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1.
Gut ; 71(12): 2463-2480, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35017197

RESUMO

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.


Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Obesidade Mórbida , Complexo Vitamínico B , Humanos , Camundongos , Animais , Prebióticos , Obesidade Mórbida/cirurgia , Biotina/farmacologia , Complexo Vitamínico B/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Inflamação
2.
AIDS ; 35(10): 1625-1630, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831906

RESUMO

OBJECTIVE: To evaluate the effect on anthropometric, metabolic and adipose tissue parameters of switching ART-controlled persons living with HIV (PLWH) from a protease inhibitor regimen to raltegravir/maraviroc. DESIGN: Sub-study of the ANRS157 ROCnRAL study with the investigation of subcutaneous abdominal adipose tissue (SCAT) biopsy at inclusion and study end. METHODS: We performed lipoaspiration of paired SCAT samples, histology on fresh/fixed samples and examined the transcriptomic profile analyzed using Illumina microarrays after RNA extraction. Statistical analyses used the Wilcoxon-paired test. RESULTS: The patients (n = 8) were mainly male (7/8), aged (mean ±â€Šstandard error of the mean) 54.9 ±â€Š1.2 years, BMI 26.1 ±â€Š1.2 kg/m2, CD4+ 699 ±â€Š56 cells/mm3, all viral load (VL) <50 copies/ml. After a follow-up of 6 ±â€Š0.5 months, all PLWH remained with VL <50 copies/ml. BMI, trunk and limb fat amounts were unchanged yet systemic insulin resistance increased. Adipose tissue histology was unchanged except for borderline increased adipocyte diameter (P = 0.1). Among the 16 094 RNA transcripts, 458 genes were up-regulated and 244 were down-regulated. Analyses of the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases, evaluating modifications in the main functional pathways, revealed that genes related to immune recognition/function were less expressed as were genes encoding T-cell receptor and receptor signaling pathways. The gene expression profiles indicated decreased inflammation but genes involved in adipogenesis and insulin resistance were overexpressed. CONCLUSION: After 6 months of raltegravir/maraviroc, adipogenesis-related gene profile was enhanced in SCAT, in agreement with a tendency for increased adipocyte size. Enhanced SCAT insulin resistance-related profile was concordant with higher systemic insulin resistance. However, the immune activation/inflammation profile was globally lowered. We propose that raltegravir/maraviroc might favor SCAT gain but reduce inflammation/immune activation.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Tecido Adiposo , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Maraviroc , Raltegravir Potássico/uso terapêutico , Gordura Subcutânea
3.
Am J Clin Nutr ; 106(4): 996-1004, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28814400

RESUMO

Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health.Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity.Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des déterminants pré et postnatals de la santé et du développement de l'enfant) population-based cohort studies, respectively. The eating behaviors-emotional eating, uncontrolled eating, and cognitive restraint-were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI.Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P-Sobel = 0.01; Fenland: P-Sobel = 0.02) and uncontrolled eating (EDEN: P-Sobel = 0.04; Fenland: P-Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association (P-Sobel > 0.10), except among EDEN women (P-Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P-interaction = 0.0001; Fenland: P-interaction = 0.04) and Fenland women (P-interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile.Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint. High levels of cognitive control over eating appear to attenuate the genetic susceptibility to obesity. Future research into interventions designed to support restraint may help to protect genetically susceptible individuals from weight gain.


Assuntos
Cognição , Ingestão de Alimentos/psicologia , Emoções , Comportamento Alimentar , Interação Gene-Ambiente , Obesidade/etiologia , Autocontrole , Adulto , Apetite , Índice de Massa Corporal , Comportamento Alimentar/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Hiperfagia/complicações , Hiperfagia/psicologia , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/psicologia , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários
4.
Cell Metab ; 25(3): 673-685, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28215843

RESUMO

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα+) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα+ cells with high CD9 expression (CD9high) originates pro-fibrotic cells whereas their CD9low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα+ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.


Assuntos
Adipócitos/patologia , Tecido Adiposo/patologia , Obesidade/metabolismo , Obesidade/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Células-Tronco/metabolismo , Tetraspanina 29/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Adulto , Animais , Peso Corporal , Epididimo/metabolismo , Fibrose , Homeostase , Humanos , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais
5.
J Clin Endocrinol Metab ; 101(1): 293-304, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26583585

RESUMO

CONTEXT: Extracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored. OBJECTIVE: The objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS. MAIN OUTCOME MEASURES: scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls. RESULTS: Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163(+) cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase [LOX], LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation. CONCLUSIONS: After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss.


