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The use of gut-hormone receptors agonists as new therapeutic options for obesity and some of its related comorbidities, such as type 2 diabetes, has resulted in an unprecedented efficacy in the medical management of people living with obesity (PLWO). Appraisal of the safety of these drugs is of utmost importance considering the large number of PLWO, and the potentially long exposure to these pharmacotherapies. In this narrative review we summarize the evidence on the safety of liraglutide, semaglutide, and tirzepatide as derived from randomized clinical trials conducted in adults living with obesity. Additionally, the safety of these drugs is put into perspective with that of other drugs currently approved for the treatment of PLWO. Overall, the available data support a favorable efficacy versus safety balance for gut-hormone hormone receptor analogues in the treatment of these subjects. Nonetheless, it should be acknowledged that in the context of a chronic disease that has reached epidemic proportions, data from randomized clinical trials aimed primarily at proving the efficacy of these drugs may have been insufficient to unveil all the safety issues. Thus, continuous surveillance on the adverse effects of liraglutide, semaglutide, and tirzepatide is required as we use these drugs in a broader population than that represented in currently available clinical trials.
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BACKGROUND & AIMS: Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature. The role of VEGF-B signaling and the contribution to hepatic steatosis and NAFLD in T2DM is currently not understood. METHODS: C57BL/6 J mice treated with a neutralizing antibody against VEGF-B, or mice with adipocyte-specific overexpression or under-expression of VEGF-B (AdipoqCre+/VEGF-BTG/+ mice and AdipoqCre+/Vegfbfl/+mice) were subjected to a 6-month high-fat diet (HFD), or chow-diet, whereafter NAFLD development was assessed. VEGF-B expression was analysed in WAT biopsies from patients with obesity and NAFLD in a pre-existing clinical cohort (n = 24 patients with NAFLD and n = 24 without NAFLD) and correlated to clinicopathological features. RESULTS: Pharmacological inhibition of VEGF-B signaling in diabetic mice reduced hepatic steatosis and NAFLD by blocking WAT lipolysis. Mechanistically we show, by using HFD-fed AdipoqCre+/VEGF-BTG/+ mice and HFD-fed AdipoqCre+/Vegfbfl/+mice, that inhibition of VEGF-B signaling targets lipolysis in adipocytes. Reducing VEGF-B signaling ameliorated NAFLD by decreasing WAT inflammation, resolving WAT insulin resistance, and lowering the activity of the hormone sensitive lipase. Analyses of human WAT biopsies from individuals with NAFLD provided evidence supporting the contribution of VEGF-B signaling to NAFLD development. VEGF-B expression levels in adipocytes from two WAT depots correlated with development of dysfunctional WAT and NAFLD in humans. CONCLUSIONS: Taken together, our data from mouse models and humans suggest that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM) and has a global prevalence of between 25-29%. There are currently no approved drugs for NAFLD, and given the scale of the ongoing diabetes epidemics, there is an urgent need to identify new treatment options. Our work suggests that VEGF-B antagonism may represent an approach to combat NAFLD by targeting hepatic steatosis through suppression of lipolysis. The neutralizing anti-VEGF-B antibody, which was used in this study, has already entered clinical trials for patients with diabetes. Therefore, we believe that our results are of great general interest to a broad audience, including patients and patient organizations, the medical community, academia, the life science industry and the public.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipólise , Fator B de Crescimento do Endotélio Vascular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Fígado/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo/metabolismoRESUMO
