lipids known to be associated with increased liver fat. Our study suggests that metabolite profiles may be used to identify the psychotic patients most vulnerable to develop metabolic co-morbidities, and may point to a pharmacological approach to counteract the antipsychotic-induced weight gain.
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Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inducido químicamente , Lípidos/sangre , Síndrome Metabólico/sangre , Síndrome Metabólico/inducido químicamente , Metabolómica , Obesidad/sangre , Obesidad/inducido químicamente , Trastornos Psicóticos/sangre , Trastornos Psicóticos/tratamiento farmacológico , Triglicéridos/sangre , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Medición de Riesgo , Adulto JovenRESUMEN
The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.
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Biomarcadores/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/patología , Estado Prediabético/diagnóstico , Estado Prediabético/patología , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Dietoterapia , Progresión de la Enfermedad , Terapia por Ejercicio , Femenino , Intolerancia a la Glucosa/epidemiología , Intolerancia a la Glucosa/terapia , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Estado Prediabético/epidemiología , Estado Prediabético/terapia , Pronóstico , Factores de Riesgo , Conducta de Reducción del Riesgo , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this 'metabolically healthy obesity' (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon. METHODS: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥ 3 kg/m(2)), aged 22.8-35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT. RESULTS: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics. CONCLUSIONS/INTERPRETATION: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.
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Peso Corporal/fisiología , Obesidad/metabolismo , Gemelos Monocigóticos , Tejido Adiposo/metabolismo , Adulto , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Obesidad/sangre , Adulto JovenRESUMEN
BACKGROUND: Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. METHODS: We conducted a randomized dietary study lasting for 18-24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m(-2) , 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. RESULTS: Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmol L(-1) 95% CI -0.35; -0.01, P = 0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37 ng L(-1) , P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, -0.23, -0.41; -0.05, P = 0.012) were associated with IL-1 Ra. CONCLUSIONS: Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.
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Biomarcadores/sangre , Glucemia/metabolismo , Dieta , Ingestión de Energía , Resistencia a la Insulina , Lípidos/sangre , Síndrome Metabólico/sangre , Apolipoproteínas A/sangre , Apolipoproteínas B/sangre , Presión Sanguínea , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Dinamarca , Dieta/métodos , Ácidos Grasos/análisis , Finlandia , Prueba de Tolerancia a la Glucosa , Humanos , Islandia , Inflamación/sangre , Proteína Antagonista del Receptor de Interleucina 1/sangre , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Suecia , Resultado del TratamientoRESUMEN
AIMS/HYPOTHESIS: Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains. METHODS: The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice. RESULTS: The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-ß and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion. CONCLUSIONS/INTERPRETATION: The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.
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Efecto Citopatogénico Viral/inmunología , Diabetes Mellitus Tipo 1/patología , Enterovirus Humano B/inmunología , Infecciones por Enterovirus/patología , Animales , Células Cultivadas , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/virología , Enterovirus Humano B/patogenicidad , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/virología , Femenino , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Inmunohistoquímica , Inflamación , Interleucina-1alfa/inmunología , Interleucina-1beta/inmunología , Masculino , Ratones , Persona de Mediana Edad , Necrosis , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND/OBJECTIVES: Lactobacillus helveticus LBK-16H-fermented milk products containing tripeptides isoleucine-proline-proline and valine-proline-proline lower blood pressure in hypertensive subjects using office and home blood pressure registration. The present study was aimed to evaluate the effects of two doses of these lactotripeptides on 24-h ambulatory blood pressure and lipidomics profiles in mildly hypertensive subjects. SUBJECTS/METHODS: In a randomized, double-blind, placebo-controlled parallel group study, 89 mildly hypertensive subjects ingested, after a 1-month run-in period, a fermented milk drink with 5 mg per day of lactotripeptides during 3 months, and a milk drink with 50 mg per day of lactotripeptides for the following 3 months, or a placebo milk drink without lactotripeptides. Ambulatory blood pressure (24 h) was recorded at baseline and at the end of the intervention periods. Lipidomics profiles were characterized before and after the 6-month intervention. RESULTS: After the second intervention period (50 mg per day of lactotripeptides), systolic and diastolic 24-h blood pressures decreased significantly in the peptide, but not in the placebo group. However, the treatment effects -2.6 mm Hg (95% confidence interval (CI): -5.7 to 0.4) in systolic and -1.3 mm Hg (95% CI: -3.4 to 0.8) in diastolic blood pressure did not reach statistic significance. Ingestion of 5 mg per day of lactotripeptides for 3 months did not lower blood pressure. The peptide group was dominated by decrease in multiple phospholipids (PL). CONCLUSIONS: Ingestion of fermented milk with daily dose of 50 mg of lactotripeptides appears to lower elevated blood pressure slightly from the baseline, but not significantly compared with the placebo group and to induce significant decreases in multiple PL.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Productos Lácteos Cultivados/química , Hipertensión/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Fosfolípidos/sangre , Adulto , Antihipertensivos/farmacología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Productos Lácteos Cultivados/metabolismo , Productos Lácteos Cultivados/microbiología , Método Doble Ciego , Femenino , Humanos , Hipertensión/sangre , Lactobacillus helveticus , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Factores de RiesgoRESUMEN
BACKGROUND: We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor. METHODS: The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells. RESULTS: Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-κB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress-inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells. CONCLUSION: Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction.
