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Adipose tissue, as an endocrine organ, secretes several adipocyte-derived hormones named 'adipokines' that are implicated in regulating energy haemostasis. Substantial evidence shows that white adipose tissue-derived adipokines mediate the link between obesity-related exogenous factors (like diet and lifestyle) and various biological events (such as pre- and postmenopausal status) that have obesity consequences (cardiometabolic disorders). One of the critical aetiological factors for obesity-related diseases is the dysfunction of adipokine pathways. Acylation-stimulating protein (ASP) is an adipokine that stimulates triglyceride synthesis and storage in adipose tissue by enhancing glucose and fatty acid uptake. ASP acts via its receptor C5L2. The primary objective of this review is to address the existing gap in the literature regarding ASP by investigating its diverse responses and receptor interactions across multiple determinants of obesity. These determinants include diet composition, metabolic disorders, organ involvement, sex and sex hormone levels. Furthermore, this article explores the broader paradigm shift from solely focusing on adipose tissue mass, which contributes to obesity, to considering the broader implications of adipose tissue function. Additionally, we raise a critical question concerning the clinical relevance of the insights gained from this review, both in terms of potential therapeutic interventions targeting ASP and in the context of preventing obesity-related conditions, highlighting the potential of the ASP-C5L2 interaction as a pharmacological target. In conclusion, these findings validate that obesity is a low-grade inflammatory status with multiorgan involvement and sex differences, demonstrating dynamic interactions between immune and metabolic response determinants.
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Adipócitos , Tecido Adiposo , Complemento C3a , Feminino , Humanos , Masculino , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Obesidade/metabolismo , Adipocinas/metabolismoRESUMO
Background: Atorvastatin has been shown to improve cardiovascular risk (CVR) indices in women with polycystic ovary syndrome (PCOS). Low-grade chronic inflammation of adipose tissue may link PCOS and adverse CVR. In pro-inflammatory states such as PCOS, spontaneous activation of the alternative pathway of complement results in increased generation of acylation stimulating protein (ASP) from adipocytes irrespective of body mass index. Methods: The objective of this study was to determine the effect of atorvastatin on markers of adipose tissue dysfunction and inflammation; acylation-stimulating-protein (ASP), interleukin-6 (IL-6), and monocyte-chemoattractant-protein-1 (MCP-1) in PCOS. This was a randomized, double-blind, placebo-controlled study where 40 medication-naive women with PCOS and biochemical hyperandrogenaemia were randomized to either atorvastatin 20 mg daily or placebo for 12 weeks. Following the 12 week randomization; both group of women with PCOS were subsequently started on metformin 1,500 mg daily for further 12 weeks to assess whether pre-treatment with atorvastatin potentiates the effects of metformin on markers of adipose tissue function We conducted a post-hoc review to detect plasma ASP and the pro-inflammatory cytokines IL6 and MCP-1 before and after 12 and 24 weeks of treatment. Results: There was significant reduction in ASP (156.7 ± 16.2 vs. 124.4 ± 14.8 ng/ml p <0.01), IL-6 (1.48 ± 0.29 vs.0.73 ± 0.34 pg/ml p = 0.01) and MCP-1 (30.4 ± 4.2 vs. 23.0 ± 4.5 pg/ml p = 0.02) after 12 weeks of atorvastatin that was maintained subsequently with 12 weeks treatment with metformin. There was a significant positive correlation between ASP levels with CRP (p < 0.01), testosterone (p < 0.01) and HOMA-IR (p < 0.01); IL-6 levels with CRP (p <0.01) and testosterone (p < 0.01) and MCP-1 with CRP (p < 0.01); testosterone (p < 0.01) and HOMA-IR (p < 0.02). Conclusions: This post-hoc analysis revealed that 12 weeks of atorvastatin treatment significantly decreased the markers of adipose tissue dysfunction and inflammation, namely ASP, IL-6 and MCP-1 in obese women with PCOS. Changes in adipose tissue markers were significantly associative with substantial improvements in HOMA-IR, testosterone and hs-CRP levels. ISRCTN Number: ISRCTN24474824.
