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Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.
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Biomarcadores , Lipidômica , Hepatopatia Gordurosa não Alcoólica , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Humanos , Biomarcadores/sangue , Lipidômica/métodos , Lipoproteínas/metabolismo , Lipoproteínas/sangue , Metabolismo dos Lipídeos , Fígado/metabolismo , AnimaisRESUMO
Obesity is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD), and the subcutaneous white adipose tissue (scWAT) is the primary lipid storage depot and regulates lipid fluxes to other organs. Our previous work identified genes upregulated in scWAT of patients with NAFLD: SOCS3, DUSP1, and SIK1. Herein, we knocked down (KD) their expression in human adipose-derived mesenchymal stem cells (hADMSCs) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology and characterized their phenotype. We found that SOCS3, DUSP1, and SIK1 expression in hADMSC-derived adipocytes was not critical for adipogenesis. However, the metabolic characterization of the cells suggested that the genes played important roles in lipid metabolism. Reduction of SIK1 expression significantly increased both de novo lipogenesis (DNL) and palmitate-induced lipogenesis (PIL). Editing out SOCS3 reduced DNL while increasing isoproterenol-induced lipolysis and insulin-induced palmitate accumulation. Conversely, DUSP1 reduced PIL and DNL. Moreover, RNA-sequencing analysis of edited cells showed that these genes not only altered lipid metabolism but also other biological pathways related to inflammatory processes, in the case of DUSP1, extracellular matrix remodeling for SOCS3, or cellular transport for SIK1. Finally, to evaluate a possible adipocyte-hepatocyte axis, human hepatoma HepG2 cells were cocultured with edited hADMSCs-derived adipocytes in the presence of [3H]-palmitate. All HepG2 cells cultured with DUSP1-, SIK1-, or SOCS3-KD adipocytes decreased [3H]-palmitate accumulation compared with control adipocytes. These results support our hypotheses that SOCS3, DUSP1, and SIK1 regulate multiple aspects of adipocyte function, which may play a role in the progression of obesity-associated comorbidities, such as NAFLD.NEW & NOTEWORTHY Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology successfully edited genomic DNA of human adipose-derived mesenchymal stem cells (hADMSC). SOCS3, SIK1, and DUSP1 regulate adipocyte lipid handling. Silencing SOCS3, SIK1, and DUSP1 expression in hADMSC-derived adipocytes reduces hepatocyte lipid storage in vitro.
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BACKGROUND: The assessment of obesity-related health risks has traditionally relied on the Body Mass Index and waist circumference, but their limitations have propelled the need for a more comprehensive approach. The differentiation between visceral (VIS) and subcutaneous (SC) fat provides a finer-grained understanding of these risks, yet practical assessment methods are lacking. We hypothesized that combining the SC-VIS fat ratio with non-invasive biomarkers could create a valuable tool for obesity-related risk assessment. METHODS AND RESULTS: A clinical study of 125 individuals with obesity revealed significant differences in abdominal fat distribution measured by CT-scan among genders and distinct models of obesity, including visceral, subcutaneous, and the SC/VIS ratio. Stratification based on these models highlighted various metabolic changes. The SC/VIS ratio emerged as an excellent metric to differentiate metabolic status. Gene expression analysis identified candidate biomarkers, with ISM1 showing promise. Subsequent validation demonstrated a correlation between ISM1 levels in SC and plasma, reinforcing its potential as a non-invasive biomarker for fat distribution. Serum adipokine levels also correlated with the SC/VIS ratio. The Receiver Operating Characteristic analysis revealed ISM1's efficacy in discriminating individuals with favorable metabolic profiles based on adipose tissue distribution. Correlation analysis also suggested that ISM1 was involved in glucose regulation pathways. CONCLUSION: The study's results support the hypothesis that the SC-VIS fat ratio and its derived non-invasive biomarkers can comprehensively assess obesity-related health risks. ISM1 could predict abdominal fat partitioning and be a potential biomarker for evaluating obesity-related health risks.