BACKGROUND/OBJECTIVES: Whether the extent of weight loss (WL) modulates bariatric surgery (BS) cardiovascular benefits has scarcely been assessed. Several WL thresholds have been commonly used to classify BS patients as good or poor responders without a proven clinical relevance. We examined the relationship between the magnitude of WL after BS and post-surgery major adverse cardiovascular-event (MACE) incidence. We also compared the performance of three different insufficient weight-loss (IWL) criteria for their association with MACE. SUBJECTS AND METHODS: All individuals who underwent a primary Roux-en Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in our institution at least six years before data analysis (12/2020) were included in the study. Data on MACE were available in 1638 of 1700 participants (96.4%). Proportional-hazard Cox analyses were performed to ascertain the association between MACE, WL, and the three IWL criteria. IWL was defined as: <50% excess weight loss (<50% EWL), <20% total body-weight loss (<20% TBWL), and -1 standard deviation of alterable weight-loss percentage (<1 SD% AWL). RESULTS: During a mean follow-up of 10.2 ± 2.8 years, 86 participants experienced a first post-surgery MACE. Higher WL at one year (HR: 0.77 (95% CI: 0.61-0.98)) and 5 years (HR: 0.63 (95% CI: 0.42-0.92)) was related to a lower incidence of MACE. All short-term criteria for defining IWL were similarly associated with MACE, yet <1 SD% AWL identified more at-risk subjects. Five-year TBWL < 20% and 5-year <1 SD-AWL% were significantly associated with a higher risk for CV events. TBWL < 20% identified more subjects at risk. CONCLUSIONS: The extent of WL is closely related to long-term MACE incidence. Patients who lost -1SD% AWL at one year or <20% TBWL at five years may be considered poor responders.
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Cirurgia Bariátrica/normas , Trajetória do Peso do Corpo , Doenças Cardiovasculares/complicações , Adulto , Cirurgia Bariátrica/métodos , Cirurgia Bariátrica/estatística & dados numéricos , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/cirurgia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The metabolic syndrome (MetS) is a cluster of the most dangerous heart attack risk factors: diabetes or raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. The goal of this study is to compare the state of the main features of obesity-associated white adipose tissue (WAT) dysfunction in 66 women with severe obesity without (MetS-) or with MetS (MetS+). Fat cell area, adipocyte size distribution and histological fibrosis were analysed in visceral (VAT) and abdominal subcutaneous WAT (SAT) in 33 age- and BMI-matched pairs of MetS- and MetS+ subjects. The mRNA expression of 93 genes implicated in obesity-associated WAT dysfunction was analysed by RT-qPCR in both fat depots. MetS+ females showed higher adipocyte hypertrophy in both fat depots and increased fibrosis and expression of macrophage and hypoxia markers in SAT. Transcriptional data suggest increased fatty acid oxidation in SAT and impaired thermogenesis and extracellular matrix remodelling in VAT from MetS+ subjects. A sPLS-DA model, including SAT expression of PPARA and LEPR genes identified MetS with an AUC = 0.87. Despite equal age, BMI and body composition, MetS+ females display morphological and transcriptional differences in both WAT depots, especially in SAT. These factors may contribute to the transition to MetS.
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Síndrome Metabólica/patologia , Obesidade Mórbida/patologia , Gordura Subcutânea Abdominal/patologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Composição Corporal/fisiologia , Índice de Massa Corporal , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Feminino , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Obesidade Abdominal/metabolismo , Obesidade Abdominal/patologia , Obesidade Mórbida/metabolismo , Gordura Subcutânea Abdominal/metabolismo , Termogênese/fisiologiaRESUMO
Development and severity of nonalcoholic fatty liver disease (NAFLD) have been linked to obesity and white adipose tissue (WAT) dysfunction plays a key role in this relation. We compared the main features of subcutaneous (SAT) and visceral WAT (VAT) tissue dysfunction in 48 obese women without (Ob) and with NAFLD (Ob-NAFLD) undergoing bariatric surgery and matched for age, BMI and T2D status. Fat cell area, adipocyte size distribution, the degree of histological fibrosis and the mRNA expression of adipokines and genes implicated in inflammation, adipogenesis, angiogenesis, metabolism and extracellular matrix remodeling were measured by RT-qPCR in both fat depots. Ob-NAFLD group showed higher TG and lower HDL circulating levels, increased VAT fat cell area and similar WAT fibrosis in comparison with Ob group. A sPLS-DA was performed in order to identify the set of genes that better characterize the presence of NAFLD. Finally, we build a multinomial logistic model including seven genes that explained 100% of the variance in NAFLD and correctly predicted 100% of cases. Our data support the existence of distinctive NAFLD signatures in WAT from women with severe obesity. A better understanding of these pathways may help in future strategies for the prevention and treatment of NAFLD.