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Aims: Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage. Methods and Results: C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ in vivo. Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils. Conclusion: Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice. STUDY HIGHLIGHTS What is the current knowledge on the topic? Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown. What question did this study address? The effects of TMZ on cardiac dysfunction via neutrophils migration. What this study adds to our knowledge TMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2. How this might change clinical pharmacology or translational science Our findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.
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Endotoxemia/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Neutrófilos/imunologia , Sepse/tratamento farmacológico , Trimetazidina/uso terapêutico , Vasodilatadores/uso terapêutico , Adenilato Quinase/metabolismo , Animais , Ceco/cirurgia , Células Cultivadas , Quimiocina CXCL2/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Endotoxemia/imunologia , Insuficiência Cardíaca/imunologia , Humanos , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Neutrófilos/efeitos dos fármacos , Sepse/imunologia , Transdução de SinaisRESUMO
Obesity closely correlates with metaflammation and characterizes with systemic-chronic-low inflammation. This study aims to evaluate effects of C5a on the inflammatory response and insulin resistance in 3T3-L1 adipocytes. 3T3-L1 pre-adipocytes were induced to the mature 3T3-L1 adipocytes. Then, 3T3-L1 were intervened with anaphylatoxin C5a, lipopolysaccharide (LPS) and C5aâ¯+â¯LPS, respectively. Levels of Omentin, Chemerin, Vaspin and Apelin 12 in supernatants of medium were examined using ELISA. C5L2, C5a receptor (C5aR), I kappa B (IkB), IkB kinase (IKK), insulin receptor substrate 1 (IRS-1), IRS-2, PI3â¯K, p-PI3â¯K and ß-actin were examined using RT-PCR and western blot assay, respectively. C5L2-C5aR colocalization was identified using immunofluorescence double label. NF-kB expression or activity was evaluated using electrophoretic mobility shift assay (EMSA), dual luciferase assay and immunofluorescence assay, respectively. The glucose uptake and insulin sensitivity were also evaluated. Results showed that C5a intervention significantly enhanced inflammatory molecule levels in supernatants of 3T3-L1 adipocytes. IKK inflammatory signaling pathway participated in C5a induced inflammation of 3T3-L1 adipocytes. C5a triggered the colocalization of C5L2 and C5aR and activated the NF-kB inflammatory signaling pathway. C5a intervention in 3T3-L1 adipocytes decreased the glucose uptake and resulted in reduction of insulin sensitivity. Insulin signaling pathway participated in C5a caused insulin sensitivity reduction. C5a intervention triggered the phosphorylation of PI3â¯K. In conclusion anaphylatoxin C5a induced inflammatory response by activating TLR4/NF-kB signaling pathway and generating C5L2-C5aR dimer, and caused insulin sensitivity reduction by activating PI3â¯K signaling pathway.
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Adipócitos/imunologia , Complemento C5a/imunologia , Resistência à Insulina/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptor 4 Toll-Like/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Complemento C5a/farmacologia , Inflamação , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B , Obesidade/imunologia , Obesidade/metabolismo , Transdução de SinaisRESUMO
Background Obesity-related alterations in the circulating steroid hormone profile remain equivocal in women. Our objective was to identify circulating steroid levels that relate to increased adiposity and altered adipose phenotype in premenopausal women. Materials and methods In a sample of 42 premenopausal women [age 46 ± 3 years; body mass index (BMI) 27.1 ± 4.2 kg/m2], 19 plasma steroids were quantified by electrospray ionization-liquid chromatography-tandem mass spectroscopy (ESI-LC-MS/MS). Body composition and fat distribution were assessed by dual-energy X-ray absorptiometry (DXA) and computed tomography (CT), respectively. Markers of adipose tissue function including adipocyte size distributions, radiological attenuation and macrophage infiltration were also analyzed in surgically obtained visceral and subcutaneous fat samples. Results Many negative correlations were observed between adiposity measurements such as BMI, body fat percentage or total abdominal adipose tissue area and plasma levels of androstenedione (Δ4) (r = -0.33 to -0.39, p ≤ 0.04), androsterone (ADT) (r = -0.30 to -0.38, p ≤ 0.05) and steroid precursor pregnenolone (PREG) (r = -0.36 to -0.46, p ≤ 0.02). Visceral adipocyte hypertrophy was observed in patients with low PREG concentrations (p < 0.05). Visceral adipose tissue radiologic attenuation, a potential marker of adipocyte size, was also positively correlated with PREG levels (r = 0.33, p < 0.05). Low levels of PREG were related to increased number of macrophages infiltrating visceral and subcutaneous adipose tissue (p < 0.05). Conclusion Plasma levels of androgens and their precursors are lower in women with increased adiposity and visceral adipocyte hypertrophy. Low circulating PREG concentration may represent a marker of adipose tissue dysfunction.
