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1.
Cell Mol Life Sci ; 81(1): 343, 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39129011

RESUMEN

The coordination of food intake, energy storage, and expenditure involves complex interactions between hypothalamic neurons and peripheral tissues including pancreatic islets, adipocytes, muscle, and liver. Previous research shows that deficiency of the transcription factor Alx3 alters pancreatic islet-dependent glucose homeostasis. In this study we carried out a comprehensive assessment of metabolic alterations in Alx3 deficiency. We report that Alx3-deficient mice exhibit decreased food intake without changes in body weight, along with reduced energy expenditure and altered respiratory exchange ratio. Magnetic resonance imaging reveals increased adiposity and decreased muscle mass, which was associated with markers of motor and sympathetic denervation. By contrast, Alx3-deficient mice on a high-fat diet show attenuated weight gain and improved insulin sensitivity, compared to control mice. Gene expression analysis demonstrates altered lipogenic and lipolytic gene profiles. In wild type mice Alx3 is expressed in hypothalamic arcuate nucleus neurons, but not in major peripheral metabolic organs. Functional diffusion-weighted magnetic resonance imaging reveals selective hypothalamic responses to fasting in the arcuate nucleus of Alx3-deficient mice. Additionally, altered expression of proopiomelanocortin and melanocortin-3 receptor mRNA in the hypothalamus suggests impaired regulation of feeding behavior. This study highlights the crucial role for Alx3 in governing food intake, energy homeostasis, and metabolic nutrient partitioning, thereby influencing body mass composition.


Asunto(s)
Composición Corporal , Ingestión de Alimentos , Metabolismo Energético , Proteínas de Homeodominio , Homeostasis , Hipotálamo , Ratones Noqueados , Animales , Masculino , Ratones , Núcleo Arqueado del Hipotálamo/metabolismo , Dieta Alta en Grasa , Ingestión de Alimentos/genética , Metabolismo Energético/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Hipotálamo/metabolismo , Resistencia a la Insulina/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Proopiomelanocortina/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética
2.
Front Pharmacol ; 15: 1428601, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39175542

RESUMEN

Introduction: Maintaining metabolic balance relies on accumulating nutrients during feeding periods and their subsequent release during fasting. In obesity and metabolic disorders, strategies aimed at reducing food intake while simulating fasting have garnered significant attention for weight loss. Caloric restriction (CR) diets and intermittent fasting (IF) interventions have emerged as effective approaches to improving cardiometabolic health. Although the comparative metabolic benefits of CR versus IF remain inconclusive, this review focuses on various forms of IF, particularly time-restricted eating (TRE). Methods: This study employs a narrative review methodology, systematically collecting, synthesizing, and interpreting the existing literature on TRE and its metabolic effects. A comprehensive and unbiased search of relevant databases was conducted to identify pertinent studies, including pre-clinical animal studies and clinical trials in humans. Keywords such as "Obesity," "Intermittent Fasting," "Time-restricted eating," "Chronotype," and "Circadian rhythms" guided the search. The selected studies were critically appraised based on predefined inclusion and exclusion criteria, allowing for a thorough exploration and synthesis of current knowledge. Results: This article synthesizes pre-clinical and clinical studies on TRE and its metabolic effects, providing a comprehensive overview of the current knowledge and identifying gaps for future research. It explores the metabolic outcomes of recent clinical trials employing different TRE protocols in individuals with overweight, obesity, or type II diabetes, emphasizing the significance of individual chronotype, which is often overlooked in practice. In contrast to human studies, animal models underscore the role of the circadian clock in mitigating metabolic disturbances induced by obesity through time-restricted feeding (TRF) interventions. Consequently, we examine pre-clinical evidence supporting the interplay between the circadian clock and TRF interventions. Additionally, we provide insights into the role of the microbiota, which TRE can modulate and its influence on circadian rhythms.