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Adipocinas/biossíntese , Regulação da Expressão Gênica , Gordura Intra-Abdominal/metabolismo , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Mórbida/metabolismo , Gordura Subcutânea/metabolismo , Adulto , Feminino , Humanos , Gordura Intra-Abdominal/patologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade Mórbida/patologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gordura Subcutânea/patologiaRESUMO
The COVID-19 pandemic is posing a great challenge worldwide. Its rapid progression has caused thousands of deaths worldwide. Although multiple aspects remain to be clarified, some risk factors associated with a worse prognosis have been identified. These include obesity and some of its main complications, such as diabetes and high blood pressure. Furthermore, although the possible long-term complications and psychological effects that may appear in survivors of COVID-19 are not well known yet, there is a concern that those complications may be greater in obese patients. In this manuscript, we review some of the data published so far and the main points that remain to be elucidated are emphasized.
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COVID-19/epidemiologia , Obesidade/epidemiologia , Comorbidade , Diabetes Mellitus/epidemiologia , Humanos , Hipertensão/epidemiologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
In recent years, a marked increase in the relative use of sleeve gastrectomy (SG) has occurred. However, long-term head-to-head comparison of the impact of this bariatric surgery (BS) procedure with the still considered "gold standard" Roux-en-Y gastric bypass (GBP) in subjects with type 2 diabetes mellitus (T2DM) is surprisingly low. The aim of this review manuscript is to appraise current evidence on the potential of GBP and SG as long-term therapeutic tool for subjects with T2DM. In our opinion, unfortunately, review of current literature does not allow to properly answer which of the two surgeries would be better as procedure of choice for subjects with T2DM. Arguably, the apparent superiority of GBP over SG could be overcome by the addition of a malabsortive component to SG in a staged approach restricted to those failing to achieve the desired metabolic outcomes. Nonetheless, whether this serves as basis for the election of SG as primary strategy for those with T2DM is questionable.
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Diabetes Mellitus Tipo 2/cirurgia , Gastrectomia , Derivação Gástrica/métodos , Humanos , Resultado do Tratamento , Redução de PesoRESUMO
BACKGROUND: Outcomes of bariatric surgery (BS) in patients with schizophrenia are poorly understood. We aimed to analyze the effects of BS in patients with schizophrenia (SZ) or schizoaffective disorder (SZA). METHODS: This was a multicenter, retrospective case-control study in patients with SZ or SZA who had undergone BS in seven public referral hospitals in Spain. Controls without psychiatric comorbidity were selected in a 1:4 ratio. Detailed clinical and biochemical data were collected preoperatively and at 12, 24, 36, 48, and 60 months after BS. RESULTS: Twenty patients with SZ (n = 15; 75%) or SZA (n = 5; 25%) and 80 matched controls were studied. There were no differences between patients and controls concerning the evolution of the percentage of total weight loss. The remission rate of the main comorbidities was similar between groups except for hypertension, which was lower in patients with a psychotic disorder from year 3. There were no mortalities within 30 days of surgery in either group. The psychiatric medication burden did not change during follow-up. CONCLUSIONS: BS is safe and effective in carefully selected patients with SZ. The course of the psychiatric disease does not seem to be worsened by the procedure.