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Tecido Adiposo/diagnóstico por imagem , Hormônios Esteroides Gonadais/sangue , Pré-Menopausa/sangue , Absorciometria de Fóton , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Distribuição da Gordura Corporal , Cromatografia Líquida , Feminino , Humanos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Tomografia Computadorizada por Raios XRESUMO
Aims: Dilated cardiomyopathy (DCM) induced chronic heart failure is a life-threatening disease worldwide. Long non-coding RNAs (lncRNAs) are potential new therapeutic targets and may provide new pathophysiological mechanisms for development of DCM. Methods and results: Microarray assays in 14 DCM and 10 control human heart samples identified 313 significantly differentially expressed lncRNAs. SiRNAs were used to explore the potential function of specific lncRNAs (RP11-544D21.2 and XLOC_014288) in human cardiac myocytes, human cardiac fibroblasts and human cardiac microvascular endothelial cells, respectively. RNA-seq and pathway analyses revealed the function of lncRNA RP11-544D21.2 and XLOC_014288 in three heart cells. Furthermore, impaired tube formation and migration were observed in si-RP11-544D21.2-treated endothelial cells. Moreover, TAF10 was predicted and verified to be one of the causes of some up-regulated lncRNAs. Then, we found that the left ventricular ejection fraction correlated with these changed lncRNAs. Conclusions: This study provides a comparison of human cardiac lncRNA profiles in control and DCM. It illustrates the function and complex roles of the differentially expressed lncRNAs in different cell types in the heart, which may lead to new insights into the mechanisms and treatment strategies for DCM in the future.
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Cardiomiopatia Dilatada/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Estudos de Casos e Controles , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Células Endoteliais/metabolismo , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , RNA Longo não Codificante/metabolismo , Volume Sistólico/genética , Função Ventricular Esquerda/genéticaRESUMO
Mutations in FBN1 have been well identified in syndromic aortic dissection (AD) and familial thoracic aortic aneurysms and dissections. However, whether mutations of FBN1 contribute to sporadic non-syndromic AD and the characteristics of mutations remain unknown. Using next-generation-sequencing technology, FBN1 was sequenced in a total of 702 sporadic cases (including 687 of non-syndromic AD and 15 of sporadic Marfan syndrome with aortic event, and 527 normal controls). For the sporadic non-syndromic AD cohort, we found 26 variants in 27 patients (18 with missense, 2 frameshift, 1 initiation codon mutation, 3 nonsense and 3 splice site mutations). The prevalence of variants was significantly high in the sporadic non-syndromic AD cohort (27/687, 3.9%). The patients with FBN1 mutations were younger, suffered from fewer risk factors such as hypertension and smoking, and were less gender partitioned than non-FBN1-mutation AD patients. The mutations were spread along the FBN1 gene in our sporadic non-syndromic AD cohort and mutation locations are not different between non-syndromic and syndromic patients. These results demonstrate that the deleterious mutations in FBN1 largely contribute to pathogenesis of sporadic non-syndromic AD, which expands our knowledge of FBN1 variants and the genetic basis and pathology of AD.
