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1.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484128

RESUMO

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Assuntos
COVID-19/metabolismo , Cardiomiopatias/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/imunologia , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiopatias/imunologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação , Gordura Intra-Abdominal/patologia , Obesidade/complicações , Obesidade/imunologia , Obesidade/patologia , Pericárdio , Prognóstico , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
2.
J Clin Med ; 9(11)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233575

RESUMO

Diabetes mellitus (DM) has been identified as a risk factor for severe COVID-19. DM is highly prevalent in the general population. Defining strategies to reduce the health care system burden and the late arrival of some patients thus seems crucial. The study aim was to compare phenotypic characteristics between in and outpatients with diabetes and infected by COVID-19, and to build an easy-to-use hospitalization prediction risk score. This was a retrospective observational study. Patients with DM and laboratory- or CT-confirmed COVID-19, who did (n = 185) and did not (n = 159) require hospitalization between 10 March and 10 April 2020, were compared. Data on diabetes duration, treatments, glycemic control, complications, anthropometrics and peripheral oxygen saturation (SpO2) were collected from medical records. Stepwise multivariate logistic regressions and ROC analyses were performed to build the DIAB score, a score using no more than five easy-to-collect clinical parameters predicting the risk of hospitalization. The DIAB score was then validated in two external cohorts (n = 132 and n = 2036). Hospitalized patients were older (68.0 ± 12.6 vs. 55.2 ± 12.6 years, p < 0.001), with more class III obesity (BMI ≥ 40 kg/m2, 9.7 vs. 3.5%, p = 0.03), hypertension (81.6 vs. 44.3%, p < 0.0001), insulin therapy (37% vs. 23.7%, p = 0.009), and lower SpO2 (91.6 vs. 97.3%, p < 0.0001) than outpatients. Type 2 DM (T2D) was found in 94% of all patients, with 10 times more type 1 DM in the outpatient group (11.3 vs. 1.1%, p < 0.0001). A DIAB score > 27 points predicted hospitalization (sensitivity 77.7%, specificity 89.2%, AUC = 0.895), and death within 28 days. Its performance was validated in the two external cohorts. Outpatients with diabetes were found to be younger, with fewer diabetic complications and less severe obesity than inpatients. DIAB score is an easy-to-use score integrating five variables to help clinicians better manage patients with DM and avert the saturation of emergency care units.

3.
Cells ; 9(2)2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012908

RESUMO

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G > T p.(Arg582Leu), and c.1892G> A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.


Assuntos
Lamina Tipo A/genética , Síndrome Metabólica/genética , Mutação/genética , Tecido Adiposo/patologia , Biópsia , Forma do Núcleo Celular , Senescência Celular , Feminino , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
4.
Arterioscler Thromb Vasc Biol ; 40(4): 986-1000, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32102570

RESUMO

OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.


Assuntos
Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Pericárdio/metabolismo , Plasmalogênios/metabolismo , Idoso , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Lipidômica , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea/metabolismo
5.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589290

RESUMO

AIMS: Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. METHODS: We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs.We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. RESULTS: In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800-1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. CONCLUSIONS: The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/patologia , Células Endoteliais/efeitos dos fármacos , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Neovascularização Patológica/patologia , Idoso , Animais , Biomarcadores/análise , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/etiologia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Morfogênese , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/etiologia , Prognóstico , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia
6.
Compr Physiol ; 7(3): 1051-1082, 2017 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-28640452

RESUMO

Epicardial adipose tissue (EAT) is a small but very biologically active ectopic fat depot that surrounds the heart. Given its rapid metabolism, thermogenic capacity, unique transcriptome, secretory profile, and simply measurability, epicardial fat has drawn increasing attention among researchers attempting to elucidate its putative role in health and cardiovascular diseases. The cellular crosstalk between epicardial adipocytes and cells of the vascular wall or myocytes is high and suggests a local role for this tissue. The balance between protective and proinflammatory/profibrotic cytokines, chemokines, and adipokines released by EAT seem to be a key element in atherogenesis and could represent a future therapeutic target. EAT amount has been found to predict clinical coronary outcomes. EAT can also modulate cardiac structure and function. Its amount has been associated with atrial fibrillation, coronary artery disease, and sleep apnea syndrome. Conversely, a beiging fat profile of EAT has been identified. In this review, we describe the current state of knowledge regarding the anatomy, physiology and pathophysiological role of EAT, and the factors more globally leading to ectopic fat development. We will also highlight the most recent findings on the origin of this ectopic tissue, and its association with cardiac diseases. © 2017 American Physiological Society. Compr Physiol 7:1051-1082, 2017.


Assuntos
Tecido Adiposo/metabolismo , Doenças Cardiovasculares/etiologia , Metabolismo dos Lipídeos , Obesidade/etiologia , Pericárdio/metabolismo , Adipocinas/genética , Adipocinas/metabolismo , Tecido Adiposo/diagnóstico por imagem , Animais , Humanos , Pericárdio/citologia , Pericárdio/diagnóstico por imagem
7.
Surg Obes Relat Dis ; 13(2): 320-326, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27720420