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Cirurgia Bariátrica , Transtornos Psicóticos , Esquizofrenia , Redução de Peso , Humanos , Esquizofrenia/cirurgia , Masculino , Feminino , Estudos Retrospectivos , Adulto , Resultado do Tratamento , Estudos de Casos e Controles , Pessoa de Meia-Idade , Espanha/epidemiologia , ComorbidadeRESUMO
The excessive accumulation and malfunctioning of visceral adipose tissue (VAT) is a major determinant of increased risk of obesity-related comorbidities. Thus, risk stratification of people living with obesity according to their amount of VAT is of clinical interest. Currently, the most common VAT measurement methods include mathematical formulae based on anthropometric dimensions, often biased by human measurement errors, bio-impedance, and image techniques such as X-ray absorptiometry (DXA) analysis, which requires specialized equipment. However, previous studies showed the possibility of classifying people living with obesity according to their VAT through blood chemical concentrations by applying machine learning techniques. In addition, most of the efforts were spent on men living with obesity while little was done for women. Therefore, this study aims to compare the performance of the multilinear regression model (MLR) in estimating VAT and six different supervised machine learning classifiers, including logistic regression (LR), support vector machine and decision tree-based models, to categorize 149 women living with obesity. For clustering, the study population was categorized into classes 0, 1, and 2 according to their VAT and the accuracy of each MLR and classification model was evaluated using DXA-data (DXAdata), blood chemical concentrations (BLDdata), and both DXAdata and BLDdata together (ALLdata). Estimation error and R 2 were computed for MLR, while receiver operating characteristic (ROC) and precision-recall curves (PR) area under the curve (AUC) were used to assess the performance of every classification model. MLR models showed a poor ability to estimate VAT with mean absolute error ≥ 401.40 and R 2 ≤ 0.62 in all the datasets. The highest accuracy was found for LR with values of 0.57, 0.63, and 0.53 for ALLdata, DXAdata, and BLDdata, respectively. The ROC AUC showed a poor ability of both ALLdata and DXAdata to distinguish class 1 from classes 0 and 2 (AUC = 0.31, 0.71, and 0.85, respectively) as also confirmed by PR (AUC = 0.24, 0.57, and 0.73, respectively). However, improved performances were obtained when applying LR model to BLDdata (ROC AUC ≥ 0.61 and PR AUC ≥ 0.42), especially for class 1. These results seem to suggest that, while a direct and reliable estimation of VAT was not possible in our cohort, blood sample-derived information can robustly classify women living with obesity by machine learning-based classifiers, a fact that could benefit the clinical practice, especially in those health centres where medical imaging devices are not available. Nonetheless, these promising findings should be further validated over a larger population.
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Absorciometria de Fóton , Gordura Intra-Abdominal , Aprendizado de Máquina , Obesidade , Humanos , Feminino , Obesidade/complicações , Pessoa de Meia-Idade , Adulto , Absorciometria de Fóton/métodos , Máquina de Vetores de Suporte , Árvores de Decisões , IdosoRESUMO
BACKGROUND: The relative contribution of anthropometric, hormonal, and metabolic changes after bariatric surgery (BS) on sexual function (SF) in severely obese subjects is not well established. METHODS: Prospective observational case series study of 39 men undergoing BS. SF was assessed by means of the international index of erectile function (IIEF) before and at 1 year after surgery. At the same time points, anthropometric (body mass index, waist circumference), hormonal (testosterone, sex hormone binding globulin, estradiol, gonadotropins, inhibin B, prolactin, leptin), and metabolic parameters (insulin sensitivity, C-reactive protein, lipid profile, hemoglobin A1c, presence of hypertension or sleep apnea) were assessed. RESULTS: BS was associated with marked weight loss (77.18% excess weight loss), improved IIEF score (baseline: 54.85 ± 16.59, 1 year: 61.21 ± 14.10; p < 0.01), gonadal function (testosterone: baseline 256.36 ± 120.98, 1 year: 508.01 ± 161.90; p < 0.001), and improved metabolic profile. However, on multivariate regression analysis whereas changes in body mass index (beta: -0.677, p = 0.001), and baseline IIEF score (beta: -0.397, p = 0.023), were independent predictors of the changes in the IIEF score at 1 year after surgery, changes in hormonal and metabolic factors were not. Variables in the model accounted for 66% of the postsurgical variation in the IIEF score. Similar results were found when the different IIEF-sexual domains were evaluated, except for intercourse satisfaction for which no independent predictor was identified. CONCLUSIONS: Weight loss's beneficial effects on SF occurring after BS are beyond the parallel improvement in gonadal and metabolic profiles.