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Dissecção Aórtica/genética , Fibrilina-1/genética , Adulto , Aneurisma da Aorta Torácica/genética , Sequência de Bases , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Mutação , Razão de ChancesRESUMO
BACKGROUND: Obesity-associated systemic hypertension (HTN) and obstructive sleep apnea (OSA) have multiple pathophysiological pathways including ectopic fat deposition, inflammation, altered adipokine profile, and increased sympathetic nervous activity. We characterized these potential mechanisms in severely obese patients with or without HTN and OSA. We also compared changes of these mechanisms at 12 months following biliopancreatic diversion with duodenal switch (BPD-DS) surgery according to HTN and OSA resolution. METHODS: Sixty-two severely obese patients were evaluated at baseline and 12 months; 40 patients underwent BPD-DS. Blood samples, bioelectrical impedance analysis, computed tomography scan, and 24-h heart rate monitoring were performed. OSA have been determined with polysomnography and HTN with blood pressure measurement and medical file. RESULTS: Patients with HTN (n = 35) and OSA (n = 32) were older men with higher ectopic fat deposition and lower parasympathetic nervous activity without difference in adipokines and inflammatory markers. Lower reduction in weight was observed in patients with unresolved HTN (-40.9 ± 3.3 kg vs. -55.6 ± 3.8 kg; p = 0.001) and OSA (-41.4 ± 10.7 kg vs. -51.0 ± 15.2 kg; p = 0.006). Visceral adipose tissue reduction was lower in patients with unresolved HTN (-171.0 ± 25.7 cm2 vs. -274.5 ± 29.0 cm2; p = 0.001) in contrast to a trend for lower abdominal subcutaneous adipose tissue reduction in patients with unresolved OSA (-247.7 ± 91.5 cm2 vs. -390.5 ± 109.1 cm2; p = 0.08). At 12 months, parasympathetic activity was lowest in unresolved HTN and OSA patients, without difference in adipokines and inflammatory biomarkers. CONCLUSION: Lower ectopic fat mobilization, lower level of parasympathetic nervous activity, and lower subcutaneous adiposity mobilization may play a role in the pathophysiology of unresolved HTN and OSA following BPD-DS surgery.
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Adipocinas/sangue , Tecido Adiposo/metabolismo , Cirurgia Bariátrica , Hipertensão/cirurgia , Obesidade Mórbida/cirurgia , Apneia Obstrutiva do Sono/cirurgia , Tecido Adiposo/patologia , Tecido Adiposo/cirurgia , Adiposidade/fisiologia , Adolescente , Adulto , Idoso , Sistema Nervoso Autônomo/fisiopatologia , Cirurgia Bariátrica/métodos , Desvio Biliopancreático , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Mediadores da Inflamação/sangue , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Masculino , Metaboloma , Pessoa de Meia-Idade , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Obesidade Mórbida/fisiopatologia , Polissonografia , Indução de Remissão , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Adulto JovemRESUMO
Acylation-stimulating protein (ASP), produced through activation of the alternative complement immune system, modulates lipid metabolism. Using a trans-well co-culture cell model, the mitigating role of α7-nicotinic acetylcholine receptor (α7nAChR)-mediated cholinergic pathway on ASP resistance was evaluated. ASP signaling in adipocytes via its receptor C5L2 and signaling intermediates Gαq, Gß, phosphorylated protein kinase C-α, and protein kinase C-ζ were markedly suppressed in the presence of TNFα or medium from palmitate-treated RAW264.7 macrophages, indicating ASP resistance. There was no direct effect of α7nAChR activation in 3T3-L1 cell culture. However, α7nAChR activation almost completely reversed the ASP resistance in adipocytes co-cultured with palmitate-treated RAW264.7 macrophages. Further, α7nAChR activation could suppress the production of pro-inflammatory molecules TNFα and interleukin-6 produced from palmitate-treated co-cultured macrophages. These results suggest that macrophages play a significant role in the pathogenesis of ASP resistance and α7nAChR activation secondarily improves adipose ASP resistance through suppression of inflammation in macrophages. Impact statement 1. Adipocyte-macrophage interaction in acylation-stimulating protein (ASP) resistance 2. Lipotoxicity induced inflammatory response in ASP resistance 3. A vicious circle between lipotoxicity and inflammatory response in ASP resistance 4. Cholinergic modulation of inflammatory response in adipocyte and macrophage.