Assuntos
Cirurgia Bariátrica , Colágeno/metabolismo , Gordura Subcutânea/metabolismo , Adulto , Composição Corporal , Técnicas de Imagem por Elasticidade , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Transcriptoma , Rigidez Vascular , Redução de Peso
6.
PLoS One ; 10(5): e0125718, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25938420

RESUMO

BACKGROUND: Bariatric surgery is associated to improvements in obesity-associated comorbidities thought to be mediated by a decrease of adipose inflammation. However, the molecular mechanisms behind these beneficial effects are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed RNA-seq expression profiles in adipose tissue from 22 obese women before and 3 months after surgery. Of 15,972 detected genes, 1214 were differentially expressed after surgery at a 5% false discovery rate. Upregulated genes were mostly involved in the basal cellular machinery. Downregulated genes were enriched in metabolic functions of adipose tissue. At baseline, 26 modules of coexpressed genes were identified. The four most stable modules reflected the innate and adaptive immune responses of adipose tissue. A first module reflecting a non-specific signature of innate immune cells, mainly macrophages, was highly conserved after surgery with the exception of DUSP2 and CD300C. A second module reflected the adaptive immune response elicited by T lymphocytes; after surgery, a disconnection was observed between genes involved in T-cell signaling and mediators of the signal transduction such as CXCR1, CXCR2, GPR97, CCR7 and IL7R. A third module reflected neutrophil-mediated inflammation; after surgery, several genes were dissociated from the module, including S100A8, S100A12, CD300E, VNN2, TUBB1 and FAM65B. We also identified a dense network of 19 genes involved in the interferon-signaling pathway which was strongly preserved after surgery, with the exception of DDX60, an antiviral factor involved in RIG-I-mediated interferon signaling. A similar loss of connection was observed in lean mice compared to their obese counterparts. CONCLUSIONS/SIGNIFICANCE: These results suggest that improvements of the inflammatory state following surgery might be explained by a disruption of immuno-inflammatory cascades involving a few crucial molecules which could serve as potential therapeutic targets.


Assuntos
Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Cirurgia Bariátrica/efeitos adversos , Inflamação/imunologia , Inflamação/metabolismo , Transdução de Sinais , Adulto , Animais , Análise por Conglomerados , Biologia Computacional , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Interferons/metabolismo , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/imunologia , Obesidade/metabolismo
7.
Diabetologia ; 57(8): 1674-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24891017

RESUMO

AIMS/HYPOTHESIS: Cathepsin S (CatS) belongs to a family of proteases that have been implicated in several disease processes. We previously identified CatS as a protein that is markedly overexpressed in adipose tissue of obese individuals and downregulated after weight loss and amelioration of glycaemic status induced by gastric bypass surgery. This prompted us to test whether the protease contributes to the pathogenesis of type 2 diabetes using mouse models with CatS inactivation. METHODS: CatS knockout mice and wild-type mice treated with orally active small-molecule CatS inhibitors were fed chow or high-fat diets and explored for change in glycaemic status. RESULTS: CatS deletion induced a robust reduction in blood glucose, which was preserved in diet-induced obesity and with ageing and was recapitulated with CatS inhibition in obese mice. In vivo testing of glucose tolerance, insulin sensitivity and glycaemic response to gluconeogenic substrates revealed that CatS suppression reduced hepatic glucose production despite there being no improvement in insulin sensitivity. This phenotype relied on downregulation of gluconeogenic gene expression in liver and a lower rate of hepatocellular respiration. Mechanistically, we found that the protein 'regulated in development and DNA damage response 1' (REDD1), a factor potentially implicated in reduction of respiratory chain activity, was overexpressed in the liver of mice with CatS deficiency. CONCLUSIONS/INTERPRETATION: Our results revealed an unexpected metabolic effect of CatS in promoting pro-diabetic alterations in the liver. CatS inhibitors currently proposed for treatment of autoimmune diseases could help to lower hepatic glucose output in obese individuals at risk for type 2 diabetes.