3.
J Clin Invest ; 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38713514

RESUMEN

Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

4.
J Crohns Colitis ; 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38747506

RESUMEN

BACKGROUND AND AIMS: Crohn's disease (CD) is characterised by the expansion of mesenteric adipose tissue (MAT), named creeping fat (CF), which seems to be directly related to disease activity. Adipose-stem cells (ASCs) isolated from the CF of patients with CD are extremely pro-inflammatory, which persists during disease remission. We hypothesised that the dysfunctional ASCs in CD accumulate epigenetic modifications triggered by the inflammatory environment that could serve as molecular markers. METHODS: Genome-wide DNA methylome and transcriptome profiling were performed in ASCs isolated from MAT adipose-tissue biopsies of patients with active and inactive disease and from non-Crohn's disease patients (non-CD). A validation cohort was used to test the main candidate genes via qPCR in other fat depots and immune cells. RESULTS: We found differences in DNA-methylation and gene expression between ASCs isolated from patients with CD and from non-CD subjects, but we found no differences related to disease activity. Pathway enrichment analysis revealed that oxidative stress and immune response were significantly enriched in active CD and integration analysis identified MAB21L2, a cell fate-determining gene, as the most affected gene in CD. Validation analysis confirmed the elevated gene expression of MAB21L2 in MAT and in adipose tissue macrophages in active CD. We also found a strong association between expression of the calcium channel subunit gene CACNA1H and disease remission, as CACNA1H expression was higher in ASCs and MAT from patients with inactive CD, and correlates negatively with C-reactive protein in peripheral blood mononuclear cells. CONCLUSION: We identified a potential gene signature of CD in ASCs obtained from MAT. Integration analysis highlighted two novel genes demonstrating a negative correlation between promoter DNA methylation and transcription: one linked to ASCs in CD (MAB21L2) and the other (CACNA1H) related to disease remission.

5.
Head Neck ; 46(7): 1752-1765, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38305029

RESUMEN

BACKGROUND: Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer-related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. METHODS: We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. RESULTS: Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease-free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro-tumoral and radioresistant phenotype in surviving cells. CONCLUSIONS: Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC.


Asunto(s)
Glucosa , Neoplasias de Cabeza y Cuello , Tolerancia a Radiación , Carcinoma de Células Escamosas de Cabeza y Cuello , Survivin , Humanos , Survivin/metabolismo , Survivin/genética , Masculino , Tolerancia a Radiación/genética , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/genética , Femenino , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Persona de Mediana Edad , Anciano , Glucosa/metabolismo , Pronóstico , Línea Celular Tumoral , Supervivencia sin Enfermedad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas Inhibidoras de la Apoptosis/genética , Adulto
6.
Diabetologia ; 67(3): 430-442, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38182909

RESUMEN

Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or the host's intermediary metabolism, are now acknowledged as key regulators of various metabolic and immune responses. This review delves into the multi-dimensional aspects of succinate, a dual metabolite with roots in both the mitochondria and microbiome. It also connects the dots between succinate's role in the Krebs cycle, mitochondrial respiration, and its double-edge function as a signalling transmitter within and outside the cell. We aim to provide an overview of the role of the succinate-succinate receptor 1 (SUCNR1) axis in diabetes, discussing the potential use of succinate as a biomarker and the novel prospect of targeting SUCNR1 to manage complications associated with diabetes. We further propose strategies to manipulate the succinate-SUCNR1 axis for better diabetes management; this includes pharmacological modulation of SUCNR1 and innovative approaches to manage succinate concentrations, such as succinate administration and indirect strategies, like microbiota modulation. The dual nature of succinate, both in terms of origins and roles, offers a rich landscape for understanding the intricate connections within metabolic diseases, like diabetes, and indicates promising pathways for developing new therapeutic strategies.


Asunto(s)
Diabetes Mellitus Tipo 2 , Succinatos , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Succinatos/metabolismo
7.
Front Endocrinol (Lausanne) ; 14: 1181744, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37916149

RESUMEN

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.


Asunto(s)
Diabetes Mellitus Tipo 2 , Derivación Gástrica , Microbioma Gastrointestinal , Humanos , Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Péptido C/metabolismo , Estudios Prospectivos , Obesidad/metabolismo , Incretinas/metabolismo , Péptido 2 Similar al Glucagón
8.
STAR Protoc ; 4(4): 102693, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37924518

RESUMEN

White adipose tissue (WAT) explants culture allows the study of this tissue ex vivo, maintaining its structure and properties. Concurrently, isolating mature adipocytes facilitates research into fat cell metabolism and hormonal regulation. Here, we present a protocol for obtaining, isolating, and processing mature adipocytes, alongside the cultivation of WAT explants from humans and mice. We describe steps for WAT retrieval, culturing of WAT explants, WAT digestion, and adipocytes separation. We then detail procedures for culturing isolated mature adipocytes. For complete details on the use and execution of this protocol, please refer to Villanueva-Carmona et al. (2023).1.