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División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Neoplasias de la Próstata/patología , Piranos/farmacología , Aldehído Deshidrogenasa/antagonistas & inhibidores , Western Blotting , Línea Celular Tumoral , Humanos , Masculino , FN-kappa B/metabolismo , Niclosamida/farmacología , Neoplasias de la Próstata/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Terfenadina/farmacologíaRESUMEN
Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.
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Enfermedad de Alzheimer/metabolismo , Disfunción Cognitiva/metabolismo , Progresión de la Enfermedad , Vía de Pentosa Fosfato/fisiología , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Biomarcadores/sangre , Biomarcadores/metabolismo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Metaboloma/fisiología , Valor Predictivo de las PruebasRESUMEN
AIM: The Wnt/ß-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo. METHODS: We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1. RESULTS: SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/ß-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects. CONCLUSIONS: Our results suggest that SFRP1 is an endogenous modulator of Wnt/ß-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.
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Adipogénesis , Tejido Adiposo Blanco/fisiología , Obesidad Mórbida/metabolismo , Proteínas/fisiología , Proteínas Wnt/metabolismo , beta Catenina/fisiología , Adipocitos Blancos/metabolismo , Anciano , Animales , Diferenciación Celular , Femenino , Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Obesidad , Obesidad Mórbida/fisiopatología , Proteínas/genética , Proteínas/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND AND AIMS: Whole-grain cereals and diets with a low glycemic index may protect against the development of type 2 diabetes and heart disease, but the mechanisms are poorly understood. We studied the effect of carbohydrate modification on serum metabolic profiles, including lipids and branched chain amino acids, and dependencies between these and specific gene expression pathways in adipose tissue. METHODS AND RESULTS: Twenty subjects with metabolic syndrome were selected from the larger FUNGENUT study population, randomized either to a diet high in oat and wheat bread and potato (OWP) or rye bread and pasta (RP). Serum metabolomics analyses were performed using ultra-performance liquid chromatography coupled to electrospray ionization mass spectrometry (UPLC/MS), gas chromatography (GC) and UPLC. In the OWP group multiple proinflammatory lysophosphatidylcholines increased, while in the RP group docosahexaenoic acid (DHA 22:6n-3) increased and isoleucine decreased. mRNA expression of stress reactions- and adipose tissue differentiation-related genes were up-regulated in adipose tissue in the OWP group. In the RP group, however, pathways related to stress reactions and insulin signaling and energy metabolism were down-regulated. The lipid profiles had the strongest association with the changes in the adipose tissue differentiation pathway when using the elastic net regression model of the lipidomic profiles on selected pathways. CONCLUSION: Our results suggest that the dietary carbohydrate modification alters the serum metabolic profile, especially in lysoPC species, and may, thus, contribute to proinflammatory processes which in turn promote adverse changes in insulin and glucose metabolism.