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Cirurgia Bariátrica , Disfunção Erétil/fisiopatologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Redução de Peso , Adulto , Biomarcadores/análise , Hormônios Esteroides Gonadais/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
Hypertriglyceridemia (HTG) has been associated with an increased risk of pancreatitis and cardiovascular disease. Adipose tissue plays a major role in lipid metabolism, mobilization and distribution. We have compared the histological and transcriptomic profiles of the subcutaneous (SAT) and visceral (VAT) adipose tissues from subjects with severe obesity undergoing bariatric surgery with (Ob-HTG, n = 37) and without HTG (Ob-NTG, n = 67). Mean age and BMI were 51.87 ± 11.21 years, 45.78 ± 6.96 kg/m2 and 50.03 ± 10.17 years, 44.04 ± 4.69 kg/m2, respectively. The Ob-HTG group showed higher levels of glycosylated hemoglobin, fasting plasma glucose, high-sensitivity C-reactive protein and prevalence of hypertension. The degree of fibrosis was increased by 14% in SAT from the Ob-HTG group (p = 0.028), while adipocyte size distribution was comparable. Twenty genes were found differentially expressed in SAT and VAT between study groups. Among them, only SAT expression of FABP4 resulted significantly associated with circulating triglyceride levels after adjusting for other covariates and independently explained 5% of the variance in triglyceride levels in the combined model. This relationship was not found in the cohort of lean or overweight patients with normotriglyceridemia (non-Ob, n = 21). These results emphasize the contribution of SAT to triglyceride concentrations in obesity and indicate that FABP4 may be a potential drug target for the treatment of HTG.
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CONTEXT: The impact of type 2 diabetes mellitus (T2D) at baseline on limited weight loss (WL) after bariatric surgery (BS) remains controversial, and the potential underlying mechanisms incompletely understood. OBJECTIVE: We aimed at gaining further insight on this relationship and identifying novel associations between adipose tissue (AT) parameters and short-term WL outcomes in subjects with or without T2D undergoing BS. METHODS: Mid-term WL trajectories after BS have been evaluated in a cohort of 1659 subjects (cohort 1) with (n = 543) and without T2D (n = 1116). Paired subcutaneous and visceral AT samples were obtained from a cohort of 48 pairs of subjects with and without T2D matched for age, sex, BMI, and type of BS (cohort 2). Differences in AT parameters between groups were evaluated and potential associations with WL response explored. RESULTS: T2D was independently associated with a 5% lesser mid-term WL in cohort 1, while HbA1c, insulin treatment, and number of T2D medications prior to BS were only related to short-term WL outcomes. In cohort 2, a number of differentially expressed genes in AT were identified between groups, while fat cell size and fibrosis were comparable. Subcutaneous ATG7 expression was found as an independent predictor of limited WL 1 year after surgery (ß: -12.21 ± 4.41, P = .008) and its addition to a clinical model significantly improved the amount of WL variability explained (R2 = 0.131 vs R2 = 0.248, F change P = .009). CONCLUSION: Our results highlight the importance of T2D as determinant of limited WL following BS and suggest that dysregulated macroautophagy in subcutaneous AT may contribute to this association.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Obesidade Mórbida , Humanos , Diabetes Mellitus Tipo 2/complicações , Resultado do Tratamento , Redução de Peso/fisiologia , Gordura Subcutânea/metabolismo , Obesidade Mórbida/cirurgiaRESUMO
