RESUMEN
Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
Asunto(s)
GTP Fosfohidrolasas/metabolismo , Proteínas Mitocondriales/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fosfatidilserinas/metabolismo , Animales , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Inflamación/metabolismo , Hígado/patología , Hepatopatías/etiología , Hepatopatías/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Cultivo Primario de Células , Transporte de Proteínas/fisiología , Transducción de Señal , Triglicéridos/metabolismoRESUMEN
Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.
Asunto(s)
Inflamación/inmunología , Macrófagos/inmunología , Obesidad/inmunología , Receptores Acoplados a Proteínas G/inmunología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Animales , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación/genética , Inflamación/metabolismo , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Ácido Succínico/inmunología , Ácido Succínico/metabolismo , Ácido Succínico/farmacología , Células THP-1RESUMEN
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 , Metabolismo Energético/genética , Hipotálamo/metabolismo , Ratones , Ingestión de Alimentos/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Dieta Alta en Grasa , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Proopiomelanocortina/genética , Resistencia a la Insulina/genética , Núcleo Arqueado del Hipotálamo/metabolismoRESUMEN
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.
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Diabetes Mellitus Tipo 2 , Succinatos , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Succinatos/metabolismoRESUMEN
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.
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Diabetes Gestacional , Femenino , Humanos , Embarazo , Proteína 3 Similar a la Angiopoyetina , Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Desarrollo Fetal , Glucosa/metabolismo , Parto , Placenta/metabolismoRESUMEN
Understanding the signaling cascades that govern adipocyte metabolism and differentiation is necessary for the development of therapies for obesity. Toll-like receptors (TLRs) are key mediators in adipogenesis, but their specific role is not completely understood. In this study, siRNA knockdown of Tlr2 in 3T3-L1 cells allowed them to differentiate more efficiently into adipocytes, whereas the opposite was observed for the knockdown of Tlr4. At the same time, we show that TLR2 knock-out mice spontaneously developed mature-onset obesity and insulin resistance. Besides a higher incidence of hyperplasia and hypertrophy in white adipose tissue (WAT), we found a significantly increased number of adipocyte precursor cells in TLR2-/- mice compared to TLR4-/- mice. Interestingly, genetic inactivation of Tlr4 in TLR2-/- mice reverted their increased adiposity, insulin resistance, and restored normal levels of adipocyte precursor cells. These findings provide evidence that TLR2 and TLR4 play opposing roles in WAT homeostasis and point to the existence of cross-regulation among TLR2 and TLR4 during adipocyte differentiation both in vitro and in vivo.
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Resistencia a la Insulina , Receptor Toll-Like 4 , Ratones , Animales , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Resistencia a la Insulina/genética , Obesidad/metabolismo , Diferenciación Celular/genética , Adipocitos/metabolismo , Adipogénesis/genética , Ratones Noqueados , Células 3T3-L1RESUMEN
BACKGROUND: Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown. METHODS: Cross-sectional study in 100 (65% women) individuals aged 18-25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample. RESULTS: Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+ 42.5%), triglycerides (+ 63.9%), C-reactive protein (+ 124.2%), diastolic blood pressure (+ 5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity. CONCLUSIONS: Plasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults.
Asunto(s)
Enfermedades Cardiovasculares/sangre , Ácido Succínico/sangre , Adiposidad , Adolescente , Adulto , Factores de Edad , Biomarcadores/sangre , Presión Sanguínea , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Estudios Transversales , Femenino , Microbioma Gastrointestinal , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Mediadores de Inflamación/sangre , Grasa Intraabdominal/fisiopatología , Masculino , Oxilipinas/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Triglicéridos/sangre , Regulación hacia Arriba , Adulto JovenRESUMEN
AIMS: a) To analyze the relationship of known and emerging biomarkers/indicators for early risk identification of cardiometabolic health risk; b) to identify early risk markers to be used in both clinical and nonclinical settings; and c) to propose a definition of early risk identification in terms of pre-metabolic syndrome (PreMetSyn). DATA SYNTHESIS: Pubmed/Medline, Web of Science, Embase, and Cochrane were searched for Systematic Reviews and Meta-analysis. Selected studies were evaluated, and relevant data were extracted and synthesized. CONCLUSIONS: Serum uric acid is a good predictive biomarker of metabolic syndrome (MetSyn) and has been associated with non-alcoholic liver fat disease (NAFLD) and type 2 diabetes. NAFLD emerges as an early risk indicator of PreMetSyn by itself. Muscle strength should also be included as an early risk marker of cardiometabolic health. High serum triglycerides and waist circumference confirm their predictive value regarding MetSyn. Indicators related to an inflammatory/pro-inflammatory status usually linked to MetSyn showed limited evidence as robust biomarkers for PreMetSyn. Authors suggest defining PreMetSyn related to cardiometabolic risk. It is also necessary to determine how close people are to the cut-off point of MetSyn components, including emerging indicators proposed by our review. Some biomarkers could be used as indicators of PreMetSyn, before any of the MetSyn components appear, allowing early health interventions to prevent its development. Defining a PreMetSyn status might consider both emerging indicators and those variables already included in the definition of MetSyn. New indicators should be considered to create a new risk score specifically meant for PreMetSyn.
