RESUMO
Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.
Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Evolução Molecular , Humanos , Camundongos , Monócitos/citologia , Especificidade de Órgãos , Proteína Smad3/metabolismo , Transativadores/metabolismoRESUMO
Exosomes, extracellular vesicles (EVs) produced within cells, mediate both the disposal of intracellular waste and communication with distant cells, and they are involved in a variety of disease processes. Although disease modifications of exosome cargos have been well studied, it has been poorly investigated how disease processes, such as endoplasmic reticulum (ER) stress, affect EV production. We previously reported that adiponectin, an adipocyte-secreted salutary factor, increases systemic exosome levels through T-cadherin-mediated enhancement of exosome biogenesis. In the present study, we demonstrated that adiponectin/T-cadherin-dependent EV production was susceptible to ER stress and that low-dose tunicamycin significantly reduced EV production in the presence, but not in the absence, of adiponectin. Moreover, pharmacological or genetic activation of inositol-requiring enzyme 1α, a central regulator of ER stress, downregulated T-cadherin at the mRNA and protein levels as well as attenuated EV production. In addition, adiponectin/T-cadherin-independent EV production was attenuated under ER stress conditions. Repeated administration of tunicamycin to mice decreased circulating small EVs without decreasing tissue T-cadherin expression. Mechanistically, inositol-requiring enzyme 1α activation by silencing of the X-box binding protein 1 transcription factor upregulated the canonical interferon pathway and decreased EV production. The interferon pathway, when it was activated by polyinosinic-polycytidylic acid, also significantly attenuated EV production. Thus, we concluded that ER stress decreases exosome production through adiponectin/T-cadherin-dependent and -independent pathways.
Assuntos
Adiponectina , Caderinas , Estresse do Retículo Endoplasmático , Exossomos , Animais , Camundongos , Adiponectina/metabolismo , Caderinas/biossíntese , Caderinas/genética , Caderinas/metabolismo , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Inositol/metabolismo , Interferons/imunologia , Poli I-C/imunologia , Tunicamicina/farmacologiaRESUMO
The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.
Assuntos
Neoplasias Encefálicas , Metilação de DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioma , Isocitrato Desidrogenase , Fator 4 Semelhante a Kruppel , Mutação , Humanos , Isocitrato Desidrogenase/genética , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Ilhas de CpG/genética , Feminino , Masculino , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/metabolismo , Pessoa de Meia-Idade , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , AdultoRESUMO
AIM AND OBJECTIVE: Our recent report showed that soluble T-cadherin promotes pancreatic beta-cell proliferation. However, how and where the secretion of soluble T-cadherin is regulated remain unclear. METHODS AND RESULTS: Soluble T-cadherin levels significantly increased in leptin receptor-deficient db/db mice with hypoinsulinaemia or in wild-type mice treated with insulin receptor blockade by S961. Similar results were observed in human subjects; Diabetic ketoacidosis patients at the time of hospitalization had increased plasma soluble T-cadherin levels, which decreased after insulin infusion therapy. Patients with recurrent ovarian cancer who were administered a phosphatidylinositol-3 kinase (PI3K)-alpha inhibitor (a new anticancer drug) had increased plasma soluble T-cadherin and plasma C-peptide levels. Endothelial cell-specific T-cadherin knockout mice, but not skeletal muscle- or cardiac muscle-specific T-cadherin knockout mice, showed a 26 % reduction in plasma soluble T-cadherin levels and a significant increase in blood glucose levels in streptozocin-induced diabetes. The secretion of soluble T-cadherin from human endothelial cells was approximately 20 % decreased by insulin and this decrease was canceled by blockade of insulin receptor/Akt signalling, not Erk signalling. CONCLUSION: We conclude that insulin regulates soluble T-cadherin levels and soluble T-cadherin secretion from endothelial cells is positively regulated by insulin/insulin receptor/Akt signalling.