Asunto(s)
Adipocitos , Tejido Adiposo Blanco , Humanos , Ratones , Animales
10.
Metabolism ; 145: 155630, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37315889

RESUMEN

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Fibrosis , Glucosa/metabolismo , Glucógeno/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Succinatos/metabolismo , Succinatos/farmacología
11.
Science ; 380(6651): eadh9351, 2023 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-37347868

RESUMEN

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.


Asunto(s)
Calcio , Retículo Endoplásmico , GTP Fosfohidrolasas , Mitocondrias , Proteínas Mitocondriales , Animales , Ratones , Calcio/metabolismo , Retículo Endoplásmico/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Hígado/metabolismo , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Isoformas de Proteínas , Ratones Noqueados , Humanos , Ratones Endogámicos C57BL , Células HeLa , Empalme Alternativo , Estrés del Retículo Endoplásmico
13.
Cell Metab ; 35(4): 601-619.e10, 2023 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-36977414

RESUMEN

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.


Asunto(s)
Relojes Circadianos , Leptina , Animales , Humanos , Ratones , Adipocitos/metabolismo , Metabolismo Energético/fisiología , Leptina/metabolismo , Ratones Noqueados , Obesidad/metabolismo , Succinatos/metabolismo
14.
Int J Mol Sci ; 24(3)2023 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-36768809

RESUMEN

Dyslipidemia in gestational diabetes has been associated with worse perinatal outcomes. The ANGPTL3-4-8 axis regulates lipid metabolism, especially in the transition from fasting to feeding. In this study, we evaluated the response of ANGPTL3, 4, and 8 after the intake of a mixed meal in women with normal glucose tolerance and gestational diabetes, and we assessed their gene expressions in different placental locations. Regarding the circulating levels of ANGPTL3, 4, and 8, we observed an absence of ANGPTL4 response after the intake of the meal in the GDM group compared to its presence in the control group. At the placental level, we observed a glucose tolerance-dependent expression pattern of ANGPTL3 between the two placental sides. When we compared the GDM pregnancies with the control pregnancies, a downregulation of the maternal side ANGPTL3 expression was observed. This suggests a dysregulation of the ANGPTL3-4-8 axis in GDM, both at the circulating level after ingestion and at the level of placental expression. Furthermore, we discerned that the expressions of ANGPTL3, 4, and 8 were related to birth weight and placental weight in the GDM group, but not in the control group, which suggests that they may play a role in regulating the transplacental passage of nutrients.


Asunto(s)
Diabetes Gestacional , Femenino , Humanos , Embarazo , Proteína 3 Similar a la Angiopoyetina , Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Desarrollo Fetal , Glucosa/metabolismo , Parto , Placenta/metabolismo
16.
Front Immunol ; 13: 912579, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36189213

RESUMEN

Background: Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. Methods: We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Results: Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes. Conclusion: Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.


Asunto(s)
COVID-19 , Biomarcadores , Proteína C-Reactiva , Creatinina , Glucosa , Humanos , Ácidos Cetoglutáricos , Lactatos , Pronóstico , Ácido Pirúvico , SARS-CoV-2 , Succinatos , Ácidos Tricarboxílicos
17.
Diabetes Care ; 45(10): 2430-2438, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35984043