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Indicadores de Salud , Síndrome Metabólico/diagnóstico , Terminología como Asunto , Biomarcadores/sangre , Factores de Riesgo Cardiometabólico , Diagnóstico Precoz , Humanos , Síndrome Metabólico/sangre , Síndrome Metabólico/clasificación , Síndrome Metabólico/epidemiología , Valor Predictivo de las Pruebas , Pronóstico , Medición de RiesgoRESUMEN
Our understanding of the interplay between human adipose tissue and the immune system is limited. The mesothelium, an immunologically active structure, emerged as a source of visceral adipose tissue. After investigating the mesothelial properties of human visceral and subcutaneous adipose tissue and their progenitors, we explored whether the dysfunctional obese and Crohn's disease environments influence the mesothelial/mesenchymal properties of their adipocyte precursors, as well as their ability to mount an immune response. Using a tandem transcriptomic/proteomic approach, we evaluated the mesothelial and mesenchymal expression profiles in adipose tissue, both in subjects covering a wide range of body-mass indexes and in Crohn's disease patients. We also isolated adipose tissue precursors (adipose-derived stem cells, ASCs) to assess their mesothelial/mesenchymal properties, as well as their antigen-presenting features. Human visceral tissue presented a mesothelial phenotype not detected in the subcutaneous fat. Only ASCs from mesenteric adipose tissue, named creeping fat, had a significantly higher expression of the hallmark mesothelial genes mesothelin (MSLN) and Wilms' tumor suppressor gene 1 (WT1), supporting a mesothelial nature of these cells. Both lean and Crohn's disease visceral ASCs expressed equivalent surface percentages of the antigen-presenting molecules human leucocyte antigen-DR isotype (HLA-DR) and CD86. However, lean-derived ASCs were predominantly HLA-DR dim, whereas in Crohn's disease, the HLA-DR bright subpopulation was increased 3.2-fold. Importantly, the mesothelial-enriched Crohn's disease precursors activated CD4+ T-lymphocytes. Our study evidences a mesothelial signature in the creeping fat of Crohn's disease patients and its progenitor cells, the latter being able to present antigens and orchestrate an immune response.
Asunto(s)
Tejido Adiposo/metabolismo , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Células Madre/metabolismo , Tejido Adiposo/patología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Biomarcadores , Biología Computacional/métodos , Enfermedad de Crohn/etiología , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Grasa Intraabdominal/metabolismo , Mesotelina , Proteómica/métodos , Grasa Subcutánea/metabolismo , TranscriptomaRESUMEN
BACKGROUND: A functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs. METHODS: Using epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals. RESULTS: We found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number. CONCLUSIONS: We identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes.
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Adipocitos/patología , Tejido Adiposo/patología , Metilación de ADN , Mitocondrias/patología , Obesidad/genética , Obesidad/patología , Células Madre/metabolismo , Células Madre/patología , Adipocitos/metabolismo , Adipogénesis , Adulto , Femenino , Humanos , Inflamación/genética , Inflamación/patología , Mitocondrias/genética , Estrés Oxidativo , Delgadez/genética , Delgadez/patologíaRESUMEN
There is now a wealth of evidence showing that communication between microbiota and the host is critical to sustain the vital functions of the healthy host, and disruptions of this homeostatic coexistence are known to be associated with a range of diseases including obesity and type 2 diabetes. Microbiota-derived metabolites act both as nutrients and as messenger molecules and can signal to distant organs in the body to shape host pathophysiology. In this review, we provide a new perspective on succinate as a gut microbiota-derived metabolite with a key role governing intestinal homeostasis and energy metabolism. Thus, succinate is not merely a major intermediary of the TCA traditionally considered as an extracellular danger signal in the host, but also a by-product of some bacteria and a primary cross-feeding metabolite between gut resident microbes. In addition to maintain a healthy microbiome, specific functions of microbiota-derived succinate in peripheral tissues regulating host nutrient metabolism should not be rule out. Indeed, recent research point to some probiotic interventions directed to modulate succinate levels in the intestinal lumen, as a new microbiota-based therapies to treat obesity and related co-morbidities. While further research is essential, a large body of evidence point to succinate as a new strategic mediator in the microbiota-host cross-talk, which might provide the basis for new therapeutically approaches in a near future.
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Microbioma Gastrointestinal/fisiología , Enfermedades Metabólicas/microbiología , Ácido Succínico/metabolismo , Animales , HumanosRESUMEN
TWEAK regulates multiple physio-pathological processes in fibroblasts such as fibrosis. It also induces migration and invasion in tumors and it can activate p38 MAPK in various cell types. Moreover, p38α MAPK promotes migration and invasion in several cancer cells types and in mouse embryonic fibroblasts (MEFs). However, it remains unknown if TWEAK could promote migration in fibroblasts and whether p38α MAPK might play a role. Our results reveal that TWEAK activates ERKs, Akt, and p38α/ß MAPKs and reduces secreted Fibulin 3 in MEFs. TWEAK also increases migration and invasion in wt and p38α deficient MEFs, which indicates that p38α MAPK is not required to mediate these effects. In contrast, ERKs inhibition significantly decreases TWEAK-induced migration and Fibulin 3 knock-down mimics TWEAK effect. These results indicate that both ERKs activation and Fibulin 3 down-regulation would contribute to mediate TWEAK pro-migratory effect. In fact, the additional regulation of ERKs and/or p38ß as a consequence of Fibulin 3 decrease might be also involved in the pro-migratory effect of TWEAK in MEFs. In conclusion, our studies uncover novel mechanisms by which TWEAK would favor tissue repair by promoting fibroblasts migration.
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Movimiento Celular , Citocina TWEAK/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/enzimología , Animales , Células Cultivadas , Citocina TWEAK/genética , Regulación hacia Abajo , Activación Enzimática , Proteínas de la Matriz Extracelular/genética , Ratones , Proteína Quinasa 11 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
The clinical effectiveness of systemically administered human mesenchymal stem cells (hMSCs) depends on their capacity to engage vascular endothelium. hMSCs derived from bone marrow (BM-hMSCs) natively lack endothelial binding capacity, but express a CD44 glycovariant containing N-linked sialyllactosamines that can be α(1,3)-fucosylated using fucosyltransferase-VI (FTVI) to enforce sLeX decorations, thereby creating hematopoietic cell E-/L-selectin ligand (HCELL). HCELL expression programs potent shear-resistant adhesion of circulating cells to endothelial beds expressing E-selectin. An alternative source of hMSCs is adipose tissue (A-hMSCs), and we assessed whether A-hMSCs bind E-selectin and/or possess sialyllactosamine-decorated CD44 accessible to α(1,3)-fucosylation. Similar to BM-hMSCs, we found that A-hMSCs natively lack E-selectin ligands, but FTVI-mediated cell surface α(1,3)-fucosylation induces sLeX expression and robust E-selectin binding secondary to conversion of CD44 into HCELL. Moreover, treatment with the α(1,3)-fucosyltransferase-FTVII also generated expression of HCELL on both BM-hMSCs and A-hMSCs, with sLeX decorations created on N-linked glycans of the "standard" CD44 (CD44s) isoform. The finding that hMSCs from both source tissues each lack native E-selectin ligand expression prompted examination of the expression of glycosyltransferases that direct lactosaminyl glycan synthesis. These studies reveal that both types of hMSCs conspicuously lack transcripts encoding α(1,3)-fucosyltransferases, but equally express glycosyltransferases critical to creation of sialyllactosamines. Collectively, these data indicate that assembly of a sialyllactosaminyl-decorated CD44s glycovariant is a conserved feature of hMSCs derived from adipose tissue and marrow, thus identifying a CD44 glycosignature of these cells and supporting the applicability of cell surface α(1,3)-fucosylation in programming migration of systemically administered A-hMSCs to sites of tissue injury/inflammation. Stem Cells 2017;35:1080-1092.
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Receptores de Hialuranos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Tejido Adiposo/citología , Células de la Médula Ósea/citología , Adhesión Celular , Diferenciación Celular , Línea Celular , Selectina E/metabolismo , Fibronectinas/metabolismo , Regulación de la Expresión Génica , Glicoproteínas/metabolismo , Glicosilación , Glicosiltransferasas/metabolismo , Humanos , Inmunofenotipificación , Selectina L/metabolismo , Ligandos , Células Madre Mesenquimatosas/citología , Neuraminidasa/metabolismo , Polisacáridos/metabolismo , Unión ProteicaRESUMEN
Adiposity and physical activity are modifiable factors that could be important determinants of breast cancer (BC) prognosis through their effects on endogenous reproductive hormones, chronic inflammation and metabolic changes. Therefore, it is necessary to evaluate whether offering lifestyle interventions to BC survivors could affect the levels of certain biomarkers involved in these mechanisms. We designed a pre-post intervention study offering diet and exercise sessions over 12 weeks to 42 overweight/obese BC survivors. Before and after the intervention, we obtained dietary information, anthropometry and cardiorespiratory fitness (CRF) measurements and blood samples to measure metabolic risk, insulin resistance and adipokines biomarkers. Wilcoxon signed-rank tests and Spearman partial correlation coefficients were used to compare pre- and post-measurements and assess the correlations between changes in biomarkers and changes in anthropometry and CRF. Breast cancer survivors showed significant improvements in metabolic risk biomarkers and insulin resistance indicators along with a non-significant leptin decrease and a significant adiponectin decrease. The improvements in metabolic risk biomarkers, insulin resistance indicators and leptin were moderately correlated (0.32 ≤ |r| ≤ 0.55) with the decrease in body mass index and the increase in CRF. Diet and exercise interventions implemented in overweight/obese BC survivors may improve metabolic risk, insulin resistance and leptin biomarkers.
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Adiponectina/metabolismo , Neoplasias de la Mama , Supervivientes de Cáncer , Dietoterapia/métodos , Ejercicio Físico , Resistencia a la Insulina , Leptina/metabolismo , Obesidad/terapia , Sobrepeso/terapia , Conducta de Reducción del Riesgo , Glucemia/metabolismo , Índice de Masa Corporal , Capacidad Cardiovascular , Femenino , Humanos , Persona de Mediana Edad , Obesidad/metabolismo , Sobrepeso/metabolismoRESUMEN
In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.
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Metabolismo Energético/genética , Metabolismo de los Lípidos/genética , Obesidad/genética , Proteína Fosfatasa 2/genética , Proteínas Quinasas Activadas por AMP/genética , Animales , Carbohidratos de la Dieta/metabolismo , Glucosa/metabolismo , Hepatocitos/metabolismo , Humanos , Resistencia a la Insulina/genética , Lipogénesis/genética , Hígado/metabolismo , Ratones , Obesidad/patología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Adipose tissue-derived stem cells (ASCs) are proposed as an alternative stem cell source to bone marrow-derived cells for immune cell therapy. However, microenvironmental factors may impact the functionality of this population in human adipose tissue (AT). We hypothesized that the fat depot in addition to the donor phenotype controls the immunomodulatory capacity of ASCs. Focusing on obesity and type 2 diabetes (T2D) as metabolic disorders that might affect the immune response of ASCs, we compared the inflammatory response of ASCs from subcutaneous and visceral AT of age-matched donors (lean n = 4, body mass index [BMI] 21.98 ± 1.9; obese n = 4 BMI 33.1 ± 2.1 and T2D n = 4 BMI 35.3 ± 1.5). Obese and particularly T2D-derived ASCs showed increased expression of inflammatory markers, activation of NLRP3 inflammasome and higher migration, invasion and phagocytosis capacities than those derived from lean donors. Remarkably, ASCs derived from obese and T2D subjects exhibited a reduction in typical immunosuppressive activities attributed to stem cells. Accordingly, obese and T2D-ASCs were less effective in suppressing lymphocyte proliferation, activating the M2 macrophage phenotype, and in increasing TGF-ß1 secretion, than lean-derived ASCs. Treatment of lean hASCs with interleukin (IL)-1ß mimicked the dysfunctional immune behavior of obese and T2D hASCs. Conversely, combined treatment with IL1RA and TGF-ß1 reverted the phenotype of obese- and T2D-ASCs. These data indicate that the donor metabolic phenotype compromises the immunomodulatory properties of ASCs. These results are relevant not only for understanding the physiology of ASCs in terms of cell-based therapies but also for their role as key regulators of the immune response. Stem Cells 2016;34:2559-2573.
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Tejido Adiposo/patología , Diabetes Mellitus Tipo 2/patología , Obesidad/patología , Células Madre/inmunología , Adulto , Femenino , Humanos , Terapia de Inmunosupresión , Inflamasomas/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Masculino , Persona de Mediana Edad , Fagocitosis , Células Madre/metabolismo , Donantes de Tejidos , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2(+/-) mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.
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Regulación hacia Abajo , Quinasa 2 del Receptor Acoplado a Proteína-G/genética , Perfilación de la Expresión Génica/métodos , Resistencia a la Insulina/genética , Miocardio/metabolismo , Animales , Western Blotting , Cardiomegalia/genética , Cardiomegalia/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Dieta Alta en Grasa/efectos adversos , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Hipoglucemiantes/farmacología , Insulina/farmacología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/etiología , Obesidad/genética , Obesidad/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARΔ1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes.
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Adipocitos/metabolismo , Ácidos Grasos/metabolismo , Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/farmacología , Macrófagos/metabolismo , Células 3T3-L1 , Adulto , Anciano , Animales , Estudios de Cohortes , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Obesidad/metabolismo , Oxidación-Reducción , Triglicéridos/metabolismoRESUMEN
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.