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Adipocinas , Obesidade , Trombospondinas , Feminino , Humanos , Masculino , Gordura Abdominal/diagnóstico por imagem , Gordura Abdominal/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Biomarcadores/metabolismo , Índice de Massa Corporal , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/metabolismo , Trombospondinas/metabolismoRESUMO
Obesity is a major risk factor for the development of Nonalcoholic fatty liver disease (NAFLD). We hypothesize that a dysfunctional subcutaneous white adipose tissue (scWAT) may lead to an accumulation of ectopic fat in the liver. Our aim was to investigate the molecular mechanisms involved in the causative role of scWAT in NALFD progression. We performed a RNA-sequencing analysis in a discovery cohort (n = 45) to identify genes in scWAT correlated with fatty liver index, a qualitative marker of liver steatosis. We then validated those targets in a second cohort (n = 47) of obese patients who had liver biopsies available. Finally, we obtained scWAT mesenchymal stem cells (MSCs) from 13 obese patients at different stages of NAFLD and established in vitro models of human MSC (hMSC)-derived adipocytes. We observed impaired adipogenesis in hMSC-derived adipocytes as liver steatosis increased, suggesting that an impaired adipogenic capacity is a critical event in the development of NAFLD. Four genes showed a differential expression pattern in both scWAT and hMSC-derived adipocytes, where their expression paralleled steatosis degree: SOCS3, DUSP1, SIK1, and GADD45B. We propose these genes as key players in NAFLD progression. They could eventually constitute potential new targets for future therapies against liver steatosis.
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Hepatopatia Gordurosa não Alcoólica , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismoRESUMO
Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Humanos , Tecido Adiposo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Diferenciação Celular , Obesidade/terapia , Obesidade/metabolismo , Terapia Genética , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
INTRODUCTION: There is a growing interest in the emotional state of cancer patients. The main objective of this pilot study is to assess the feasibility, acceptability, and preliminary efficacy of Meaning-Centered Psychotherapy and Essential Care (MCP-EC) in patients with advanced cancer compared with usual psychological support. We define "Essential Care" as the promotion of patient care and self-care through the recall of good care experiences and discussion of the concepts: responsibility, self-compassion, kindness, and attitude. METHOD: Pilot, single-center, and prospective study of 30 patients with advanced cancer and emotional distress. Our adaptation consisted in three session Meaning-Centered Psychotherapy-Palliative Care, plus a fourth session named "Essential Care". The study was carried out in two phases. First, 20 patients were randomized to one of the two arms: individual MCP-EC (experimental, n = 10) or usual psychological supportive (control, n = 10). In a second phase, 10 patients were assigned consecutively to Group MCP-EC (n = 10). All patients were evaluated at baseline (pre-) and post-intervention with questionnaires for sociodemographic data and clinical scales. RESULTS: Nineteen patients completed the 4 sessions of MCP-EC, 9 individual format and 10 group format. Usual supportive intervention was delivered to 10 control patients. Total 28 patients completed pre- and post-treatment evaluations. There were no pre- vs. post-differences in the evaluations of the control group. In the experimental group, significant pre- vs. post-differences were found in EQ-5D-3L, HADS, FACIT, DM, HAI, SCS-SF, and TD questionnaires. These results indicated that MCP-EC reduced anxiety and depression symptoms, hopelessness, demoralization, as well as increased spiritual well-being and sense of meaning. Participants were satisfied and found the MCP-EC intervention positively. CONCLUSIONS: This pilot study suggests that the MCP-EC has feasibility, acceptability, and preliminary efficacy reducing the emotional distress in advanced cancer patients. Larger studies are warranted to clarify the strengths and limitations of this psychotherapy.