RESUMO
Visceral fat accumulation is a major determinant of type 2 diabetes mellitus and cardiovascular diseases. Recent studies have reported that glutamate is the most elevated amino acid in the plasma amino acid profile in patients with obesity and/or visceral fat accumulation. Here, we show the relationship between plasma glutamate and the clinical features of patients with type 2 diabetes. The study subjects were 62 (28 men and 34 women) Japanese patients with type 2 diabetes. Blood profiles, including glutamate and adiponectin (APN) levels and estimated visceral fat area (eVFA), were measured. We also evaluated the plasma amino acid levels in mice with or without obesity by GC/MS analysis. In patients with type 2 diabetes, plasma glutamate was positively correlated with BMI, eVFA, and fasting insulin but negatively correlated with APN and duration of diabetes. Additionally, multiple regression analysis revealed that plasma glutamate was a significant determinant of APN. The plasma glutamate level was most significantly increased in obese mice compared to control mice, and it was negatively correlated with APN. These results suggest that the level of plasma glutamate could be a strong indicator of adipocyte dysfunction in patients with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Masculino , Humanos , Feminino , Animais , Camundongos , Adiponectina , Ácido Glutâmico , Obesidade , InsulinaRESUMO
At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into "non-severe" (mild, moderate-I and moderate-II) (n = 80) and "severe" (n = 27) groups. The "severe" patients were significantly older than "non-severe" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of "severe" patients at the time of admission were significantly greater than those of "non-severe" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.
Assuntos
Adiponectina , COVID-19 , Índice de Gravidade de Doença , Humanos , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/complicações , COVID-19/diagnóstico , Adiponectina/sangue , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , SARS-CoV-2 , Japão/epidemiologia , Idoso de 80 Anos ou mais , Adulto , Hospitalização , Índice de Massa CorporalRESUMO
The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism. However, it remains unclear whether and how the promotion of exosome production by adiponectin in vivo is beneficial for glucose and lipid metabolism. In the present study, overexpression of human adiponectin in mice resulted in an increased number of circulating exosomes, but it did not significantly improve glucose metabolism, change body weights, or change triglyceride clearance under a high-fat diet. Multiple small doses of streptozotocin increased blood glucose and decreased triglyceride clearance similarly in both wild-type and transgenic mice. Thus, these results indicated that human adiponectin overexpression in mice increases plasma exosomes but does not significantly influence glucose and lipid metabolism.
Assuntos
Exossomos , Glucose , Camundongos , Animais , Humanos , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Adiponectina/genética , Exossomos/genética , Exossomos/metabolismo , Camundongos Transgênicos , Triglicerídeos/metabolismoRESUMO
AIMS/HYPOTHESIS: Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. METHODS: The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. RESULTS: PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(-)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. CONCLUSIONS/INTERPRETATION: Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy.
Assuntos
Diabetes Mellitus Tipo 1 , Células-Tronco Mesenquimais , Neoplasias , Animais , Anticorpos Monoclonais , Antígeno B7-H1/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Inibidores de Checkpoint Imunológico , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.
Assuntos
Adiponectina/genética , Exossomos/metabolismo , Insuficiência Cardíaca/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Animais , Caderinas/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Suscetibilidade a Doenças , Vesículas Extracelulares/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , CamundongosRESUMO
A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinß1 subunit and transforming growth factor (TGF)-ß receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-ß signaling by regulating the abundance of the integrinß1 and TGF-ß receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.
Assuntos
Proteína ADAM12/genética , Cardiomegalia/prevenção & controle , Desintegrinas/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Miocárdio/patologia , Proteína ADAM12/antagonistas & inibidores , Proteína ADAM12/efeitos dos fármacos , Animais , Pressão Sanguínea , Fibrose , Adesões Focais/efeitos dos fármacos , Integrina beta1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme that specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI-PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in the liver. GPI-PLD mRNA was most highly expressed in the liver, and the hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet. Furthermore, diacylglycerol (DAG) content was significantly decreased, and PKCε activity was suppressed in the livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI-PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (R = 0.37, P = 0.0006) and triglyceride (R = 0.34, P = 0.001) levels in male subjects with metabolic syndrome. In conclusion, upregulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in the liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and the progression of NAFLD.
