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1.
Science ; 368(6490)2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355002

RESUMO

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.


Assuntos
Adaptação Fisiológica/imunologia , Glicogênio/metabolismo , Interleucina-13/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Resistência Física/imunologia , Animais , Glicemia/metabolismo , Linhagem Celular , Ácidos Graxos/metabolismo , Feminino , Humanos , Interleucina-13/sangue , Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mioblastos/metabolismo , Oxirredução , Condicionamento Físico Animal , Corrida , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
2.
Food Microbiol ; 69: 170-178, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28941898

RESUMO

A collaborative validation study was performed to evaluate the performance of a new U.S. Food and Drug Administration method developed for detection of the protozoan parasite, Cyclospora cayetanensis, on cilantro and raspberries. The method includes a sample preparation step in which oocysts are recovered from produce using an enhanced produce washing solution containing 0.1% Alconox and a commercially available method to disrupt the C. cayetanensis oocysts and extract DNA. A real-time PCR assay targeting the C. cayetanensis 18S rDNA gene with an internal amplification control to monitor PCR inhibition provides species-specific identification. Five laboratories blindly analyzed a total of 319 samples consisting of 25 g of cilantro or 50 g of raspberries which were either uninoculated or artificially contaminated with C. cayetanensis oocysts. Detection rates for cilantro inoculated with 200, 10, and 5 oocysts, were 100%, 80%, and 31%, respectively. For raspberries, the detection rates for samples inoculated with 200, 10, and 5 oocysts were 100%, 90% and 50%, respectively. All uninoculated samples, DNA blank extracts, and no-template PCR controls were negative. Reproducibility between laboratories and analysts was high and the method was shown to be an effective analytical tool for detection of C. cayetanensis in produce.


Assuntos
Coriandrum/parasitologia , Cyclospora/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Rubus/parasitologia , Cyclospora/genética , DNA Ribossômico/genética , Contaminação de Alimentos/análise , Reprodutibilidade dos Testes , Estados Unidos , United States Food and Drug Administration
3.
Mol Metab ; 6(10): 1186-1197, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29031719

RESUMO

OBJECTIVE: Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS: We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and ß-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS: Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Pparδ/γ-/- macrophages. In concert, ß-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ-/- or Stat6-/- mice. CONCLUSIONS: Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.


Assuntos
Tecido Adiposo Branco/metabolismo , Ativação de Macrófagos/fisiologia , Macrófagos/fisiologia , Tecido Adiposo Branco/patologia , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Homeostase , Inflamação/metabolismo , Inflamação/patologia , Interleucina-4/metabolismo , Metabolismo dos Lipídeos , Lipólise/fisiologia , Lipopolissacarídeos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR delta/agonistas , PPAR delta/genética , PPAR gama/agonistas , PPAR gama/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Transcriptoma
4.
Nature ; 502(7472): 550-4, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24153306

RESUMO

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/ß and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.


Assuntos
Ritmo Circadiano , Ácidos Graxos/metabolismo , Lipídeos/sangue , Lipogênese , Fígado/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Diabetes Mellitus/metabolismo , Regulação da Expressão Gênica , Homeostase , Lipogênese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , Obesidade/metabolismo , PPAR delta/metabolismo , Fosfatidilcolinas/sangue , Análise de Componente Principal
5.
J Clin Invest ; 123(1): 261-71, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23257358

RESUMO

Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.


Assuntos
Glucose/metabolismo , Interleucina-13/metabolismo , Fígado/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Gluconeogênese/genética , Gluconeogênese/imunologia , Glucose/genética , Glucose/imunologia , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Interleucina-13/genética , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
6.
Nat Med ; 18(11): 1665-72, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23104131

RESUMO

Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto-N-fucopentaose III (LNFPIII), a Lewis(X)-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-α, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases.


Assuntos
Tecido Adiposo , Amino Açúcares , Inflamação , Redes e Vias Metabólicas , Polissacarídeos , Receptores Citoplasmáticos e Nucleares , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/patologia , Amino Açúcares/administração & dosagem , Amino Açúcares/imunologia , Amino Açúcares/metabolismo , Animais , Células Dendríticas/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/terapia , Dieta Hiperlipídica , Fígado Gorduroso/imunologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/terapia , Células Hep G2 , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Resistência à Insulina/imunologia , Interleucina-10/metabolismo , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Redes e Vias Metabólicas/imunologia , Camundongos , Camundongos Obesos/imunologia , Camundongos Obesos/metabolismo , Polissacarídeos/administração & dosagem , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Receptores Citoplasmáticos e Nucleares/imunologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais
7.
Adipocyte ; 1(1): 4-12, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22916336

RESUMO

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.