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Neoplasias , Psicoterapia de Grupo , Humanos , Neoplasias/complicações , Neoplasias/psicologia , Neoplasias/terapia , Cuidados Paliativos/métodos , Projetos Piloto , Estudos Prospectivos , Psicoterapia/métodos , Psicoterapia de Grupo/métodosRESUMO
BACKGROUND & AIMS: Oral phase dysphagia is dependent on ability to chew. As people age, general muscle atrophy contributes to decreased masseter strength. The main objective of this study was to assess the relationship between the thickness of the masseter muscle measured by ultrasonography and the presence of dysphagia in a group of institutionalized elderly people. As a secondary objective, we aimed to establish cutoff points of masseters muscle thickness (MMT) to identify elderly individuals at risk of oral dysphagia. METHODS: Cross-sectional study of all residents from 3 nursing homes. All individuals underwent ultrasonographic measurements of left and right MMT and were classified according to the presence of dysphagia assessed by both the EAT-10 screening questionnaire and the volume-viscosity swallow test (V-VST). RESULTS: 469 patients (69% women, mean age 84.7 yrs) were recruited. Dysphagia was present in 41.6% and 26% of individuals according the EAT-10 and V-VST, respectively. Multivariate logistic regression showed that 1 mm increase in MMT reduced the risk of dysphagia by 21% according to the EAT-10 tool and by 30% using the V-VST after adjusting for age, sex, mini-nutritional assessment score, and body mass index. We used receiver operative characteristic (ROC) curves to identify cutoff points of MMT to detect dysphagic individuals according to either EAT-10 or V-VST. CONCLUSIONS: The MMT measured by ultrasonography is reduced in elderly individuals with dysphagia. Based on MMT, clinicians may be better informed about the patients'´ ability to masticate solid foods and identify potential nutrient deficiencies in geriatric settings.
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Transtornos de Deglutição , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Transtornos de Deglutição/diagnóstico por imagem , Feminino , Humanos , Masculino , Músculo Masseter/diagnóstico por imagem , Fase Oral , UltrassonografiaRESUMO
Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2, ε3, and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes.
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Apolipoproteínas E/genética , Alelos , Encéfalo/metabolismo , Diabetes Mellitus , Feminino , Genótipo , Humanos , Longevidade/genética , Masculino , Síndrome Metabólica/genética , Obesidade/genéticaRESUMO
PURPOSE: Oral squamous cell carcinoma (OSCC) is a highly prevalent type of immunogenic cancer with a low survival rate in patients with comorbidities owing to toxic habits. MATERIALS AND METHODS: A retrospective cohort study was conducted of patients with resectable OSCC at a tertiary Spanish hospital from 2011 to 2014. The primary predictor variables were comorbidity and immune biomarkers. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) and scored from 1 to 3 (mild to severe decompensation, respectively). The immune biomarkers were neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). The primary outcome variable was 5-year overall survival (OS). Other study variables were stage, margin, and neck management. Receiver operating characteristic curves were built for each ratio. For the survey of immune biomarkers, area under the curve was computed to determine cutoff points and investigate their association with OS. Kaplan-Meier estimates of survival and Cox proportional hazards models were used for longitudinal analysis. RESULTS: Overall 215 patients were identified (median age, 67 yr; range, 32 to 96 yr; median follow-up, 31 months; range, 7 to 78 months); 159 patients had at least 1 comorbid condition. Results showed that a severe comorbidity (according to the ACE-27) increased the risk of death by 4 times in patients with OSCC regardless of stage. NLR, dNLR, LMR, and PLR were associated with OS in the univariate study. Cutoff points to predict increased mortality were 3, 1.9, 2.6, and 66 for NLR, dNLR, LMR, and PLR, respectively. Age, comorbidity, stage, margins, and management of the neck were important independent predictors of decreased OS in OSCC. PLR was marginally associated with OS in the multivariate model. CONCLUSION: These results suggest that comorbidity and NLR, dNLR, LMR, and PLR are associated with 5-year OS in patients with resectable OSCC.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Comorbidade , Humanos , Pessoa de Meia-Idade , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Neutrófilos , Prognóstico , Estudos RetrospectivosRESUMO
