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Inervação autonômica da articulação temporomandibular em condições de normalidade e, padrão de ativação neuronal no tronco encefálico durante a vigência de artrite no complexo articular temporomandibular.; Temporomandibular joint autonomic innervation inder normal conditions and, neuronal activation pattern in the brain stem during monoarthritis induced in the temporomandibular joint complex.

Ervolino, Edilson
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 10/08/2009 PT
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Os objetivos do presente trabalho foram: 1) analisar a distribuição das fibras nervosas autonômicas na articulação temporomandibular (ATM) do rato, através da detecção de tirosina hidroxilase (TH), neuropeptídeo Y (NPY) e peptídeo intestinal vasoativo (VIP); 2) realizar um estudo topográfico ultra-estrutural das fibras e terminações nervosas autonômicas na ATM do rato; 3) determinar o padrão de ativação neuronal no complexo nuclear trigeminal e, em centros nervosos moduladores da dor, durante a vigência de monoartrite no complexo articular temporomandibular (CATM) do rato. Para o primeiro propósito o método imunoistoquímico, para a detecção simultânea de TH, NPY e VIP, foi executado em ATMs que apresentavam as seguintes condições: inervação intacta ou desprovida de inervação simpática e/ou parassimpática. Para o segundo propósito aliamos o tratamento prévio com 5-hidroxidopamina, para evidenciação de terminações nervosas simpáticas, com a remoção cirúrgica do gânglio ótico, para a visualização das fibras e terminações nervosas parassimpáticas em degeneração, em seguida analisamos as ATMs ao microscópio eletrônico de transmissão. O terceiro propósito foi obtido induzindo-se monoartrite (fase aguda...

Posição da cabeça da mandíbula à tomografia computadorizada por feixe cônico em adultos com mordida aberta anterior tratados ortodonticamente com auxílio de mini-implantes; Position of the condyle to the cone beam computed tomography in adults with open bite orthodontically treated with mini-implants

Horliana, Ricardo Fidos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/05/2010 PT
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O objetivo deste estudo prospectivo foi avaliar a posição da cabeça da mandíbula em relação à fossa mandibular das articulações temporomandibulares (ATMs), por meio de tomografia computadorizada por feixe cônico (TCFC), em pacientes adultos portadores de má oclusão de Classe I e de Classe II divisão 1ª de Angle com mordida aberta anterior dento-alveolar, tratados ortodonticamente durante período médio de 12 meses com auxílio de mini-implantes. A amostra constou de 10 adultos brasileiros (20 ATMs), de ambos os gêneros (cinco do gênero masculino e 5 do gênero feminino), com idade média de 23 anos e 6 meses, desvio padrão de 5 anos e 3,5 meses, assintomáticos. As imagens de TCFC foram adquiridas em dois tempos do tratamento: T1 ao início e T2 ao final do tratamento e período de observação. Foi realizada avaliação quantitativa da posição da cabeça da mandíbula na fossa mandibular em posição de máxima intercuspidação habitual (MIH). Os valores obtidos com a avaliação quantitativa da posição da cabeça da mandíbula na fossa mandibular ao início do tratamento demonstram que em MIH a cabeça da mandíbula encontra-se ligeiramente deslocada no sentido ântero-posterior com assimetria entre os lados direito e esquerdo e que o espaço articular superior encontra-se aumentado em relação aos demais espaços articulares avaliados. Ao término do tratamento (T2) demonstraram que em MIH a cabeça da mandíbula tendeu a um deslocamento anterior mantendo a assimetria entre os lados direito e esquerdo e que o espaço articular superior apresentou valores próximos aos demais espaços articulares. Entre o início e o término do tratamento os resultados demonstraram que não houve diferença estatisticamente significante na posição ântero-posterior da cabeça da mandíbula...