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Adipócitos/fisiologia , Colinérgicos/metabolismo , Complemento C3a/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Palmitatos/metabolismo , Animais , Linhagem Celular , Técnicas de Cocultura , Camundongos , Receptor Nicotínico de Acetilcolina alfa7/agonistasRESUMO
BACKGROUND: Previous longitudinal studies have shown inconsistent results regarding the influence of adipokines on changes in weight and body fat. We aimed to determine the predictive value of serum leptin, adiponectin, and their ratio on subsequent changes in obesity measures in children. METHODS: Two hundred forty-six obese and 532 nonobese children aged 6-11 years were remeasured for BMI and waist circumference after 6.4 ± 0.2 years. Z-score of BMI was used to standardize for age and sex. Obesity was defined using the international BMI cutoffs. Waist-to-height ratio (WHtR) was calculated to define central obesity using a boundary value of 0.5. Fasting serum leptin and adiponectin levels were measured at baseline. RESULTS: Newly identified obese children had significantly higher levels of leptin and leptin-to-adiponectin ratio than nonobese children. There were lower adiponectin levels in boys with persistent obesity versus those with transient obesity. After adjusting for age, Tanner stage, and corresponding adiposity measures at baseline, leptin levels and leptin-to-adiponectin ratio were positively associated with BMI Z-score gain in girls and WHtR gain in boys. An inverse association between leptin and BMI Z-score gain was detected in boys. Stratified analyses revealed significant associations only in the nonobese and prepubertal group. There were no significant associations between adiponectin and changes in obesity measures. CONCLUSIONS: High leptin levels and leptin-to-adiponectin ratio are sex-specific predictors of obesity measures gain in nonobese and prepubertal children. Body composition measurement is necessary to assess fat mass growth and distribution during childhood and adolescence.
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Adiponectina/sangue , Adiposidade/fisiologia , Leptina/sangue , Aumento de Peso/fisiologia , Estatura , Índice de Massa Corporal , Peso Corporal , Criança , China , Jejum , Feminino , Humanos , Masculino , Obesidade Infantil/sangue , Obesidade Infantil/diagnóstico , Estudos Prospectivos , Fatores Sexuais , Circunferência da CinturaRESUMO
CONTEXT: Nesfatin-1 is a neuroendocrine peptide with potent anorexigenic activity in rodents. The potential role of nesfatin-1 on the regulation of energy balance, metabolic functions and inflammation is currently debated in obese humans. In the present study, nesfatin-1 fluctuations and their associations with metabolic factors were investigated in severely obese patients who underwent biliopancreatic diversion with duodenal switch (BPD/DS) and severely obese controls (SOC). BASIC PROCEDURES: Sixty severely obese patients who underwent BPD/DS and 15 SOC (matched for BMI and age) were included in the study. Associations between nesfatin-1 levels and body composition, glucose metabolism, lipid profile as well as inflammatory markers were evaluated at baseline and over a post-surgery12-month (12M) period. MAIN FINDINGS: Body weight was reduced at 6M and at 12M in BPD/DS patients (P<0.001). Nesfatin-1 levels were reduced at 6M (women: P<0.05) and at 12M (men and women; P<0.001) in BPD/DS patients. At baseline, nesfatin-1 levels negatively correlated with weight, fat (FM) and fat-free mass (FFM) in the whole population (combined BPD/DS and SOC patients). At 12M, nesfatin-1 concentrations positively correlated with weight, FM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, triglyceride and apoB values. At 12M, % changes in nesfatin-1 were positively associated with% changes in weight, FM, FFM, fasting insulin, insulin resistance, total cholesterol, LDL-cholesterol, apoB and C-reactive protein. CONCLUSION: Nesfatin-1 levels decrease following BPD/DS-induced weight loss and are significantly associated with parameters of metabolic health.