The beneficial actions of n-3 fatty acids on obesity-induced insulin resistance and inflammation have been related to the synthesis of specialized proresolving lipid mediators (SPMs) like resolvins. The aim of this study was to evaluate the ability of one of these SPMs, maresin 1 (MaR1), to reverse adipose tissue inflammation and/or insulin resistance in two models of obesity: diet-induced obese (DIO) mice and genetic (ob/ob) obese mice. In DIO mice, MaR1 (2 µg/kg; 10 d) reduced F4/80-positive cells and expression of the proinflammatory M1 macrophage phenotype marker Cd11c in white adipose tissue (WAT). Moreover, MaR1 decreased Mcp-1, Tnf-α, and Il-1ß expression, upregulated adiponectin and Glut-4, and increased Akt phosphorylation in WAT. MaR1 administration (2 µg/kg; 20 d) to ob/ob mice did not modify macrophage recruitment but increased the M2 macrophage markers Cd163 and Il-10. MaR1 reduced Mcp-1, Tnf-α, Il-1ß, and Dpp-4 and increased adiponectin gene expression in WAT. MaR1 treatment also improved the insulin tolerance test of ob/ob mice and increased Akt and AMPK phosphorylation in WAT. These data suggest that treatment with MaR1 can counteract the dysfunctional inflamed WAT and could be useful to improve insulin sensitivity in murine models of obesity.-Martínez-Fernández, L., González-Muniesa, P., Laiglesia, L. M., Sáinz, N., Prieto-Hontoria, P. L., Escoté, X., Odriozola, L., Corrales, F. J., Arbones-Mainar, J. M., Martínez, J. A., Moreno-Aliaga, M. J. Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet-induced obese mice.
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Tecido Adiposo/metabolismo , Dieta , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Ração Animal , Animais , Interleucina-10/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BLRESUMO
Healthy expansion of human adipose tissue requires mesenchymal stem cells (hMSC) able to proliferate and differentiate into mature adipocytes. Hence, characterization of those factors that coordinate hMSC-to-adipocyte transition is of paramount importance to modulate the adipose tissue expansion. It has been previously reported that the adipogenic program of hMSC can be disrupted by upregulating caveolar proteins, and polymerase I and transcript release factor (PTRF) is an integral component of caveolae, highly expressed in adipose tissue. Here, we hypothesized that the role of PTRF in adipocyte functionality might stem from an effect on hMSC. To test this hypothesis, we isolated hMSC from the subcutaneous fat depot. We found an upregulated expression of the PTRF associated with decreased adipogenic potential of hMSC, likely due to the existence of senescent adipocyte precursors. Employing short hairpin RNA-based constructs to stably reduce PTRF, we were able to restore insulin sensitivity and reduced basal lipolysis and leptin levels in human adipocytes with high levels of PTRF. Additionally, we pinpointed the detrimental effect caused by PTRF on the adipose tissue to the existence of senescent adipocyte precursors unable to proliferate and differentiate into adipocytes. This study provides evidence that impaired adipocyte functionality can be corrected, at least partially, by PTRF downregulation and warrants further in vivo research in patients with dysfunctional adipose tissue to prevent metabolic complications.
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Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Proteínas de Ligação a RNA/metabolismo , Adipogenia/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Adipocytes derived from human mesenchymal stem cells (MSCs) are widely used to investigate adipogenesis. Taking into account both the novelty of these MSCs and the scarcity of studies focused on the effects of phenolic compounds, the aim of the present study was to analyze the effect of apigenin, hesperidin and kaempferol on pre-adipocyte and mature adipocytes derived from this type of cells. In addition, the expression of genes involved in TG accumulation was also measured. METHODS: Pre-adipocytes were cultured from day 0 to day 8 and mature adipocytes for 48 h with the polyphenols at doses of 1, 10 and 25 µM. RESULTS: Apigenin did not show an anti-adipogenic action. Pre-adipocytes treated with hesperidin and kaempferol showed reduced TG content at the three experimental doses. Apigenin did not modify the expression of the main adipogenic genes (c/ebpß, c/ebpα, pparγ and srebp1c), hesperidin inhibited genes involved in the three phases of adipogenesis (c/ebpß, srebp1c and perilipin) and kaempferol reduced c/ebpß. In mature adipocytes, the three polyphenols reduced TG accumulation at the dose of 25 µM, but not at lower doses. All compounds increased mRNA levels of atgl. Apigenin and hesperidin decreased fasn expression. The present study shows the anti-adipogenic effect and delipidating effects of apigenin, hesperidin and kaempferol in human adipocytes derived from hMSCs. While hesperidin blocks all the stages of adipogenesis, kaempferol only inhibits the early stage. Regarding mature adipocytes, the three compounds reduce TG accumulation by activating, at least in part, lipolysis, and in the case of hesperidin and apigenin, also by reducing lipogenesis. CONCLUSIONS: The present study shows for the first time the anti-adipogenic effect and delipidating effect of apigenin, hesperidin and kaempferol in human adipocytes derived from MSCs for the first time.