Caracterização das gelatinases no gânglio trigeminal durante o desenvolvimento de inflamação crônica temporomandibular em ratos; Characterization of gelatinases in the trigeminal ganglion during development of chronic temporomandibular inflammation in rats

Nascimento, Glauce Crivelaro do
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 03/05/2011 PT
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A dor é um importante sintoma que sinaliza danos teciduais ou agentes potencialmente prejudiciais ao organismo, evocando respostas sensoriais e motoras de proteção. A dor orofacial apresenta alta prevalência na sociedade atual, sendo esta condição associada a tecidos duros e moles da cabeça, face, pescoço e a estruturas intraorais. Considerando as dores orofaciais de origem músculo-esquelética, destacam-se àquelas causadas pela Disfunção Temporomandibular (DTM). A DTM apresenta etiologia multifatorial, caracterizada por quadros crônicos envolvendo a região cervical, a musculatura mastigatória e a articulação temporomandibular (ATM). Desde que a inflamação das ATMs é considerada a principal causa da dor em pacientes portadores de DTM, a busca por novas opções terapêuticas para esta disfunção envolve estudos desta articulação, abrangendo aspectos fisiológicos, morfológicos e moleculares. Considerando o processo inflamatório e os aspectos moleculares envolvidos no desenvolvimento desta condição, é possível que as enzimas proteolíticas extracelulares, destacando-se as Metaloproteinases da Matriz (MMPs), as quais estão envolvidas na reabsorção de colágeno e de outras macromoléculas, tenham participação ativa neste processo. Em particular...

Análise tomográfica da articulação temporomandibular no tratamento com Herbst em adulto jovem

Maia, Savana de Alencar; Dib, Luana Paz Sampaio; Landázuri, Denise Rocha Goes; Raveli, Taisa Boamorte; Raveli, Dirceu Barnabé
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 71-78
POR
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Class II malocclusion features a high prevalence in Brazil, being considered as a routine in orthodontic clinics. A number of appliances are shown in the literature in order to correct Class II malocclusion with mandibular retrusion. Herbst´s fixed functional appliance, idealized by Emil Herbst (1905) and reintroduced, in the 1980´s, by Hans Pancherz is highlighted for maintaining the mandible continuously advanced, showing a shorter active treament time, an immediate esthetic impact on the facial profile, as well as requiring no patient´s commitment. Recent researches indicate the use of this appliance in individuals after pubertal growth surge. The aim of the present study is to show the orthodontics practitioner the option to use this appliance so as to treat Class II in individuals after the growth surge, obtaining satisfactory outcomes and further Class II correction.; O aparelho funcional fixo Herbst idealizado por Emil Herbst (1905) e reintroduzido, na década de 1980, por Hans Pancherz; destaca-se por manter a mandíbula avançada de modo contínuo e pesquisas recentes indicam a utilização deste aparelho em indivíduos após o surto de crescimento pubertário. O objetivo da apresentação deste caso clínico é elucidar os mecanismos de adaptação das ATMs...

Avaliação da articulação temporomandibular de individuos sintomaticos por meio de tomografia computadorizada e ressonancia magnetica

Jose Jorge Gomes Lima
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 01/09/2000 PT
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O presente estudo teve como objetivos verificar a prevalência de alterações estruturais e funcionais da A TM_ avaliadas por Ressonância Magnética e das alterações ósseas por Tomografia Computadoriza_ correlacionar as alterações estruturais e funcionais com as alterações ósseas e correlacionar os dois métodos de imagem utilizados quanto à avaliação dos componentes ósseos. Foram selecionados clinicamente 50 indivíduos com sinais e sintomas de desordens temporomandibulares e 20 indivíduos assintomáticos_ sendo posteriormente avaliados em exames bilaterais da A TM por Ressonância Magnética (RM) e Tomografia Computadorizada Helicoidal (TC). Os resultados obtidos permitiram concluir que os indivíduos assintomáticos não apresentaram alterações estruturais ou funcionais da A TM. Os indivíduos sintomáticos apresentaram posição normal do disco em 49% das ATMs_ anterior em 44% e outras posições em 7%. Quanto à função do disco_ 49% das ATMs apresentaram-se normais_ 34% apresentaram deslocamento do disco com redução e 17% sem redução. Morfologia normal do disco foi observada em 69% e deformidades em 31% das ATMs. A RM mostrou alterações ósseas em 22% e a TC em 29% das ATMs. Os tipos de alterações ósseas mais comumente verificadas foram o aplainamento...