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Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação a DNA/sangue , Proteínas do Tecido Nervoso/sangue , Obesidade Mórbida/sangue , Adulto , Cirurgia Bariátrica , Desvio Biliopancreático , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nucleobindinas , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , Resultado do Tratamento , Redução de PesoRESUMO
Heart failure is characterized by immune activation leading to production and release of proinflammatory cytokines. Interleukin 17A (IL-17A) is a proinflammatory cytokine and multiple lines of evidence from animal and human studies suggest crucial roles of IL-17A in heart failure. Therefore, we investigated whether common polymorphisms of genes IL17A and IL17RA (coding interleukin 17 receptor A) contribute to genetic predisposition to heart failure and adverse clinical outcomes associated with it.A total of 1713 adult patients with congestive heart failure and 1713 age- and sex-matched controls were genotyped for promoter single nucleotide polymorphisms (SNPs), rs2275913 and rs8193037 in IL17A and rs4819554 in IL17RA, to assess the relationship between individual SNPs and the risk of congestive heart failure. Results showed that rs8193037 in IL17A was associated with the risk of congestive heart failure (odds ratio [OR] = 0.76; 95% confidence interval [CI] 0.63-0.90, adjusted P = 0.002) after adjustment for multiple cardiovascular risk factors including age, sex, smoking status, diabetes, hypertension, and dyslipidemia. This association was evident in both ischemic and nonischemic heart failure (P = 0.005 and P = 0.05, respectively). Furthermore, prospective follow-up of 12.7 months for the occurrence of adverse clinical outcomes showed that rs4819554 in IL17RA was significantly associated with cardiovascular mortality (hazard ratio [HR] = 1.28; 95% CI = 1.02-1.59, adjusted P = 0.03) after adjustments for multiple cardiovascular risk factors and New York Heart Association functional class.This study demonstrated associations of rs8193037 in the promoter of IL17A with the risk of congestive heart failure, and of rs4819554 in the promoter of IL17RA with the risk of cardiovascular mortality in patients with congestive heart failure. These data lend further support to the notion that immune activation and genetic polymorphisms contribute to heart failure pathogenesis and progression.
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Insuficiência Cardíaca/genética , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-17/genética , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença , Genótipo , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The objective of the study was to assess the impact of protein composition and/or fibre enrichment of yogurt on appetite sensations and subsequent energy intake. In this double-blind crossover study, 20 healthy men (aged 32.4 ± 9.1 years) were submitted to 5 randomized testing sessions, during which they had to consume 5 isocaloric and isonproteinemic yogurt snacks (120-g servings, â¼230 kJ, â¼4.5 g protein) differing by their casein-to-whey protein ratio (C:W) or dietary fibre content: (i) control C:W = 2.8:1; (ii) high whey (HW) C:W = 1.5:1, and fibre-enriched formulations using control; (iii) 2.4 g of inulin; (iv) 1.9 g of inulin and 0.5 g of ß-glucan (+IN-ßG); and (v) 0.5 g of ß-glucan. Appetite sensations were assessed using 150-mm visual analog scales. Plasma variables (glucose, insulin, ghrelin) were measured at 30-min intervals post-yogurt consumption for 2 h. Finally, energy intakes during ad libitum lunches offered 2 h after yogurt snacks were recorded. None of the yogurts impacted appetite sensations. Ad libitum energy intake was significantly different only between HW and control yogurts (-812 kJ; p = 0.03). Regarding post-yogurt plasma variables, a significant difference was found only between ghrelin area under the curve of the +IN-ßG and the HW yogurts (-15 510 pmol/L per 120 min, p = 0.04). In conclusion, although appetite sensations were not influenced by variations in yogurts' protein compositions, a reduced energy intake was observed during the ad libitum lunch after the HW yogurt that may be attributable to its lower C:W. Surprisingly, the fibre enrichments studied did not exert effect on appetite sensations and energy intake.