Assuntos
Diglicerídeos/metabolismo , Intolerância à Glucose/genética , Resistência à Insulina/genética , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/metabolismo , Fosfolipase D/genética , Idoso , Alanina Transaminase/metabolismo , Animais , Dieta Hiperlipídica , Sacarose Alimentar , Técnicas de Silenciamento de Genes , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Síndrome Metabólica/metabolismo , Camundongos Knockout , Camundongos Obesos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína Quinase C-épsilon/metabolismo , RNA Mensageiro/metabolismo , Ratos , Triglicerídeos/metabolismoRESUMO
Adiponectin, an adipocyte-derived circulating protein, accumulates in the heart, vascular endothelium, and skeletal muscles through an interaction with T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored cadherin. Recent studies have suggested that this interaction is essential for adiponectin-mediated cardiovascular protection. However, the precise protein-protein interaction between adiponectin and T-cad remains poorly characterized. Using ELISA-based and surface plasmon analyses, we report here that T-cad fused with IgG Fc as a fusion tag by replacing its glycosylphosphatidylinositol-anchor specifically bound both hexameric and larger multimeric adiponectin with a dissociation constant of â¼1.0 nm and without any contribution from other cellular or serum factors. The extracellular T-cad repeats 1 and 2 were critical for the observed adiponectin binding, which is required for classical cadherin-mediated cell-to-cell adhesion. Moreover, the 130-kDa prodomain-bearing T-cad, uniquely expressed on the cell surface among members of the cadherin family and predominantly increased by adiponectin, contributed significantly to adiponectin binding. Inhibition of prodomain-processing by a prohormone convertase inhibitor increased 130-kDa T-cad levels and also enhanced adiponectin binding to endothelial cells both by more preferential cell-surface localization and by higher adiponectin-binding affinity of 130-kDa T-cad relative to 100-kDa T-cad. The preferential cell-surface localization of 130-kDa T-cad relative to 100-kDa T-cad was also observed in normal mice aorta in vivo In conclusion, our study shows that a unique key feature of the T-cad prodomain is its involvement in binding of the T-cad repeats 1 and 2 to adiponectin and also demonstrates that adiponectin positively regulates T-cad abundance.
Assuntos
Adiponectina/química , Caderinas/química , Adiponectina/genética , Animais , Células CHO , Cálcio/química , Adesão Celular , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Dissulfetos/química , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Glicosilfosfatidilinositóis/química , Células HEK293 , Humanos , Imunoglobulina G/química , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Ressonância de Plasmônio de SuperfícieRESUMO
Obesity is closely associated with various metabolic disorders. However, little is known about abnormalities in the metabolic change of obese adipose tissue. Here we use static metabolic analysis and in vivo metabolic turnover analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of the TCA cycle were increased in the white adipose tissue (WAT) of ob/ob and diet-induced obesity mice but not in the liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that these glucose-derived metabolites were dynamically and specifically produced in obese WAT compared with lean WAT. Glutamate rise in obese WAT was associated with down-regulation of glutamate aspartate transporter (GLAST), a major glutamate transporter for adipocytes, and low uptake of glutamate into adipose tissue. In adipocytes, glutamate treatment reduced adiponectin secretion and insulin-mediated glucose uptake and phosphorylation of Akt. These data suggest that a high intra-adipocyte glutamate level potentially relates to adipocyte dysfunction in obesity. This study provides novel insights into metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.
Assuntos
Tecido Adiposo Branco/metabolismo , Ciclo do Ácido Cítrico , Glutamatos/metabolismo , Metaboloma , Obesidade/metabolismo , Células 3T3-L1 , Animais , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Obesidade/etiologiaRESUMO
BACKGROUND: Although obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated. METHODS: We enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation. RESULTS: The prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (-) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (-) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018). CONCLUSIONS: T2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.