BACKGROUND: We evaluated the association between white adipose tissue parameters before bariatric surgery (BS) and post-surgical weight loss, with an especial focus on extracellular matrix (ECM) gene expression. METHODS: Paired samples from subcutaneous (SAT) and visceral adipose tissue (VAT) were obtained from 144 subjects undergoing BS. The association between total body weight loss (%TBWL) at 12 months after BS and the histological characteristics and gene expression of selected genes in SAT and VAT was analyzed. RESULTS: Fat cell area, size-frequency distribution, and fibrosis in SAT or VAT prior to surgery were not associated with %TBWL. On the contrary, the SAT expression of COL5A1 and COL6A3 was associated with %TBWL after BS (both p < 0.001), even after adjusting for age, gender, baseline BMI, and type 2 diabetes status (T2D). Furthermore, in logistic regression analyses, the expression of these genes was significantly associated with insufficient WL (IWL = TBWL < 20%) after BS (respectively, p = 0.030 and p = 0.031). Indeed, in ROC analysis, the prediction of IWL based on sex, age, BMI, T2D, and the type of surgery (AUC = 0.71) was significantly improved with the addition of SAT-COL5A1 gene expression (AUC = 0.88, Z = 2.13, p = 0.032). CONCLUSIONS: Our data suggest that the expression of SAT ECM-related genes may help explain the variability in TBWL following BS.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Humanos , Gordura Subcutânea/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Tecido Adiposo , Redução de Peso/genética , Matriz Extracelular/genética , Colágeno/metabolismoRESUMO
Bariatric surgery (BS) is currently the most effective treatment for severe obesity, requiring ongoing multidisciplinary follow-up to ensure proper progress and nutrition post-procedure. Despite its favourable safety profile, it is not exempt from complications, one of which being exocrine pancreatic insufficiency (EPI). The underlying pathophysiological mechanisms of EPI after BS are multifactorial, including poorly synchronized pancreatic enzyme secretion with the passage of nutrients (pancreaticocibal or postcibal asynchrony), insufficient pancreatic stimulation and bacterial overgrowth. We conducted a short literature review of the topic through a case of a patient who underwent BS in our centre and subsequently developed EPI and severe malnutrition. EPI initially was attributed to the surgery, but after a comprehensive evaluation, an unexpected cause was revealed.
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Cirurgia Bariátrica , Insuficiência Pancreática Exócrina , Humanos , Insuficiência Pancreática Exócrina/etiologia , Pâncreas , Cirurgia Bariátrica/efeitos adversos , Estado Nutricional , CausalidadeRESUMO
CONTEXT: Large extracellular vesicles (lEVs) enriched for endothelial and blood cell markers are increased in metabolic conditions such as obesity or type 2 diabetes (T2D), actively contribute to the atherosclerotic process, and have been identified as diagnostic and prognostic biomarkers for cardiovascular disease (CVD). Although bariatric surgery (BS) in individuals with obesity is related to decreased cardiovascular (CV) risk and increased life expectancy, after BS these subjects are still at higher CV risk than the general population. OBJECTIVE: We aimed to compare the lEV profiles between individuals with obesity, with or without T2D, before and 1 year after BS, and normal-weight controls. METHODS: Prospective longitudinal study with individuals eligible for BS, with or without T2D (T2D and OB groups, respectively) and healthy controls (HC group) matched by age and sex. The concentration and phenotype of lEVs were assessed by flow cytometry. RESULTS: The study cohort included 108 individuals (age 48.0 ± 10.5 years; 84.3% females). Before BS, the OB group presented higher concentrations of lEV enriched for endothelial and blood cell biomarkers than the HC group, but lower concentrations than those observed in the T2D group (P < .05). BS resulted in a significant reduction in most of the lEVs enriched for cell-specific markers in both subgroups. lEV differences between OB and T2D groups were no longer observed after BS (P > .05). However, compared with HC group, OB and T2D groups still showed increased concentrations of lEVs enriched for platelet and endothelial cell markers (P < .05). CONCLUSION: At 1 year after BS, lEV concentrations remain above the physiological range. These abnormalities might contribute to explaining the increased CV risk after BS and underscore the importance of long-term CV risk factor control in post-BS individuals.