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Regulação do Apetite/fisiologia , Fibras na Dieta/farmacologia , Proteínas Alimentares/farmacologia , Ingestão de Energia/fisiologia , Alimentos Fortificados , Lanches , Iogurte , Adulto , Apetite , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Valores de ReferênciaRESUMO
Obesity is a heterogeneous disease and is associated with comorbidities such as type 2 diabetes mellitus, cardiovascular disease and cancer. Several studies have examined the role of dysfunctional adipose tissue in the pathogenesis of obesity, highlighting the contrasting properties and impact of distinct fat compartments, sometimes with contradictory results. Dysfunctional adipose tissue involves enlargement, or hypertrophy, of pre-existing fat cells, which is thought to confer increases in cardiometabolic risk, independent of the level of obesity per se. In this article, we critically analyze available literature that examined the ability of adipocyte cell size to predict metabolic disease and adipose tissue dysfunction in humans. Many studies demonstrate that increased fat cell size is a significant predictor of altered blood lipid profiles and glucose-insulin homeostasis independent of adiposity indices. The contribution of visceral adiposity to these associations appears to be of particular importance. However, available studies are not unanimous and many fat depot-specific aspects of the relationship between increased fat cell size and cardiometabolic risk or parameters of adipose tissue dysfunction are still unresolved. Methodological factors such as the approach used to express the data may represent significant confounders in these studies. Additional studies should consider the fact that the relationship between fat cell size and common adiposity indices is non-linear, particularly when reaching the obese range. In conclusion, our analysis demonstrates that fat cell size is a significant predictor of the cardiometabolic alterations related to obesity. We propose that adipocyte hypertrophy, especially in the visceral fat compartment, may represent a strong marker of limited hyperplasic capacity in subcutaneous adipose tissues, which in turn is associated with the presence of numerous cardiometabolic alterations.
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Adipócitos/patologia , Lipomatose/patologia , Doenças Metabólicas/patologia , Paniculite/patologia , Tamanho Celular , Medicina Baseada em Evidências , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Testosterone can be converted into androstenedione (4-dione) by 17ß-hydroxysteroid dehydrogenase (HSD) activity likely performed by 17ß-HSD type 2. Our objective was to evaluate the rate of testosterone conversion to 4-dione as well as expression and localization of 17ß-HSD type 2 in omental (OM) vs. subcutaneous (SC) adipose tissues of men. Formation of 4-dione from testosterone was significantly higher in homogenates (p ≤ 0.001) and explants (p ≤ 0.01) of OM than SC tissue. Microscopy analyses and biochemical assays in cell fractions localized the enzyme in the vasculature/endothelial cells of adipose tissues. Conversion of testosterone to 4-dione was weakly detected in most OM and/or SC preadipocyte cultures. Positive correlations were found between 17ß-HSD type 2 activity in whole tissue and BMI or SC adipocyte diameter. We conclude that conversion of testosterone to 4-dione detected in abdominal adipose tissue is caused by 17ß-HSD type 2 which is localized in the vasculature of the adipose compartment.
Assuntos
Gordura Abdominal/enzimologia , Androstenodiona/metabolismo , Estradiol Desidrogenases/metabolismo , Testosterona/metabolismo , Gordura Abdominal/citologia , Gordura Abdominal/metabolismo , Índice de Massa Corporal , Células Cultivadas , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Estradiol Desidrogenases/genética , Humanos , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/metabolismo , Masculino , Obesidade/enzimologia , Obesidade/metabolismo , Omento/enzimologia , Omento/metabolismo , Gordura Subcutânea Abdominal/citologia , Gordura Subcutânea Abdominal/enzimologia , Gordura Subcutânea Abdominal/metabolismoRESUMO
Inflammation is a key feature in adipose tissue, especially in association with obesity comorbidies. The novel adipokine acylation stimulating protein (ASP) is one factor implicated in the inflammatory response. The disruption of the α7 nicotine acetylcholine receptor (α7nAChR), an important component of the endogenous non-neural cholinergic defense system, may exacerbate sustained inflammatory phenotype. We examined cholinergic regulation of ASP-initiated inflammatory response in 3T3-L1 adipocytes. Our results show that preincubation of 3T3-L1 cells with α7nAChR agonist GTS-21 significantly reduces ASP-mediated chemokine MCP-1 secretion, which is regulated though nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3). Treatment of 3T3-L1 cells with GTS-21 significantly reduced NFκB activation by DNA binding and STAT3 activation by disturbing post-translational modification.