Assuntos
Adiposidade , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Força da Mão , Gordura Intra-Abdominal/fisiopatologia , Músculo Esquelético/fisiopatologia , Obesidade Abdominal/fisiopatologia , Sarcopenia/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/diagnóstico , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologia , Prevalência , Fatores de Risco , Sarcopenia/diagnóstico , Sarcopenia/epidemiologiaRESUMO
Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. In vitro, knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.
Assuntos
Adiponectina/metabolismo , Aterosclerose/metabolismo , Caderinas/metabolismo , Adiponectina/sangue , Adiponectina/genética , Animais , Aterosclerose/patologia , Caderinas/genética , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Túnica Íntima/metabolismo , Túnica Íntima/patologiaRESUMO
BACKGROUND: Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat.MethodsâandâResults:Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm2) and was also reduced in the high EFV group (EFV ≥80 cm3). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis. CONCLUSIONS: Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.
Assuntos
Doença da Artéria Coronariana/etiologia , Cardiopatias/metabolismo , Gordura Intra-Abdominal , Pericárdio/patologia , Gordura Subcutânea , Idoso , Feminino , Cardiopatias/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysM(EGFP)) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysM(EGFP)-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-α and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysM(EGFP)-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ.
Assuntos
Adiposidade , Calgranulina A/metabolismo , Macrófagos/patologia , Obesidade/metabolismo , Obesidade/patologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adiposidade/efeitos dos fármacos , Animais , Anticorpos/farmacologia , Calgranulina A/genética , Quimiotaxia/efeitos dos fármacos , Dieta Hiperlipídica , Epididimo/efeitos dos fármacos , Epididimo/patologia , Proteínas de Fluorescência Verde/metabolismo , Inflamação/patologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Muramidase/metabolismo , Obesidade/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: We assessed the cerebrovascular CO2 reactivity (CO2R) in chronic renal failure (CRF) patients without diabetes mellitus (DM), uncontrolled hypertension, peripheral vascular disease, or neurological disease under isoflurane-nitrous oxide anesthesia. METHODS: Forty-nine patients undergoing surgery, including 36 CRF patients (30 receiving dialysis and six pre-dialysis patients) and 13 patients without CRF (controls). Middle cerebral artery flow velocity (VMCA) was measured by transcranial Doppler ultrasonography at an end-tidal CO2 of 35 to 45 mmHg. CO2R was calculated as an absolute value (change in VMCA per mmHg PaCO2) and a relative value (absolute CO2R/baseline VMCA × 100). Factors associated with CO2R were evaluated simultaneously. RESULTS: Despite no significant differences in the absolute and relative values of CO2R between the CRF (mean 2.5 cm/s/mmHg; median 5.0%/mmHg) and control (2.4 cm/s/mmHg; 5.0%/mmHg) groups, blood urea nitrogen (BUN) concentrations in the CRF group correlated inversely with both absolute and relative CO2R. BUN concentration was higher (mean 72 versus 53 mg/dl, p = 0.006) and relative CO2R was lower (mean 2.6 versus 5.7%/mmHg, p = 0.011) in patients with pre-dialysis CRF (n = 6) versus CRF patients receiving dialysis (n = 30). CONCLUSIONS: CO2R in CRF patients was not significantly different from that in controls. However, in CRF patients with high BUN concentrations, CO2R might be impaired, leading to reduced cerebrovascular reserve capacity. Because DM is a major cause of CRF and we excluded DM patients, our results might not be applicable to patients with DM-induced CRF.
Assuntos
Dióxido de Carbono/metabolismo , Isoflurano/administração & dosagem , Falência Renal Crônica/fisiopatologia , Óxido Nitroso/administração & dosagem , Adulto , Anestesia/métodos , Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média , Estudos Prospectivos , Ultrassonografia Doppler TranscranianaRESUMO
In the original publication of the article, the first sentence was published incorrectly under the section "Patients and preoperative assessment". The correct sentence should read as, "The Yamaguchi University Graduate School of Medicine Ethics Committee for Human Study approved the study protocol (18th August 2004: H16-71)".