RESUMEN

OBJECTIVE: Vascular aging (arterial stiffness [AS]) is an inflammation-linked process that predicts macro- and microvascular complications in adults with type 1 diabetes (T1D). We evaluated the utility of measuring the inflammation-linked N-glycans GlycA and GlycB to assess vascular aging in adults with T1D. RESEARCH DESIGN AND METHODS: Eighty-four adults with T1D (>10-year duration without cardiovascular events) and 68 healthy control subjects were evaluated for clinical characteristics (including microvascular complications in patients with T1D), aortic pulse wave velocity (aPWV) (surrogate measure of AS), and serum GlycA and GlycB (peak area [concentration] and height/width [H/W] ratio) using 1H-nuclear magnetic resonance spectroscopy. RESULTS: Patients with T1D had higher median (interquartile range) values than healthy control subjects for (P < 0.001 for all comparisons) aPWV 7.9 (6.9-9.1) vs. 6.1 (5.5-6.7) m/s, GlycA 850.4 (781.3-916.1) vs. 652.4 (581.5-727.1) µmoL; GlycB 386.1 (353.2-426.3) vs. 310.0 (280.5-331.9) µmol/L), H/W ratio of GlycA 16.5 (14.9-18.1) vs. 15.0 (13.7-16.7), and H/W ratio of GlycB 5.0 (4.6-5.5) vs. 4.0 (3.4-4.3). Moreover, aPWV correlated (P < 0.001 for all correlations) with GlycA (r = 0.550) and GlycB (r = 0.423) concentrations and with H/W ratios of GlycA (r = 0.453) and GlycB (r = 0.510). Adjusting for potential confounders, GlycA concentration (ß = 0.212, P < 0.001) and the H/W ratios of GlycA (ß = 0.150, P = 0.009) and GlycB (ß = 0.155, P = 0.011) remained independently associated with aPWV. C-statistics for detecting individuals with aPWV >10 m/s were 0.866 (95% CI 0.794-0.937) for GlycA levels and 0.862 (0.780-0.943) for H/W ratio of GlycB. CONCLUSIONS: Measurement of serum GlycA and GlycB may have utility in assessing vascular aging in adults with T1D of >10-year duration and no previous cardiovascular events.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 1 , Rigidez Vascular , Adulto , Envejecimiento , Biomarcadores , Enfermedades Cardiovasculares/diagnóstico , Humanos , Inflamación , Polisacáridos , Análisis de la Onda del Pulso
18.
Microbiome ; 10(1): 135, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-36002880

RESUMEN

BACKGROUND: Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting. RESULTS: Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity (db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp. CONCLUSIONS: Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation. Video Abstract.


Asunto(s)
Glucemia , Diabetes Mellitus Tipo 2 , Animales , Bacteroidetes , Diabetes Mellitus Tipo 2/microbiología , Dieta Alta en Grasa , Humanos , Inflamación , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Ácido Succínico
19.
J Clin Endocrinol Metab ; 107(10): 2748-2757, 2022 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-35914803

RESUMEN

CONTEXT: DNA methylation in the diagnosis of gestational diabetes. OBJECTIVE: To assess the value of DNA methylation in the diagnosis of gestational diabetes (GDM) and in the prediction of maternal postpartum glucose disturbances. METHODS: Two-stage observational study performed between July 2006 and December 2010, at University Hospital. Forty-eight randomly selected pregnant women formed the discovery cohort (24 with GDM and 24 controls) and 252 pregnant women (94 with GDM and 158 controls) formed the replication cohort. GDM women were re-evaluated 4 years postpartum. The main outcome measures were GDM, type 2 diabetes or prediabetes at 4 years postpartum. RESULTS: We identified 3 CpG sites related to LINC00917, TRAPPC9, and LEF1 that were differentially methylated in women with GDM and abnormal glucose tolerance; and sites associated with LINC00917 and TRAPPC9 were independently associated with an abnormal glucose tolerance status 4 years postpartum after controlling for clinical variables. Moreover, the site associated with LINC00917 and the combination of the 3 sites had the highest predictive values. CONCLUSION: Our results suggest that some of these sites may be implicated in the development of GDM and postpartum abnormal glucose tolerance.


Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Intolerancia a la Glucosa , Glucemia , Metilación de ADN , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Femenino , Glucosa , Intolerancia a la Glucosa/diagnóstico , Intolerancia a la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Humanos , Periodo Posparto , Embarazo
20.
Redox Biol ; 54: 102353, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35777200

RESUMEN

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.


Asunto(s)
Resistencia a la Insulina , Tejido Adiposo/metabolismo , Animales , Homeostasis , Grasa Intraabdominal/metabolismo , Ratones , Obesidad/genética , Obesidad/metabolismo , Proteómica
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