Assuntos
Glicemia/metabolismo , Catepsinas/antagonistas & inibidores , Catepsinas/genética , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Animais , Catepsinas/metabolismo , Dieta Hiperlipídica , Insulina/metabolismo , Camundongos , Camundongos Knockout , Consumo de Oxigênio/fisiologia
8.
Am J Clin Nutr ; 98(1): 16-24, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23719559

RESUMO

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is one of the most efficient procedures for treating morbid obesity and results in weight-loss and improvements in metabolism and inflammation. OBJECTIVE: We examined the impact of RYGB on modifications of gut microbiota and its potential associations with changes in gene expression in white adipose tissue (WAT). DESIGN: Gut microbiota were profiled from fecal samples by using pyrosequencing in morbidly obese individuals, explored before (0 mo), 3 mo after, and 6 mo after RYGB. WAT gene expression was studied at 0 and 3 mo. We explored associations between microbial genera and differentially expressed genes in WAT and clinical markers. RESULTS: The richness of gut microbiota increased after RYGB; 37% of increased bacteria belonged to Proteobacteria. The associations between gut microbiota composition and WAT gene expression increased after RYGB. Fourteen discriminant bacterial genera (7 were dominant and 7 were subdominant) and 202 WAT genes changed after RYGB. Variations in bacterial genera correlated with changes in both clinical phenotype and adipose tissue gene expression. Some genes encode metabolic and inflammatory genes. Almost half of the correlations were independent of the change in calorie intake. CONCLUSION: These results show an increase in gut microbiota richness and in the number of associations between gut microbiota and WAT genes after RYGB in obesity. Variations of gut microbiota were associated with changes in WAT gene expression. These findings stimulate deeper explorations of the mechanisms linking gut microbiome and WAT pathological alterations in human obesity and its changes after weight loss.


Assuntos
Tecido Adiposo Branco/metabolismo , Derivação Gástrica/métodos , Trato Gastrointestinal/microbiologia , Metagenoma , Obesidade Mórbida/microbiologia , Tecido Adiposo Branco/patologia , Biologia Computacional , DNA Bacteriano/isolamento & purificação , Fezes/microbiologia , Feminino , Seguimentos , Trato Gastrointestinal/cirurgia , Regulação Bacteriana da Expressão Gênica , Humanos , Inflamação/cirurgia , Análise em Microsséries , Família Multigênica , Avaliação Nutricional , Obesidade Mórbida/cirurgia , RNA Ribossômico 16S/isolamento & purificação , Redução de Peso
9.
J Clin Invest ; 123(1): 362-79, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23221346

RESUMO

Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery-induced weight loss in morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes promoted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARγ and TWIST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.


Assuntos
Adipócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Correpressor 2 de Receptor Nuclear/metabolismo , Obesidade Mórbida/metabolismo , Adipócitos/patologia , Células Cultivadas , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/biossíntese , Interleucina-6/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Correpressor 2 de Receptor Nuclear/genética , Obesidade Mórbida/genética , Obesidade Mórbida/patologia , Obesidade Mórbida/cirurgia , PPAR gama/antagonistas & inibidores , PPAR gama/genética , PPAR gama/metabolismo , Transcrição Gênica/genética , Proteína 1 Relacionada a Twist/biossíntese , Proteína 1 Relacionada a Twist/genética
10.
J Hepatol ; 56(5): 1152-1158, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22245892

RESUMO

BACKGROUND & AIMS: In addition to total body fat, the regional distribution and inflammatory status of enlarged adipose tissue are strongly associated with metabolic co-morbidities of obesity. We recently showed that the severity of histological liver lesions related to obesity increases with the amount of macrophage accumulation in visceral adipose tissue (VAT), while no association was found with the subcutaneous adipose tissue (SAT). In the abdominal region, SAT is anatomically divided into two layers, i.e. superficial (sSAT) and deep (dSAT). The aim of the present study was to test the hypothesis that these distinct compartments differentially contribute to hepatic alterations in obesity. METHODS: Biopsies of the liver, sSAT, dSAT, and VAT were collected in 45 subjects with morbid obesity (age 43.7±1.6 years; BMI 48.5±1.2kg/m(2)) during bariatric surgery. Large scale gene expression analysis was performed to identify the pathways that discriminate sSAT from dSAT. Adipose tissue macrophages were quantified by immunohistochemistry using HAM56 antibody in subjects scored for liver histopathology. RESULTS: An inflammatory gene pattern discriminates between sSAT and dSAT. dSAT displayed an intermediate level of macrophage accumulation between sSAT and VAT. The abundance of macrophages in dSAT, but not in sSAT, was significantly increased in patients with non-alcoholic steatohepatitis (NASH) and/or fibroinflammatory hepatic lesions. CONCLUSIONS: These data show distinct gene signature and macrophage abundance in the two compartments of SAT, with dSAT more closely related to VAT than to sSAT in terms of inflammation and relation with the severity of liver diseases in morbid obesity.