Assuntos
Adipócitos/metabolismo , Complemento C3a/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Células 3T3-L1 , Animais , Quimiocina CCL2/metabolismo , Camundongos , Transdução de SinaisRESUMO
OBJECTIVE: Bariatric surgery remains the most effective treatment for obesity and metabolic syndrome. Surgical benefit arises from early-phase resolution of hyperglycemia and late-phase weight loss. The adipokine chemerin is of interest given its roles in immunity, adipogenesis, and metabolism. The study objective was to examine the effects of biliopancreatic diversion with duodenal switch (BPD-DS) on plasma chemerin in the early and late post-operative stages. METHODS: 83 adults with obesity undergoing BPD-DS, 45 obese non-surgical controls, and 9 lean surgical controls were enrolled. Plasma parameters and anthropometric measures were obtained at baseline and at, early (24 h, 5 D) and late (6 months and 12 months) post-operative stages. RESULTS: Plasma chemerin dropped from 176±49 ng/mL at baseline to 132±52 ng/mL 24 h after BPD-DS, rebounded to 200±66 ng/mL after 5 D, and declined to 124±51 and 110±34 ng/mL after 6 and 12 months. Plasma chemerin correlated negatively with measures of inflammation and hepatic injury and positively with measures of obesity, metabolic syndrome, and inflammation in the early and late post-operative periods, respectively. CONCLUSIONS: Chemerin has a novel role in surgical injury but not hyperglycemia resolution early after BPD-DS. Over the long term, plasma chemerin declines to a new set point that is partially determined by body fat reductions.
Assuntos
Desvio Biliopancreático , Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Adulto , Cirurgia Bariátrica , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Acylation Stimulating Protein (ASP) stimulates adipocyte triglyceride synthesis and glucose transport. The aim was to examine ethnic difference in ASP and the relation to lipid profile and other parameters among Han, Uygur, and Kazak healthy populations matched for BMI, age and gender distribution. METHODS: 331 healthy persons were recruited in total (age 30-60 yr): 137 Han, 114 Uygur, and 80 Kazak. Anthropometric measurements including height, weight, waist circumference, hip circumference, blood pressure, ankle brachial index (ABI), and pulse wave velocity (PWV) were measured in all participants. Fasting concentrations of fasting glucose, uric acid, and lipids, including triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), ASP, complement C3, insulin, non-esterified fatty acid (NEFA) and C-reactive protein (CRP) were measured. RESULTS: ASP in Uygurs was significantly lower than Han subjects (P=0.0003). The Uygurs demonstrated the highest C3 (P<0.001), CRP (P=0.001), and NEFA concentrations (P=0.008), the lowest %ASP/C3 (P<0.001) and TC levels (P=0.0008) vs those in Han and Kazak populations. In the Han group, glucose, the average ABI (an index of peripheral response) and diastolic blood pressure were significantly different from both Uygur and Kazak group (P=0.0007, P=0.0003, P=0.0001) while Kazaks show the lowest waist/hip circumference (WHR) (P=0.0003). CONCLUSION: There are ethnic differences in ASP, C3, CRP and lipid profiles in healthy Han, Uygur, and Kazak populations. Overall, the Uygur populations presents with a disadvantageous metabolic profile as compared to Han and Kazak groups.
RESUMO
Excessive activation of complement is associated with many diseases including schizophrenia. Investigation of C3 polymorphisms, circulating C3, cleavage product ASP/C3adesArg, and lipid metabolism. Cross-sectional analysis. C3 genotyping (CC vs GG for R102L) was performed on 434 Tunisian people consisting of 272 schizophrenic (SZ) patients and 162 control subjects. In a age- and gender-matched subgroups of the three genotypes (131 SZ and 112 NOR), plasma triglycerides, total cholesterol (C), LDL-C, HDL-C, ASP, and complement C3 were measured. C3 gene polymorphism influences BMI and plasma C3, ASP, triglyceride, total cholesterol, LDL-C and HDL-C among SZ patients (p < 0.05-0.0001), with increasing values demonstrated from CC (common form) to CG (heterozygote form) to GG (rare homozygote) forms. Significant correlations between plasma C3 and BMI, triglyceride, HDL-C and ASP (p < 0.05-0.0001) were observed, while ASP correlated with BMI and LDL-C (p = 0.005, p = 0.001, respectively) in SZ patients. Further, proportional conversion of C3 to ASP (%ASP/C3) also increased (p < 0.0001, GG>CG>CC). C3 polymorphisms and plasma C3, ASP and %ASP/C3 correlated with lipid parameters in this SZ population, suggesting that factors predisposing patients to schizophrenia are permissive for complement pathway activation and dyslipidemic influences.