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Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Apigenina/farmacologia , Hesperidina/farmacologia , Quempferóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Adipócitos/fisiologia , Adipogenia/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Cultura Primária de Células , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Obesity is an excessive accumulation of fat frequently, but not always, associated with health problems, mainly type 2 diabetes and cardiovascular disease. During a positive energy balance, as caused by excessive intake or sedentary lifestyle, subcutaneous adipose tissue expands and accumulates lipids as triglycerides. However, the amount of adipose tissue per se is unlikely to be the factor linking obesity and metabolic complications. The expandability hypothesis states that, if this positive energy balance is prolonged, a point is eventually reached where subcutaneous adipose tissue can not further expand and energy surplus no longer can be safely stored. Once the limit on storage capacity has been exceeded, the dietary lipids start spilling and accumulate ectopically in other organs (omentum, liver, muscle, pancreas) forming lipid byproducts toxic to cells. METHODS/DESIGN: FATe is a multidisciplinary clinical project aimed to fill gaps that still exist in the expandability hypothesis. Imaging techniques (CT-scan), metabolomics, and transcriptomics will be used to identify the factors that set the limit expansion of subcutaneous adipose tissue in a cohort of caucasian individuals with varying degrees of adiposity. Subsequently, a set of biomarkers that inform the individual limits of expandability will be developed using computational and mathematical modeling. A different validation cohort will be used to minimize the risk of false positive rates and increase biomarkers' predictive performance. DISCUSSION: The work proposed here will render a clinically useful screening method to predict which obese individuals will develop metabolic derangements, specially diabetes and cardiovascular disease. This study will also provide mechanistic evidence that promoting subcutaneous fat expansion might be a suitable therapy to reduce metabolic complications associated with positive energy balance characteristic of Westernized societies.
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Adiposidade , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/fisiopatologia , Metabolismo Energético , Obesidade/fisiopatologia , Gordura Subcutânea/fisiopatologia , Adiposidade/etnologia , Adiposidade/genética , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus/etnologia , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Progressão da Doença , Metabolismo Energético/genética , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Humanos , Metabolômica/métodos , Obesidade/diagnóstico , Obesidade/etnologia , Obesidade/genética , Obesidade/metabolismo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/metabolismo , Tomografia Computadorizada por Raios X , População Branca/genéticaRESUMO
Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet glucose-tolerant mice, and prediabetic mice with impaired glucose tolerance and reduced circulating insulin. Using proteomics, we compared subcutaneous adipose tissues from mice in these groups and found that the expression of PTRF (polymerase I and transcript release factor) associated selectively with their glucose tolerance status. Lentiviral and pharmacologically overexpressed PTRF, whose function is critical for caveola formation, compromised adipocyte differentiation of cultured 3T3-L1cells. In human adipose tissue, PTRF mRNA levels positively correlated with markers of lipolysis and cellular senescence. Furthermore, a negative relationship between telomere length and PTRF mRNA levels was observed in human subcutaneous fat. PTRF is associated with limited adipose tissue expansion underpinning the key role of caveolae in adipocyte regulation. Furthermore, PTRF may be a suitable adipocyte marker for predicting pathological obesity and inform clinical management.