Assuntos
Fígado/patologia , Obesidade Mórbida/patologia , Gordura Subcutânea/patologia , Adulto , Biópsia , Feminino , Fibrose , Humanos , Inflamação/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade
11.
Environ Health Perspect ; 120(4): 508-14, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22262711

RESUMO

BACKGROUND: Epidemiological studies emphasize the possible role of persistent organic pollutants (POPs) in obesity and the metabolic syndrome. These pollutants are stored in adipose tissue (AT). OBJECTIVES: Our aim was to study the effects of POPs on human adipose cells and rodent AT. METHODS: Using human multipotent adipose-derived stem cells, we carried out large-scale gene expression analysis to identify the major pathways modified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyl (PCB) congener 126 (PCB-126), and PCB-153 and to evaluate their toxic effects. The effects of TCDD on gene expression and AT histology were also assessed in mice. RESULTS: The most significantly regulated genes in both precursor cells and adipocytes were those involved in the inflammatory/immune response, cancer, and metabolism pathways. Interestingly, the fold induction and the number of modulated genes were higher in precursors than in adipocytes, suggesting that the former could be more sensitive to the effect of pollutants. When cells were treated with combinations of pollutants, the effects of the AhR ligands TCDD and PCB-126 were dominant compared with those of the non-dioxin-like PCB-153. The effects of AhR ligands were reduced by the AhR antagonist α-naphthoflavone. The regulation of inflammatory pathway was observed in wild-type AT but not in AhR-knockout mice. CONCLUSIONS: Both in vitro and in vivo studies showed that adipose cells were targets of AhR ligands and suggest that inflammation is one of the main regulated pathways. These observations suggest a possible contribution of pollutants to low-grade AT inflammation that accompanies the pathogenesis of metabolic diseases.


Assuntos
Adipócitos/efeitos dos fármacos , Diferenciação Celular , Obesidade/induzido quimicamente , Bifenilos Policlorados/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Adipócitos/citologia , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Animais , Benzoflavonas/farmacologia , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Knockout , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/efeitos dos fármacos , Obesidade/patologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Aumento de Peso/efeitos dos fármacos
12.
Am J Clin Nutr ; 95(1): 49-63, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22170375

RESUMO

BACKGROUND: The most effective and safe dietary approach for weight loss and its impact on the metabolic functions and morphology of adipose tissue remain unclear. OBJECTIVES: We evaluated whether an energy-restricted high-protein diet with a low glycemic index and soluble fiber (LC-P-LGI) would be more effective than a low-calorie conventional diet (LC-CONV) on weight loss and related metabolic risk factors. We further determined factors that may influence adipocyte size during energy restriction. DESIGN: Thirteen obese participants were randomly assigned in a crossover design to 2 periods of a 4-wk hypocaloric diet as either LC-P-LGI or LC-CONV, separated by 8-wk washout intervals. RESULTS: In comparison with the LC-CONV diet, the main effect of the LC-P-LGI diet was a greater decrease in adipocyte diameter (P = 0.048), plasma plasminogen activator inhibitor protein-1 (P = 0.019), vascular endothelial growth factor (P = 0.032), and interferon-γ inducible protein 10 (P = 0.010). Whereas fasting plasma glucose and high-sensitivity C-reactive protein decreased only after the LC-P-LGI diet, with no differences between diets, fasting plasma insulin and insulin resistance were lower after the LC-CONV diet. The diet results did not differ for body composition and lipid variables. Kinetic modifications in adipocyte diameter were associated with metabolic variables and genes implicated in adipocyte proliferation, apoptosis, and angiogenesis. CONCLUSIONS: In comparison with the LC-CONV diet, the LC-P-LGI diet was associated with improvement in some cardiometabolic risk factors and greater reduction in adipocyte size. Profiles of genes involved in inhibiting adipogenesis and angiogenesis, but increasing apoptosis, were correlated with decreased adipocyte size. This study provides insight into the adipose tissue-remodeling changes that induce regulation of adipocyte size during dietary weight loss. This trial was registered at clinicaltrials.gov as NCT01312740.