Relação entre o espaço articular da ATM e a posição do disco articular; Relatioship between temporomanbular joint space and articular disk position

Andrea Kuroiva Yanikian
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 17/08/2009 PT
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Sistemas avançados de imagem, como a tomografia computadorizada de feixe cônico (TCFC) e a imagem por ressonância magnética (IRM) têm sido utilizados para avaliação da articulação temporomandibular (ATM). Dentre as entidades patológicas que mais comumente afetam a ATM está o deslocamento de disco (DD). O objetivo neste estudo foi verificar a posição da cabeça da mandíbula na fossa em imagens de TCFC e investigar sua relação com a posição do disco articular em IRM. Cinqüenta e dois pacientes da clínica de Ortodontia da FOUSP foram submetidos à RM bilateral das ATMs. Cem imagens de TCFC da ATM foram obtidas com o tomógrafo Newtom 3G. As reconstruções secundárias foram realizadas com o programa NemoScan e utilizadas para obtenção das medidas dos espaços articulares e verificação da posição da cabeça da mandíbula na fossa. Para a comparação das medidas dos espaços articulares e da posição da cabeça da mandíbula, diferentes diagnósticos da posição do disco articular foram reunidos em grupos, para os cortes sagital e coronal, de acordo com a direção do DD. Os resultados foram submetidos à análise de variância one way e teste de Tukey, ao teste de Kruskal Wallis e Dunn e ao teste exato de Fisher (a=0...

Caixa Multibanco para Pessoas com Necessidades Especiais – Aspectos a melhorar

Matos, Ana Isabel Pinto de
Fonte: Universidade de Trás-os-Montes e Alto Douro Publicador: Universidade de Trás-os-Montes e Alto Douro
Tipo: Dissertação de Mestrado
POR
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Dissertação de Mestrado em Informática; Esta dissertação aborda a problemática da utilização das caixas Multibanco pelas Pessoas com Necessidades Especiais (PNEs). As caixas Multibanco ou ATM (Automatic Teller Machine) são uma tecnologia pública de grande utilidade para a sociedade. Utilizar os seus serviços é considerado algo banal e faz parte do quotidiano da maioria da população. Todavia, nem todas as pessoas apresentam as mesmas capacidades de aceder e interagir com as mesmas e em alguns casos torna-se mesmo impossível usar certos e determinados serviços. É o caso das PNEs. Não existindo uma atenção especial relativamente a estas pessoas, estas são excluídas em grande escala dos benefícios proporcionados por esta tecnologia. Para contornar esta situação é necessário, entre outras iniciativas, que surjam ferramentas adequadas a estes indivíduos, permitindo-lhes usufruir da tecnologia como o resto da população. Com este trabalho, pretende-se analisar a interacção desta população relativamente aos constrangimentos/barreiras/obstáculos com as respectivas caixas, evidenciando sempre as suas dificuldades. Pretende-se propor uma série aspectos/recomendações a melhorar que possam adequar as funcionalidades das caixas Multibanco às aptidões de interacção das PNEs...

Robust and efficient synthetic method for forming DNA microarrays

Dolan, Patricia L.; Wu, Yang; Ista, Linnea K.; Metzenberg, Robert L.; Nelson, Mary Anne; Lopez, Gabriel P.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 01/11/2001 EN
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The field of DNA microarray technology has necessitated the cooperative efforts of interdisciplinary scientific teams to achieve its primary goal of rapidly measuring global gene expression patterns. A collaborative effort was established to produce a chemically reactive surface on glass slide substrates to which unmodified DNA will covalently bind for improvement of cDNA microarray technology. Using the p-aminophenyl trimethoxysilane (ATMS)/diazotization chemistry that was developed, microarrays were fabricated and analyzed. This immobilization method produced uniform spots containing equivalent or greater amounts of DNA than commercially available immobilization techniques. In addition, hybridization analyses of microarrays made with ATMS/diazotization chemistry showed very sensitive detection of the target sequence, two to three orders of magnitude more sensitive than the commercial chemistries. Repeated stripping and re-hybridization of these slides showed that DNA loss was minimal, allowing multiple rounds of hybridization. Thus, the ATMS/diazotization chemistry facilitated covalent binding of unmodified DNA, and the reusable microarrays that were produced showed enhanced levels of hybridization and very low background fluorescence.