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Carbohidratos de la Dieta/farmacología , Síndrome Metabólico/sangre , Síndrome Metabólico/dietoterapia , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiología , Aminoácidos de Cadena Ramificada/sangre , Vías Biosintéticas , Cromatografía Líquida de Alta Presión , Dieta , Ingestión de Alimentos , Ácidos Grasos/sangre , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Índice Glucémico , Humanos , Lípidos/sangre , Síndrome Metabólico/genética , Metabolómica , Grosor de los Pliegues Cutáneos , Espectrometría de Masa por Ionización de Electrospray , Resultado del TratamientoRESUMEN
AIMS: In this review metabolomics is introduced in historic perspective, with key platforms and bioinformatics methodologies described. An overview is provided covering recent applications of metabolomics and lipidomics in the context of human physiology, lipid metabolism and nutrition. DATA SYNTHESIS: Global coverage of human metabolome requires application of multiple analytical platforms. The choice of a particular targeted or non-targeted analytical strategy depends on the hypothesis tested, state-of-the-art in the field, as well as on sample availability. Human metabolome has been shown to be sensitive to age, gut microbial composition, and lifestyle. Several studies have shown that, given the appropriate experimental design, subtle effects of interventions such as change of diet or weight loss can be detected by metabolomics and studied in the context of human physiology and health status. CONCLUSION: Metabolome provides a sensitive intermediate phenotype linking the genotype, gut microbial composition and personal health status. Innovative experimental designs combined with novel computational tools for handling metabolomics data offer new opportunities for early disease detection as well as for characterization of dietary and therapeutic interventions in the context of human physiology.
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Dislipidemias/metabolismo , Metabolismo de los Lípidos , Enfermedades Metabólicas/metabolismo , Metabolómica , Fenómenos Fisiológicos de la Nutrición , Biología Computacional , Dislipidemias/fisiopatología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Enfermedades Metabólicas/fisiopatología , Metabolómica/historia , Metabolómica/métodos , Fenotipo , Biología de SistemasRESUMEN
AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD. METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index). RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001). CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.
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Ceramidas/sangre , Enfermedad Coronaria/sangre , Inflamación/sangre , Interleucina-6/sangre , Proteína C-Reactiva/metabolismo , Enfermedad Coronaria/fisiopatología , Estudios Transversales , Humanos , Isquemia/sangre , Isquemia/fisiopatología , Lípidos/sangre , Infarto del Miocardio/sangre , Infarto del Miocardio/fisiopatología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
AIMS/HYPOTHESIS: The weak relationship between insulin resistance and total serum triacylglycerols (TGs) could be in part due to heterogeneity of TG molecules and their distribution within different lipoproteins. We determined concentrations of individual TGs and the fatty acid composition of serum and major lipoprotein particles and analysed how changes in different TGs and fatty acid composition are related to features of insulin resistance and abdominal obesity. METHODS: We performed lipidomic analyses of all major lipoprotein fractions using two analytical platforms in 16 individuals, who exhibited a broad range of insulin sensitivity. RESULTS: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins. CONCLUSIONS/INTERPRETATION: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.
Asunto(s)
Biomarcadores/sangre , Ácidos Grasos/sangre , Resistencia a la Insulina/fisiología , Triglicéridos/sangre , Adulto , Índice de Masa Corporal , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Ayuno , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
The 2,8-dihydroxy-1,3,7,9-tetramethyl-6,12-dihydrodipyrido[1,2-a:1', 2'-d]pyrazinediylium dication possesses 2/m symmetry and lies in the mirror plane together with a chloride anion and the water O atom. The dication also lies on an inversion centre, i.e. C(16)H(20)N(2)O(2)(2+).2Cl(-).2H(2)O. Due to these symmetry constrictions the dication adopts an unexpected planar conformation. Molecules are linked by O-H.O and O-H.Cl hydrogen bonds to form chains, which are cross-connected by C-H.Cl attractive interactions forming a complex three-dimensional hydrogen-bond network.
RESUMEN
We found significant species-specific correlations between the use of two synonymous codons and protein secondary structure units by comparing the three-dimensional structures of human and Escherichia coli proteins with their mRNA sequences. The correlations are not explained by codon-context, expression level, GC/AU content, or positional effects. The E. coli correlation is between Asn AAC and the C-terminal regions of beta-sheet segments; it may result from selection for translational accuracy, suggesting the hypothesis that downstream Asn residues are important for beta-sheet formation. The correlation in human proteins is between Asp GAU and the N termini of alpha-helices; it may be important for eukaryote-specific sequential, cotranslational folding. The kingdom-specific correlations may reflect kingdom-specific differences in translational mechanisms. The correlations may help identify residues that are important for secondary structure formation, be useful in secondary structure prediction algorithms, and have implications for recombinant gene expression.