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Adipócitos/patologia , Adipogenia/fisiologia , Cavéolas/fisiologia , Dieta/efeitos adversos , Intolerância à Glucose/etiologia , Hiperinsulinismo/etiologia , Obesidade/etiologia , Estado Pré-Diabético/etiologia , Proteínas de Ligação a RNA/fisiologia , Gordura Subcutânea/metabolismo , Células 3T3-L1 , Adiponectina/sangue , Animais , Aorta/patologia , Apolipoproteína E2/genética , Senescência Celular , Feminino , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Intolerância à Glucose/sangue , Intolerância à Glucose/patologia , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/patologia , Resistência à Insulina , Lipólise , Fígado/química , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/classificação , Obesidade/patologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/patologia , Gravidez , RNA Mensageiro/biossíntese , Proteínas Recombinantes de Fusão/metabolismo , Gordura Subcutânea/patologia , Encurtamento do Telômero , Triglicerídeos/metabolismoRESUMO
Research on the microbiome has progressed from identifying specific microbial communities to exploring how these organisms produce and modify metabolites that impact a wide range of health conditions, including gastrointestinal, metabolic, autoimmune, and neurodegenerative diseases. This review provides an overview of the bacteria commonly found in the intestinal tract, focusing on their main functional outputs. We explore biomarkers that not only indicate a well-balanced microbiota but also potential dysbiosis, which could foreshadow susceptibility to future health conditions. Additionally, it discusses the establishment of the microbiota during the early years of life, examining factors such as gestational age at birth, type of delivery, antibiotic intake, and genetic and environmental influences. Through a comprehensive analysis of current research, this article aims to enhance our understanding of the microbiota's foundational development and its long-term implications for health and disease management.
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Disbiose , Microbioma Gastrointestinal , Microbioma Gastrointestinal/fisiologia , Humanos , Bactérias/metabolismo , Recém-Nascido , Lactente , Antibacterianos , BiomarcadoresRESUMO
The eradication of the hepatitis C virus (HCV) has revolutionized the hepatology paradigm, halting the progression of advanced liver disease in patients with chronic infection and reducing the risk of hepatocarcinoma. In addition, treatment with direct-acting antivirals can reverse the lipid and carbohydrate abnormalities described in HCV patients. Although HCV eradication may reduce the overall risk of vascular events, it is uncertain whether altered lipid profiles increase the risk of cerebrovascular disease in certain patients. We have conducted a review on HCV and lipid and carbohydrate metabolism, as well as new scientific advances, following the advent of direct-acting antivirals.
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Adipose tissue (AT), once considered a mere fat storage organ, is now recognized as a dynamic and complex entity crucial for regulating human physiology, including metabolic processes, energy balance, and immune responses. It comprises mainly two types: white adipose tissue (WAT) for energy storage and brown adipose tissue (BAT) for thermogenesis, with beige adipocytes demonstrating the plasticity of these cells. WAT, beyond lipid storage, is involved in various metabolic activities, notably lipogenesis and lipolysis, critical for maintaining energy homeostasis. It also functions as an endocrine organ, secreting adipokines that influence metabolic, inflammatory, and immune processes. However, dysfunction in WAT, especially related to obesity, leads to metabolic disturbances, including the inability to properly store excess lipids, resulting in ectopic fat deposition in organs like the liver, contributing to non-alcoholic fatty liver disease (NAFLD). This narrative review delves into the multifaceted roles of WAT, its composition, metabolic functions, and the pathophysiology of WAT dysfunction. It also explores diagnostic approaches for adipose-related disorders, emphasizing the importance of accurately assessing AT distribution and understanding the complex relationships between fat compartments and metabolic health. Furthermore, it discusses various therapeutic strategies, including innovative therapeutics like adipose-derived mesenchymal stem cells (ADMSCs)-based treatments and gene therapy, highlighting the potential of precision medicine in targeting obesity and its associated complications.