8.
Hum Mol Genet ; 19(13): 2706-15, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20418489

RESUMO

To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10,870 cases and 73,735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR=0.90, 95% CI=0.86-0.93; P=3.7x10(-8)). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P<0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance.


Assuntos
Cromossomos Humanos Par 2 , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Glucose/metabolismo , Humanos , Resistência à Insulina/genética , Cadeias beta de Integrinas/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética
9.
Cell Div ; 4: 7, 2009 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-19383165

RESUMO

Corepressors are large proteins that facilitate transcriptional repression through recruitment of histone-modifying enzymes. Two major corepressors, SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor), have been shown to mediate repression associated with nuclear receptors and a myriad of other transcription factors. This review will focus on recent studies on these proteins, including newly discovered physiological roles of the corepressors, their modes of regulation, their roles in antiestrogen-resistant breast cancer and their functions during the cell cycle.

10.
J Cell Biol ; 183(1): 49-61, 2008 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-18838553

RESUMO

Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.


Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Peptidilprolil Isomerase/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/fisiologia , Animais , Benzotiazóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Quinase 2 Dependente de Ciclina/genética , Ciclinas/metabolismo , Proteínas de Ligação a DNA/genética , Expressão Gênica/efeitos dos fármacos , Genes myc/genética , Humanos , Camundongos , Modelos Biológicos , Mutação , Peptidilprolil Isomerase de Interação com NIMA , Neuregulina-1/farmacologia , Correpressor 2 de Receptor Nuclear , Fragmentos de Peptídeos/metabolismo , Peptidilprolil Isomerase/genética , Fosforilação , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/agonistas , Receptor ErbB-2/antagonistas & inibidores , Receptores de Progesterona/genética , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Técnicas do Sistema de Duplo-Híbrido , Tirfostinas/farmacologia
11.
Mol Cell Biol ; 28(18): 5658-67, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18625722

RESUMO

Promyelocytic leukemia protein (PML) sumoylation has been proposed to control the formation of PML nuclear bodies (NBs) and is crucial for PML-dependent cellular processes, including apoptosis and transcriptional regulation. However, the regulatory mechanisms of PML sumoylation and its specific roles in the formation of PML NBs remain largely unknown. Here, we show that histone deacetylase 7 (HDAC7) knockdown reduces the size and the number of the PML NBs in human umbilical vein endothelial cells (HUVECs). HDAC7 coexpression stimulates PML sumoylation independent of its HDAC activity. Furthermore, HDAC7 associates with the E2 SUMO ligase, Ubc9, and stimulates PML sumoylation in vitro, suggesting that it possesses a SUMO E3 ligase-like activity to promote PML sumoylation. Importantly, HDAC7 knockdown inhibits tumor necrosis factor alpha-induced PML sumoylation and the formation of PML NBs in HUVECs. These results demonstrate a novel function of HDAC7 and provide a regulatory mechanism of PML sumoylation.


Assuntos
Histona Desacetilases/metabolismo , Corpos de Inclusão Intranuclear/metabolismo , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células HeLa , Histona Desacetilases/genética , Humanos , Proteínas Nucleares/genética , Proteína da Leucemia Promielocítica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Supressoras de Tumor/genética , Veias Umbilicais/citologia
12.
Mol Cell Biol ; 28(3): 997-1006, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18039859

RESUMO

Promyelocytic leukemia protein (PML) is an important regulator due to its role in numerous cellular processes including apoptosis, viral infection, senescence, DNA damage repair, and cell cycle regulation. Despite the role of PML in many cellular functions, little is known about the regulation of PML itself. We show that PML stability is regulated through interaction with the peptidyl-prolyl cis-trans isomerase Pin1. This interaction is mediated through four serine-proline motifs in the C terminus of PML. Binding to Pin1 results in degradation of PML in a phosphorylation-dependent manner. Furthermore, our data indicate that sumoylation of PML blocks the interaction, thus preventing degradation of PML by this pathway. Functionally, we show that in the MDA-MB-231 breast cancer cell line modulating levels of Pin1 affects steady-state levels of PML. Furthermore, degradation of PML due to Pin1 acts both to protect these cells from hydrogen peroxide-induced death and to increase the rate of proliferation. Taken together, our work defines a novel mechanism by which sumoylation of PML prevents Pin1-dependent degradation. This interaction likely occurs in numerous cell lines and may be a pathway for oncogenic transformation.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Peptidilprolil Isomerase/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Motivos de Aminoácidos , Neoplasias da Mama/etiologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Fenótipo , Proteína da Leucemia Promielocítica , Ligação Proteica , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
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