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in obese patients undergoing bariatric surgery (BS), but there is neither consensus nor high-level guidelines yet on VTE prophylaxis in this specific population. OBJECTIVE: We aimed to evaluate patterns of BS perioperative thromboprophylaxis practices. SETTING: French obesity specialized care centers (CSO), which are tertiary care referral hospitals for the most severe cases of obesity METHODS: A detailed questionnaire survey (11 opened, 15 closed questions) investigating their prophylactic schemes of anticoagulation (molecule, dose, weight-adjustment, duration, associated measures, follow-up) was sent to the 37 CSO. RESULTS: Completion rate was 92%. Over 90% of respondents indicated using low molecular weight heparin. Enoxaparin was the most commonly used molecule (89%), twice daily (71%), started mostly 6 hours after BS (74%), whereas fondaparinux (9%), dalteparin (6%), and tinzaparin (6%) were less often prescribed. Dosing varied significantly according to centers from 4000 to 12,000 IU/d, with the most commonly used dose being 8000 IU once daily, 83%, as well as treatment duration (1 week, 9%; 3 weeks, 47%). Half CSO adjusted low molecular weight heparin dose to weight. Biological monitoring was performed in 88%. Only 1 center followed systematically anti-Xa activity. Associated measures such as elastic stoking or intermittent pneumatic compression were used in 32% and 26%, respectively, and both were used in 39%. CONCLUSION: This study finds significant discrepancies in thromboprophylaxis practices in obese patients undergoing BS, particularly with respect to treatment duration and dose adjustment, highlighting the urgent need for improved implementation of existing clinical practice guidelines in this VTE high-risk population.


Assuntos
Cirurgia Bariátrica/métodos , Obesidade Mórbida/cirurgia , Tromboembolia Venosa/prevenção & controle , Idoso , Anticoagulantes/administração & dosagem , Estudos Transversais , Esquema de Medicação , Feminino , França , Humanos , Dispositivos de Compressão Pneumática Intermitente/estatística & dados numéricos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória/métodos , Hemorragia Pós-Operatória/etiologia , Padrões de Prática Médica/estatística & dados numéricos , Autorrelato , Meias de Compressão/estatística & dados numéricos , Centros de Atenção Terciária/estatística & dados numéricos , Trombose Venosa/etiologia
8.
Nat Med ; 22(7): 780-91, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27270589

RESUMO

Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/metabolismo , Obesidade/genética , Tecido Adiposo/citologia , Tecido Adiposo/imunologia , Adulto , Animais , Western Blotting , Transplante de Medula Óssea , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação/genética , Inflamação/imunologia , Resistência à Insulina/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/imunologia , Obesidade/metabolismo , Células RAW 264.7 , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico
11.
J Cardiovasc Magn Reson ; 17: 95, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26546347

RESUMO

BACKGROUND: Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist). METHODS: Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 µg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR. RESULTS: HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05). CONCLUSION: CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Dieta Hiperlipídica , Sacarose na Dieta , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Cardiopatias/prevenção & controle , Imagem Cinética por Ressonância Magnética , Imagem Multimodal/métodos , Imagem de Perfusão do Miocárdio/métodos , Miocárdio/metabolismo , Obesidade/tratamento farmacológico , Peptídeos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Peçonhas/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Circulação Coronária/efeitos dos fármacos , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Modelos Animais de Doenças , Exenatida , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Cardiopatias/sangue , Cardiopatias/etiologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Análise Multivariada , Contração Miocárdica/efeitos dos fármacos , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Fatores de Tempo , Triglicerídeos/metabolismo , Função Ventricular/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
12.
Cardiovasc Res ; 108(1): 62-73, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26239655

RESUMO

AIMS: Human epicardial adipose tissue (EAT) is a visceral and perivascular fat that has been shown to act locally on myocardium, atria, and coronary arteries. Its abundance has been linked to coronary artery disease (CAD) and atrial fibrillation. However, its physiological function remains highly debated. The aim of this study was to determine a specific EAT transcriptomic signature, depending on its anatomical peri-atrial (PA), peri-ventricular (PV), or peri-coronary location. METHODS AND RESULTS: Samples of EAT and thoracic subcutaneous fat, obtained from 41 patients paired for cardiovascular risk factors, CAD, and atrial fibrillation were analysed using a pangenomic approach. We found 2728 significantly up-regulated genes in the EAT vs. subcutaneous fat with 400 genes being common between PA, PV, and peri-coronary EAT. These common genes were related to extracellular matrix remodelling, inflammation, infection, and thrombosis pathways. Omentin (ITLN1) was the most up-regulated gene and secreted adipokine in EAT (fold-change >12, P < 0.0001). Among EAT-enriched genes, we observed different patterns depending on adipose tissue location. A beige expression phenotype was found in EAT but PV EAT highly expressed uncoupled protein 1 (P = 0.01). Genes overexpressed in peri-coronary EAT were implicated in proliferation, O-N glycan biosynthesis, and sphingolipid metabolism. PA EAT displayed an atypical pattern with genes implicated in cardiac muscle contraction and intracellular calcium signalling pathway. CONCLUSION: This study opens new perspectives in understanding the physiology of human EAT and its local interaction with neighbouring structures.


Assuntos
Tecido Adiposo/metabolismo , Pericárdio/metabolismo , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Med ; 21(6): 610-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25939064

RESUMO

Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor ß1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.


Assuntos
Tecido Adiposo Branco/metabolismo , Inflamação/genética , Fatores Reguladores de Interferon/genética , Obesidade/genética , Animais , Dieta Hiperlipídica , Regulação da Expressão Gênica , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Resistência à Insulina/genética , Macrófagos , Camundongos , Obesidade/tratamento farmacológico , Obesidade/patologia , Fator de Crescimento Transformador beta1/biossíntese
14.
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 Genética/genética , Proteína 1 Relacionada a Twist/biossíntese , Proteína 1 Relacionada a Twist/genética
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