Assuntos
Tecido Adiposo/patologia , Restrição Calórica , Doenças Cardiovasculares/prevenção & controle , Dieta Redutora , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/uso terapêutico , Obesidade/dietoterapia , Adipócitos/fisiologia , Adipogenia/genética , Adipogenia/fisiologia , Tecido Adiposo/citologia , Adulto , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Quimiocina CXCL10/sangue , Estudos Cross-Over , Fibras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/farmacologia , Ingestão de Energia , Feminino , Expressão Gênica , Índice Glicêmico , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/patologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular , Redução de Peso/fisiologia
13.
Obes Facts ; 4(2): 131-44, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21577020

RESUMO

OBJECTIVE: Cystatin C, a protein coded by CST3 gene, is implicated in adipose tissue biology. Our hypothesis is that common variants in CST3 gene could play a role in the development of corpulence during lifetime. METHODS: Two tag SNPs were selected to capture all SNPs in the CST3 region. We first investigated the association of the two tag SNPs individually and combined into haplotypes with corpulence related phenotypes in 4,288 French subjects (BMI = 24.31 ( 3.74 kg/m²). Significant findings were replicated in five independent populations--790 Danish lean men (BMI = 24.63 ( 2.30 kg/m²), 672 Danish obese men (BMI = 33.23 ( 2.34 kg/m²), 763 Swedish women (BMI = 21.73 ( 2.87 kg/m²), 1,848 Danish lean women (BMI = 22.66 ( 2.85 kg/m²) and 2,061 Danish obese women (BMI = 37.01 ( 3.59 kg/m²). RESULTS: Rs2424577 was associated with BMI in three independent populations--G/G carriers were less corpulent than A/A carriers in the French individuals (p = 0.045) and in the Danish lean men (p = 0.021), and they were more corpulent in the group of Swedish women (p = 0.004). This phenomenon has been described as a flip-flop phenomenon, probably caused by a multilocus effect. CONCLUSION: CST3 rs2424577 is associated with BMI in a complex fashion. This association is probably caused by the interaction between several functional variants.


Assuntos
Distribuição da Gordura Corporal , Cistatina C/genética , Haplótipos , Obesidade/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
14.
Am J Clin Nutr ; 89(1): 51-7, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19056587

RESUMO

BACKGROUND: Adipose tissue gene expression analysis in humans now provides a tremendous means to discover the physiopathologic gene targets critical for our understanding and treatment of obesity. Clinical studies are emerging in which adipose gene expression has been examined in hundreds of subjects, and it will be fundamentally important that these studies can be compared so that a common consensus can be reached and new therapeutic targets for obesity proposed. OBJECTIVE: We studied the effect of the biopsy sampling methods (needle-aspirated and surgical) used in clinical investigation programs on the functional interpretation of adipose tissue gene expression profiles. DESIGN: A comparative microarray analysis of the different subcutaneous adipose tissue sampling methods was performed in age-matched lean (n = 19) and obese (n = 18) female subjects. Appropriate statistical (principal components analysis) and bioinformatic (FunNet) functional enrichment software were used to evaluate data. The morphology of adipose tissue samples obtained by needle-aspiration and surgical methods was examined by immunohistochemistry. RESULTS: Biopsy techniques influence the gene expression underlying the biological themes currently discussed in obesity (eg, inflammation, extracellular matrix, and metabolism). Immunohistochemistry experiments showed that the easier to obtain needle-aspirated biopsies poorly aspirate the fibrotic fraction of subcutaneous adipose tissue, resulting in an underrepresentation of the stroma-vascular fraction. CONCLUSIONS: The adipose tissue biopsy technique is an important caveat to consider when designing, interpreting, and, most important, comparing microarray experiments. These results will have crucial implications for the clinical and physiopathologic understanding of human obesity and therapeutic approaches.


Assuntos
Biópsia/métodos , Perfilação da Expressão Gênica/métodos , Obesidade/genética , Obesidade/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Adulto , Biópsia/instrumentação , Biópsia por Agulha/instrumentação , Biópsia por Agulha/métodos , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Componente Principal , Magreza/genética , Magreza/patologia
15.
Diabetes ; 54(8): 2277-86, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16046292

RESUMO

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.


Assuntos
Tecido Adiposo/patologia , Fatores Quimiotáticos/genética , Macrófagos/patologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Redução de Peso , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Adulto , Anastomose em-Y de Roux , Quimiocina CCL2/genética , Proteínas de Ligação a DNA/genética , Feminino , Filgrastim , Derivação Gástrica , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/genética , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Obesidade Mórbida/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de Superfície Celular/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Proteínas Recombinantes , Fatores de Transcrição/genética
16.
FASEB J ; 19(11): 1540-2, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15985526

RESUMO

The molecular mechanisms by which obesity increases the risk of cardiovascular diseases are poorly understood. The purpose of this study was to identify candidate biomarkers overexpressed in adipose tissue of obese subjects that could link expanded fat mass to atherosclerosis. We compared gene expression profile in subcutaneous adipose tissue (scWAT) of 28 obese and 11 lean subjects using microarray technology. This analysis identified 240 genes significantly overexpressed in scWAT of obese subjects. The genes were then ranked according to the correlation between gene expression and body mass index (BMI). In this list, the elastolytic cysteine protease cathepsin S was among the highly correlated genes. RT-PCR and Western blotting confirmed the increase in cathepsin S mRNA (P=0.006) and protein (P<0.05) in obese scWAT. The circulating concentrations of cathepsin S were also significantly higher in obese than in nonobese subjects (P<0.0001). Both cathepsin S mRNA in scWAT and circulating levels were positively correlated with BMI, body fat, and plasma triglyceride levels. In addition, we show that the proinflammatory factors, lipopolysaccharide, interleukin-1beta, and tumor necrosis factor-alpha increase cathepsin S secretion in human scWAT explants. This study identifies cathepsin S as a novel marker of adiposity. Since this enzyme has been implicated in the development of atherosclerotic lesions, we propose that cathepsin S represents a molecular link between obesity and atherosclerosis.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade , Aterosclerose/etiologia , Catepsinas/genética , Adipócitos/metabolismo , Biomarcadores , Catepsinas/biossíntese , Catepsinas/sangue , Proteínas da Matriz Extracelular/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Músculo Liso Vascular/química , Obesidade/complicações , Obesidade/metabolismo , RNA Mensageiro/análise
17.
J Clin Endocrinol Metab ; 89(5): 2000-14, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15126512

RESUMO

The stress hormone epinephrine produces major physiological effects on skeletal muscle. Here we determined skeletal muscle mRNA expression profiles before and during a 6-h epinephrine infusion performed in nine young men. Stringent statistical analysis of data obtained using 43000 cDNA element microarrays showed that 1206 and 474 genes were up- and down-regulated, respectively. Microarray data were validated using reverse transcription quantitative PCR. Gene classification was performed through data mining of Gene Ontology annotations, cluster analysis of regulated genes among 14 human tissues, and correlation analysis of mRNA and clinical parameter variations. Evidence of an autoregulatory control was provided by the regulation of key genes of the cAMP-dependent transcription pathway. Genes with known functional cAMP response elements were regulated by the hormone. The impact on metabolism was illustrated by coordinated regulations of genes involved in carbohydrate and protein metabolisms. Epinephrine had a profound effect on genes involved in immunity and inflammatory response, a previously unappreciated aspect of catecholamine action. Information on 526 mRNAs corresponded to genes of unknown function. These data define the molecular signatures of epinephrine action in human skeletal muscle. They may contribute to the understanding of skeletal muscle alterations observed in pathological conditions characterized by sympathetic nervous system overdrive.


Assuntos
Agonistas Adrenérgicos/metabolismo , Epinefrina/fisiologia , Músculo Esquelético/fisiologia , Agonistas Adrenérgicos/farmacologia , Adulto , Fenômenos Fisiológicos Cardiovasculares , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Metabolismo Energético/fisiologia , Epinefrina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Metabolismo/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Estresse Fisiológico/genética , Regulação para Cima
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