Functional Heterogeneity of CD11c-positive Adipose Tissue Macrophages in Diet-induced Obese Mice*

Li, Pingping; Lu, Min; Nguyen, M. T. Audrey; Bae, Eun Ju; Chapman, Justin; Feng, Daorong; Hawkins, Meredith; Pessin, Jeffrey E.; Sears, Dorothy D.; Nguyen, Anh-Khoi; Amidi, Arezou; Watkins, Steven M.; Nguyen, UyenThao; Olefsky, Jerrold M.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
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Obesity represents a state of chronic, low grade inflammation and is associated with infiltration of increased numbers of adipose tissue macrophages (ATMs). Diet-induced obesity leads to an increase in non-inflammatory M1-like ATMs displaying the CD11c surface marker. We assessed the function of CD11c-positive ATMs when insulin resistant high fat diet (HFD) mice become insulin-sensitive after switching from HFD to normal chow (NC). HFD mice rapidly become insulin-sensitive in all major insulin-target tissues, including muscle, liver, and adipose tissue, after the diet switch. In adipose tissue the CD11c-positive macrophages remain constant in number despite the presence of insulin sensitivity, but these macrophages now assume a new phenotype in which they no longer exhibit increased inflammatory pathway markers. Adipose tissue markers of apoptosis and necrosis were elevated on HFD and remain high after the HFD → NC diet switch. Furthermore, ATM accumulation preceded detectable adipocyte necrosis at the early phase of HFD. Together, these results indicate that 1) CD11c-positive M1-like ATMs can exhibit phenotypic plasticity and that the polarization of these cells between inflammatory and non-inflammatory states is well correlated to the presence of absence of insulin resistance...

Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue

Kosteli, Aliki; Sugaru, Eiji; Haemmerle, Guenter; Martin, Jayne F.; Lei, Jason; Zechner, Rudolf; Ferrante, Anthony W.
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
EN
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Obesity elicits an immune response characterized by myeloid cell recruitment to key metabolic organs, including adipose tissue. However, the response of immune cells to nonpathologic metabolic stimuli has been less well studied, and the factors that regulate the metabolic-dependent accumulation of immune cells are incompletely understood. Here we characterized the response of adipose tissue macrophages (ATMs) to weight loss and fasting in mice and identified a role for lipolysis in ATM recruitment and accumulation. We found that the immune response to weight loss was dynamic; caloric restriction of high-fat diet–fed mice led to an initial increase in ATM recruitment, whereas ATM content decreased following an extended period of weight loss. The peak in ATM number coincided with the peak in the circulating concentrations of FFA and adipose tissue lipolysis, suggesting that lipolysis drives ATM accumulation. Indeed, fasting or pharmacologically induced lipolysis rapidly increased ATM accumulation, adipose tissue chemoattractant activity, and lipid uptake by ATMs. Conversely, dietary and genetic manipulations that reduced lipolysis decreased ATM accumulation. Depletion of macrophages in adipose tissue cultures increased expression of adipose triglyceride lipase and genes regulated by FFA...

Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity1

Spite, Matthew; Hellmann, Jason; Tang, Yunan; Mathis, Steven P.; Kosuri, Madhavi; Bhatnagar, Aruni; Jala, Venkatakrishna R.; Haribabu, Bodduluri
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Chronic inflammation is an underlying factor linking obesity with insulin resistance. Diet-induced obesity promotes an increase in circulating levels of inflammatory monocytes and their infiltration into expanding adipose tissue. Nevertheless, the endogenous pathways that trigger and sustain chronic low-grade inflammation in obesity are incompletely understood. Here, we report that a high-fat diet selectively increases the circulating levels of CD11b+ monocytes in wild-type mice that express leukotriene B4 receptor, BLT-1, and that this increase is abolished in BLT-1-null mice. The accumulation of classically activated (M1) adipose tissue macrophages (ATMs) and the expression of pro-inflammatory cytokines and chemokines (i.e. IL-6 and Ccl2) was largely blunted in adipose tissue of obese BLT-1-/- mice, while the ratio of alternatively activated (M2) ATMs to M1 ATMs was increased. Obese BLT-1-/- mice were protected from systemic glucose and insulin intolerance and this was associated with a decrease in inflammation in adipose tissue and liver and a decrease in hepatic triglyceride accumulation. Deletion of BLT-1 prevented high-fat induced loss of insulin signaling in liver and skeletal muscle. These observations elucidate a novel role of chemoattractant receptor...

Obesity and Weight Loss Result in Increased Adipose Tissue ABCG1 Expression in db/db Mice

Edgel, Kimberly A.; McMillen, Timothy S.; Wei, Hao; Pamir, Nathalie; Houston, Barbara A.; Caldwell, Mark T.; Mai, Phuong-Oanh T.; Oram, John F.; Tang, Chongren; LeBoeuf, Renée C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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The prevalence of obesity has reached epidemic proportions and is associated with several co-morbid conditions including diabetes, dyslipidemia, cancer, atherosclerosis and gallstones. Obesity is associated with low systemic inflammation and an accumulation of adipose tissue macrophages (ATMs) that are thought to modulate insulin resistance. ATMs may also modulate adipocyte metabolism and take up lipids released during adipocyte lipolysis and cell death. We suggest that high levels of free cholesterol residing in adipocytes are released during these processes and contribute to ATM activation and accumulation during obesity and caloric restriction. Db/db mice were studied for extent of adipose tissue inflammation under feeding conditions of ad libitum (AL) and caloric restriction (CR). The major finding was a marked elevation in epididymal adipose ABCG1 mRNA levels with obesity and CR (6-fold and 16-fold, respectively) over that seen for lean wild-type mice. ABCG1 protein was also elevated for CR as compared to AL adipose tissue. ABCG1 is likely produced by cholesterol loaded ATMs since this gene is not highly expressed in adipocytes and ABCG1 expression is sterol mediated. Our data supports the concept that metabolic changes in adipocytes due to demand lipolysis and cell death lead to cholesterol loading of ATMs. Based on finding cholesterol-loaded peritoneal leukocytes with elevated levels of ABCG1 in CR as compared to AL mice...

Adipose tissue signaling by nuclear receptors in metabolic complications of obesity

Jacobi, David; Stanya, Kristopher; Lee, Chih-Hao
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em 01/01/2012 EN
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In recent years white adipose tissue inflammation has been recognized to be associated with obesity. Adipocytes and adipose tissue associated macrophages (ATMs) secrete bioactive molecules, including adipokines, chemokines/cytokines and free fatty acids that modulate the development of low-grade inflammation and insulin resistance responsible for obesity-related metabolic and cardiovascular diseases. Nuclear receptors, notably peroxisome-proliferator-activated receptors, are sensors of dietary lipids and control transcriptional programs of key metabolic and inflammatory pathways in adipocytes and macrophages. This review focuses on mechanisms by which nuclear receptors maintain white adipose tissue homeostasis. The identification of ATMs as active players in the initiation of chronic inflammation and the links between inflammatory signaling and metabolic dysfunction will be presented, followed by discussion of recent evidence for nuclear receptors in ATM function, with an emphasis on the paracrine interaction between adipocytes and ATMs.