Assuntos
Tecido Adiposo Branco , Obesidade , Humanos , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Marrom/metabolismo , Biomarcadores/metabolismo , Fígado/metabolismoRESUMO
BACKGROUND: Numerous scores are designed to predict outcomes of patients with liver cirrhosis. Our study aimed to evaluate the ability of the Liver Disease Undernutrition Screening Tool (LDUST) in predicting mortality and decompensation in outpatients with clinically significant portal hypertension (CSPH). We hypothesized that LDUST could help identify patients in need of nutritional supplementation and intervention. METHODS: A prospective study of 57 CSPH patients (36.8% female, mean age: 63.5 ± 9.9 years) with a median follow-up of 41 months was conducted. Baseline liver function, nutrition, and sarcopenia were assessed, alongside LDUST. During follow-up, the occurrence of liver decompensation, hospital admission, need for emergency care, and mortality were evaluated. RESULTS: A total of 56.1% of patients were Child A, and the most frequent etiology was alcohol (50.9%). Malnutrition risk according to LDUST raised mortality (HR: 25.96 (1.47-456.78)), decompensation (HR 9.78 (2.08-45.89)), and admission (HR 4.86 (1.09-21.61)) risks in multivariate Cox analysis. Combining LDUST with Child and MELD scores improved their decompensation prediction (0.936 vs. 0.811 and 0.866 vs. 0.700). CONCLUSIONS: The LDUST has a solid ability to predict complications in cirrhosis outpatients with CSPH, and its integration with Child and MELD models enhances their predictive power. LDUST implementation could identify individuals necessitating early nutritional support.
Assuntos
Hipertensão Portal , Cirrose Hepática , Desnutrição , Humanos , Pessoa de Meia-Idade , Idoso , Desnutrição/diagnóstico , Hepatopatias , Estudos Prospectivos , Hipertensão Portal/complicações , Hipertensão Portal/mortalidade , Masculino , Feminino , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Pacientes AmbulatoriaisRESUMO
BACKGROUND & AIMS: Hepatitis C virus (HCV) interferes with carbohydrate and lipid metabolism causing cardiovascular disease and insulin resistance (IR). Direct-acting antivirals (DAAs) are highly effective for the eradication of HCV, with positive effects on metabolic health although paradoxically associated with increased total and LDL-cholesterol. The aims of this study were 1) to characterize dyslipidemia (lipoprotein content, number, and size) in naive HCV-infected individuals and 2) to evaluate the longitudinal association of metabolic changes and lipoparticle characteristics after DAA therapy. METHODS: We conducted a prospective study with one-year follow-up. 83 naive outpatients treated with DAAs were included. Those co-infected with HBV or HIV were excluded. IR was analyzed using the HOMA index. Lipoproteins were studied by fast-protein liquid chromatography (FPLC) and Nuclear Magnetic Resonance Spectroscopy (NMR). RESULTS: FPLC analysis showed that lipoprotein-borne HCV was only present in the VLDL region most enriched in APOE. There was a lack of association between HOMA and total cholesterol or cholesterol carried by LDL or HDL at baseline. Alternatively, a positive association was found between HOMA and total circulating triglycerides (TG), as well as with TG transported in VLDL, LDL, and HDL. HCV eradication with DAAs resulted in a strong and significant decrease in HOMA (-22%) and HDL-TG (-18%) after one-year follow-up. CONCLUSIONS: HCV-dependent lipid abnormalities are associated with IR and DAA therapy can reverse this association. These findings may have potential clinical implications as the HDL-TG trajectory may inform the evolution of glucose tolerance and IR after HCV eradication.
Assuntos
Hepatite C Crônica , Hepatite C , Resistência à Insulina , Humanos , Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Estudos Prospectivos , Lipoproteínas , Triglicerídeos , Colesterol , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepacivirus/genéticaRESUMO
OBJECTIVE: Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. METHODS: MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6-/-) mice. RESULTS: In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6-/- mice. CONCLUSIONS: These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.