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Obesidade Mórbida , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/cirurgia , Estudos Prospectivos , Estudos Longitudinais , Obesidade/cirurgia , Cirurgia Bariátrica/métodos , Biomarcadores , Obesidade Mórbida/cirurgiaRESUMO
Obesity increases the risk of developing chronic kidney disease (CKD), which has a major negative impact on global health. Bariatric surgery (BS) has demonstrated a substantial improvement of obesity-related comorbidities and thus, it has emerged as a potential therapeutic tool in order to prevent end-stage renal disease. A limited number of publications to date have examined the beneficial effects and risks of BS in patients with non-advanced stages of CKD. We aimed to investigate the safety of BS in patients with CKD stages 3-4 (directly related or not to obesity) and both the metabolic/renal outcomes post-BS. A total of 57 individuals were included (n = 19 for CKD-group; n = 38 for patients with obesity, but normal eGFR [control-group]). Weight loss and obesity comorbidities resolution after BS were similar in both groups. Renal function (eGFR [CKD-EPI]) improved significantly at the 1-year follow-up: Δ10.2 (5.2-14.9) (p < 0.001) for CKD-group and Δ4.0 (-3.9-9.0) mL/min/1.73 m2 (p = 0.043) for controls. Although this improvement tended to decrease in the 5-year follow-up, eGFR remained above its basal value for the CKD-group. Noteworthy, eGFR also improved in those patients who presented CKD not directly attributed to obesity. For patients with CKD, BS appears to be safe and effective regarding weight loss and obesity comorbidities resolution, irrespective of the main cause of CKD (related or not to obesity).
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Asthma is a complex condition resulting from the interaction of genes and environment. Obesity is a risk factor to develop asthma and contributes to poor response to asthma therapy and severity. The aim of the study was to evaluate the effect of obesity on the expression levels of genes previously associated with severe asthma. Three groups of subjects were studied: non-obese asthmatics (NOA), obese asthma patients (OA), and non-asthmatic obese subjects (O). Previously reported overexpressed (IL-10, MSR1, PHLDA1, SERPINB2, and CD86) and underexpressed genes (CHI3L1, CPA3, IL-8, and PI3) in severe asthma were analyzed by RT-qPCR in peripheral blood mononuclear cells (PBMCs). In the overexpressed genes, obesity significantly decreased the expression of MSR1 and PHLDA1 and had no effects on CD86, IL-10, and SERPINB2. In underexpressed genes, obesity did not affect PI3, CHI3L1, and IL-8 and significantly reduced CPA3 expression. The results of this study show that obesity should be included among the known factors that can contribute toward modifying the expression of genes associated with asthma and, in particular, severe asthma.
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Background & Aims: : The accumulation of adipose tissue macrophages (ATMs) in obesity has been associated with hepatic injury. However, the contribution of ATMs to hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Herein, we investigate the relationship between ATMs and liver fibrosis in patients with patients with NAFLD and evaluate the impact of modulation of ATMs over hepatic fibrosis in an experimental non-alcoholic steatohepatitis (NASH) model. Methods: Adipose tissue and liver biopsies from 42 patients with NAFLD with different fibrosis stages were collected. ATMs were characterised by immunohistochemistry and flow cytometry and the correlation between ATMs and liver fibrosis stages was assessed. Selective modulation of the ATM phenotype was achieved by i.p. administration of dextran coupled with dexamethasone in diet-induced obesity and NASH murine models. Chronic administration effects were evaluated by histology and gene expression analysis in adipose tissue and liver samples. In vitro crosstalk between human ATMs and hepatic stellate cells (HSCs) and liver spheroids was performed. Results: Patients with NAFLD presented an increased accumulation of pro-inflammatory ATMs that correlated with hepatic fibrosis. Long-term modulation of ATMs significantly reduced pro-inflammatory phenotype and ameliorated adipose tissue inflammation. Moreover, ATMs modulation was associated with an improvement in steatosis and hepatic inflammation and significantly reduced fibrosis progression in an experimental NASH model. In vitro, the reduction of the pro-inflammatory phenotype of human ATMs with dextran-dexamethasone treatment reduced the secretion of inflammatory chemokines and directly attenuated the pro-fibrogenic response in HSCs and liver spheroids. Conclusions: Pro-inflammatory ATMs increase in parallel with fibrosis degree in patients with NAFLD and their modulation in an experimental NASH model improves liver fibrosis, uncovering the potential of ATMs as a therapeutic target to mitigate liver fibrosis in NAFLD. Impact and implications: We report that human adipose tissue pro-inflammatory macrophages correlate with hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Furthermore, the modulation of adipose tissue macrophages (ATMs) by dextran-nanocarrier conjugated with dexamethasone shifts the pro-inflammatory phenotype of ATMs to an anti-inflammatory phenotype in an experimental murine model of non-alcoholic steatohepatitis. This shift ameliorates adipose tissue inflammation, hepatic inflammation, and fibrosis. Our results highlight the relevance of adipose tissue in NAFLD pathophysiology and unveil ATMs as a potential target for NAFLD.
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It has been suggested that weight-loss-independent Mediterranean diet benefits on cardiometabolic health and diabetes prevention may be mediated, at least in part, through the modulation of white adipose tissue (WAT) biology. This study aimed to evaluate the short-term effects of a dietary intervention based on the Mediterranean diet supplemented with almonds (MDSA) on the main features of obesity-associated WAT dysfunction. A total of 38 women with obesity were randomly assigned to a 3-month intervention with MDSA versus continuation of their usual dietary pattern. Subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies were obtained before and after the dietary intervention, and at the end of the study period, respectively. MDSA favored the abundance of small adipocytes in WAT. In SAT, the expression of angiogenesis genes increased after MDSA intervention. In VAT, the expression of genes implicated in adipogenesis, angiogenesis, autophagy and fatty acid usage was upregulated. In addition, a higher immunofluorescence staining for PPARG, CD31+ cells and M2-like macrophages and increased ADRB1 and UCP2 protein contents were found compared to controls. Changes in WAT correlated with a significant reduction in circulating inflammatory markers and LDL-cholesterol levels. These results support a protective effect of a Mediterranean diet supplemented with almonds on obesity-related WAT dysfunction.
Assuntos
Dieta Mediterrânea , Obesidade Mórbida , Prunus dulcis , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Biologia , Feminino , Humanos , Obesidade/metabolismo , Obesidade Mórbida/metabolismoRESUMO
Obesity and kidney transplantation (KTx) are closely related. Obesity increases the risk of chronic kidney disease and can be a relative contraindication for KTx. Besides, KTx recipients are predisposed to obesity and its comorbidities. Consequently, bariatric surgery (BS) emerges as a powerful therapeutic tool either before or after KTx. Since evidence regarding the best approach is still scarce, we aimed to describe renal and metabolic outcomes in a single centre with more than 15-year experience in both surgeries. METHODS: A retrospective study including patients who had received a KTx either before or after BS. Usual metabolic and renal outcomes, but also new variables (as renal graft dysfunction) were collected for a minimum follow-up of 1-year post-BS. RESULTS: A total of 11 patients were included: n = 6 (BS-post-KTx) and n = 5 (BS-pre-KTx). One patient was assessed in both groups. No differences in the main outcomes were identified, but BS-post-KTx group tended to gain more weight during the follow-up. The incidence of renal graft dysfunction was comparable (4/6 for BS-post-KTx, 3/5 for BS-pre-KTx) between groups. CONCLUSIONS: BS in patients with KTx appears to be safe and effective attending to metabolic and renal outcomes. These results seem irrespective of the time course, except for weight regain, which appears to be a common pattern in the BS-post-KTx group.