Release of TGFβig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression

Holmberg, Chris; Quante, Michael; Steele, Islay; Kumar, Jothi Dinesh; Balabanova, Silviya; Duval, Cedric; Czepan, Matyas; Rakonczay, Zoltan; Tiszlavicz, Laszlo; Nemeth, Istvan; Lazar, Gyorgy; Simonka, Zsolt; Jenkins, Rosalind; Hegyi, Peter; Wang, Timothy
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are stromal cells that are often increased in tumors but their contribution to cancer progression is not well understood. Here, we show that the secretomes of myofibroblasts derived from gastric cancers [cancer-associated myofibroblasts (CAMs)] differ in a functionally significant manner from those derived from adjacent tissue [adjacent tissue myofibroblasts (ATMs)]. CAMs showed increased rates of migration and proliferation compared with ATMs or normal tissue myofibroblasts (NTMs). Moreover, conditioned medium (CM) from CAMs significantly stimulated migration, invasion and proliferation of gastric cancer cells compared with CM from ATMs or NTMs. Proteomic analysis of myofibroblast secretomes revealed decreased abundance of the extracellular matrix (ECM) adaptor protein like transforming growth factor-β-induced gene-h3 (TGFβig-h3) in CAMs, which was correlated with lymph node involvement and shorter survival. TGFβig-h3 inhibited IGF-II-stimulated migration and proliferation of both cancer cells and myofibroblasts, and suppressed IGF-II activation of p42/44 MAPkinase; TGFβig-h3 knockdown increased IGF-II- and CM-stimulated migration. Furthermore...

Neuropeptide Y Is Produced by Adipose Tissue Macrophages and Regulates Obesity-Induced Inflammation

Singer, Kanakadurga; Morris, David L.; Oatmen, Kelsie E.; Wang, Tianyi; DelProposto, Jennifer; Mergian, Taleen; Cho, Kae Won; Lumeng, Carey N.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 05/03/2013 EN
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Neuropeptide Y (NPY) is induced in peripheral tissues such as adipose tissue with obesity. The mechanism and function of NPY induction in fat are unclear. Given the evidence that NPY can modulate inflammation, we examined the hypothesis that NPY regulates the function of adipose tissue macrophages (ATMs) in response to dietary obesity in mice. NPY was induced by dietary obesity in the stromal vascular cells of visceral fat depots from mice. Surprisingly, the induction of Npy was limited to purified ATMs from obese mice. Significant basal production of NPY was observed in cultured bone marrow derived macrophage and dendritic cells (DCs) and was increased with LPS stimulation. In vitro, addition of NPY to myeloid cells had minimal effects on their activation profiles. NPY receptor inhibition promoted DC maturation and the production of IL-6 and TNFα suggesting an anti-inflammatory function for NPY signaling in DCs. Consistent with this, NPY injection into lean mice decreased the quantity of M1-like CD11c+ ATMs and suppressed Ly6chi monocytes. BM chimeras generated from Npy−/− donors demonstrated that hematopoietic NPY contributes to the obesity-induced induction of Npy in fat. In addition, loss of Npy expression from hematopoietic cells led to an increase in CD11c+ ATMs in visceral fat with high fat diet feeding. Overall...

Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice

Aouadi, Myriam; Tencerova, Michaela; Vangala, Pranitha; Yawe, Joseph C.; Nicoloro, Sarah M.; Amano, Shinya U.; Cohen, Jessica L.; Czech, Michael P.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
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Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack of methods to ablate inflammatory genes expressed in macrophages specifically localized within AT depots, leaving macrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-α or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistent with the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance.

Interferon Regulatory Factor 4 Regulates Obesity-Induced Inflammation Through Regulation of Adipose Tissue Macrophage Polarization

Eguchi, Jun; Kong, Xingxing; Tenta, Masafumi; Wang, Xun; Kang, Sona; Rosen, Evan D.
Fonte: American Diabetes Association Publicador: American Diabetes Association
Tipo: Artigo de Revista Científica
EN
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Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet–induced obese mice. Irf4−/− macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell–specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4−/− ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity...

Epigenetic Regulation of Macrophage Polarization by DNA Methyltransferase 3b

Yang, Xiaosong; Wang, Xianfeng; Liu, Dongxu; Yu, Liqing; Xue, Bingzhong; Shi, Hang
Fonte: Endocrine Society Publicador: Endocrine Society
Tipo: Artigo de Revista Científica
EN
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Adipose tissue macrophages (ATMs) undergo a phenotypic switch from alternatively activated antiinflammatory M2 macrophages in lean individuals to classically activated proinflammatory M1 macrophages in obese subjects. However, the molecular mechanism underlying this process remains unclear. In this study we aim to determine whether DNA methyltransferase 3b (DNMT3b) regulates macrophage polarization and inflammation. We found that the expression of DNMT3b was significantly induced in macrophages exposed to the saturated fatty acid stearate, was higher in ATMs isolated from obese mice, but was significantly lower in alternatively activated M2 vs classically activated M1 ATMs, suggesting a role for DNMT3b in regulation of macrophage polarization and inflammation in obesity. DNMT3b knockdown promoted macrophage polarization to alternatively activated M2 phenotype and suppressed macrophage inflammation, whereas overexpressing DNMT3b did the opposite. Importantly, in a macrophage-adipocyte coculture system, we found that DNMT3b knockdown significantly improved adipocyte insulin signaling. The promoter of peroxisome proliferator activated receptor (PPAR)γ1, a key transcriptional factor that regulates macrophage polarization, is enriched with CpG sites. Chromatin immunoprecipitation assays showed that DNMT3b bound to the methylation region at PPARγ1 promoter...

CX3CR1 Deficiency Does Not Influence Trafficking of Adipose Tissue Macrophages in Mice With Diet-Induced Obesity

Morris, David L.; Oatmen, Kelsie E.; Wang, Tianyi; DelProposto, Jennifer L.; Lumeng, Carey N.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Adipose tissue macrophages (ATMs) accumulate in fat during obesity and resemble foam cells in atherosclerotic lesions, suggesting that common mechanisms underlie both inflammatory conditions. CX3CR1 and its ligand fractalkine/CX3CL1 contribute to macrophage recruitment and inflammation in atherosclerosis, but their role in obesity-induced adipose tissue inflammation is unknown. Therefore, we tested the hypothesis that CX3CR1 regulates ATM trafficking to epididymal fat and contributes to the development of adipose tissue inflammation during diet-induced obesity. Cx3cl1 and Cx3cr1 expression was induced specifically in epididymal fat from mice fed a high-fat diet (HFD). CX3CR1 was detected on multiple myeloid cells within epididymal fat from obese mice. To test the requirement of CX3CR1 for ATM trafficking and obesity-induced inflammation, Cx3cr1+/GFP and Cx3cr1GFP/GFP mice were fed a HFD. Ly-6cLow monocytes were reduced in lean Cx3cr1GFP/GFP mice; however, HFD-induced monocytosis was comparable between strains. Total ATM content, the ratio of type 1 (CD11c+) to type 2 (CD206+) ATMs, expression of inflammatory markers, and T-cell content were similar in epididymal fat from obese Cx3cr1+/GFP and Cx3cr1GFP/GFP mice. Cx3cr1 deficiency did not prevent the development of obesity-induced insulin resistance or hepatic steatosis. In summary...

An MHC Class II Dependent Activation Loop Between Adipose Tissue Macrophages and CD4+ T cells Controls Obesity-Induced Inflammation

Cho, Kae Won; Morris, David L.; DelProposto, Jennifer L.; Geletka, Lynn; Zamarron, Brian; Martinez-Santibanez, Gabriel; Meyer, Kevin A.; Singer, Kanakadurga; O'Rourke, Robert W.; Lumeng, Carey N.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4+ T cells by unclear mechanisms. We have examined if interactions between adipose tissue macrophages (ATMs) and CD4+ T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHCII) showed protection from diet-induced obesity. Deletion of MHCII expression in macrophages led to an adipose tissue specific decrease in the effector/memory CD4+ T cells, attenuation of CD11c+ ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c+ ATMs in obese mice. These studies demonstrate the importance of MHC Class II restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation.