RESUMO
Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.
Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Febre/induzido quimicamente , Febre/metabolismo , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Caracteres Sexuais , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Criança , Dinoprostona/metabolismo , Feminino , Febre/complicações , Perfilação da Expressão Gênica , Humanos , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/complicações , Pneumonia/metabolismo , Ligante RANK/administração & dosagem , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Ratos , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP3RESUMO
Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.
Assuntos
Anorexia/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Comportamento Alimentar/fisiologia , Histamina/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Anorexia/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Histamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/metabolismo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior.
Assuntos
Proteínas de Ligação ao Cálcio/sangue , Hormônio Liberador da Corticotropina/metabolismo , Proteínas de Ligação a DNA/sangue , Comportamento Alimentar/fisiologia , Histamina/metabolismo , Hipotálamo/citologia , Proteínas do Tecido Nervoso/sangue , Neurônios/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Animais , Proteínas de Ligação ao Cálcio/farmacologia , Hormônio Liberador da Corticotropina/administração & dosagem , Proteínas de Ligação a DNA/farmacologia , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Histamina/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/farmacologia , Neurônios/efeitos dos fármacos , Nucleobindinas , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H1/deficiência , Hormônio Liberador de Tireotropina/farmacologiaRESUMO
BACKGROUND: Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. METHODS: We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. RESULTS: Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. CONCLUSIONS: We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Inflamação/etiologia , Interleucina-10/fisiologia , Obesidade/complicações , Insuficiência Renal Crônica/etiologia , Baço/metabolismo , Esplenectomia , Animais , Determinação da Pressão Arterial , Western Blotting , Proliferação de Células , Citocinas/metabolismo , Feminino , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/patologiaRESUMO
OBJECTIVE: Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process. METHODS: CD4+ T cells, CD14+ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump. RESULTS: Tofacitinib treatment of CD4+ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-γ (IFNγ) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14+ monocytes. However, conditioned medium from CD4+ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14+ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage. CONCLUSION: Tofacitinib directly suppressed the production of IL-17 and IFNγ and the proliferation of CD4+ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14+ cells and decreased cartilage destruction. In CD4+ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Interferon gama/biossíntese , Interleucina-17/biossíntese , Janus Quinase 3/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Membrana Sinovial/efeitos dos fármacos , Sinovite/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Piperidinas , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Sinovite/imunologiaRESUMO
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase-IV (DPP-IV) inhibitor extends the half-life of endogenous GLP-1 by preventing its degradation. This study aimed to determine whether DPP-IV inhibitor-induced elevation of portal GLP-1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP-IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP-1 levels, food intake, and plasma insulin and glucose was examined in sham-operated and vagotomized male Sprague-Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP-IV inhibitor significantly increased portal (but not peripheral) GLP-1 levels, increased insulin levels, and decreased glucose levels. The DPP-IV inhibitor suppressed 1- and 12- but not 24-h cumulative food intake. Intraportal infusion of the DPP-IV inhibitor increased hypothalamic neuronal histamine turnover and increased c-fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP-IV inhibitor-induced changes in portal but not systemic GLP-1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP-IV inhibitor.
Assuntos
Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Ingestão de Alimentos/fisiologia , Insulina/metabolismo , Neurônios Aferentes/metabolismo , Veia Porta/metabolismo , Nervo Vago/metabolismo , Animais , Ingestão de Alimentos/efeitos dos fármacos , Infusões Intravenosas , Secreção de Insulina , Fígado/efeitos dos fármacos , Fígado/inervação , Fígado/metabolismo , Masculino , Neurônios Aferentes/efeitos dos fármacos , Veia Porta/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vagotomia/métodos , Nervo Vago/efeitos dos fármacosRESUMO
Obesity can be associated with systemic low-grade inflammation that contributes to obesity-related metabolic disorders. Recent studies raise the possibility that hypothalamic inflammation contributes to the pathogenesis of diet-induced obesity (DIO), while another study reported that obesity decreases the expression of pro-inflammatory cytokines in spleen. The following study examines the hypothesis that obesity suppresses the splenic synthesis of the anti-inflammatory cytokine, interleukin (IL)-10, thereby resulting in chronic hypothalamic inflammation. The results showed that due to oxidative stress or apoptosis, the synthesis of splenic IL-10 was decreased in DIO when compared with non-obesity rats. Splenectomy (SPX) accelerated DIO-induced inflammatory responses in the hypothalamus. Interestingly, SPX suppressed the DIO-induced increases in food intake and body weight and led to a hypothalamic pro-inflammatory state that was similar to that produced by DIO, indicating that hypothalamic inflammation exerts a dual effect on energy metabolism. These SPX-induced changes were inhibited by the systemic administration of IL-10. Moreover, SPX had no effect on hypothalamic inflammatory responses in IL-10-deficient mice. These data suggest that spleen-derived IL-10 plays an important role in the prevention of hypothalamic inflammation and may be a therapeutic target for the treatment of obesity and hypothalamic inflammation.
Assuntos
Citocinas/metabolismo , Encefalite/tratamento farmacológico , Encefalite/etiologia , Hipotálamo/patologia , Interleucina-10/uso terapêutico , Obesidade/complicações , Aldeídos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Área Sob a Curva , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Citocinas/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/metabolismo , Marcação In Situ das Extremidades Cortadas , Interleucina-10/deficiência , Interleucina-10/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Obesidade/etiologia , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Baço/metabolismo , Esplenectomia/métodos , alfa-MSH/metabolismoRESUMO
Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 µg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 µg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.
Assuntos
Apolipoproteínas A/metabolismo , Colecistocinina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Saciação/efeitos dos fármacos , Animais , Apolipoproteínas A/genética , Duodeno/metabolismo , Ingestão de Alimentos/genética , Comportamento Alimentar/fisiologia , Vesícula Biliar/metabolismo , Masculino , Camundongos , Camundongos Knockout , Gânglio Nodoso/metabolismo , Receptores da Colecistocinina/genética , Receptores da Colecistocinina/metabolismo , Saciação/fisiologiaRESUMO
Visceral fat accumulation has an important role in increasing the morbidity and mortality rates, by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that are associated with increased systolic and diastolic blood pressures have been identified by genome-wide association studies in Caucasian populations. This study investigates whether single nucleotide polymorphisms (SNPs) that confer susceptibility to high blood pressure are also associated with visceral fat obesity. We genotyped 1279 Japanese subjects (556 men and 723 women) who underwent computed tomography for measuring the visceral fat area (VFA) and subcutaneous fat area (SFA) at the following SNPs: FGF5 rs16998073, CACNB2 rs11014166, C10orf107 rs1530440, CYP17A1 rs1004467, NT5C2 rs11191548, PLEKHA7 rs381815, ATP2B1 rs2681472 and rs2681492, ARID3B rs6495112, CSK rs1378942, PLCD3 rs12946454, and ZNF652 rs16948048. In an additive model, risk alleles of the CYP17A1 rs1004467 and NT5C2 rs11191548 were found to be significantly associated with reduced SFA (P=0.00011 and 0.0016, respectively). When the analysis was performed separately in men and women, significant associations of rs1004467 (additive model) and rs11191548 (recessive model) with reduced VFA (P=0.0018 and 0.0022, respectively) and SFA (P=0.00039 and 0.00059, respectively) were observed in women, but not in men. Our results suggest that polymorphisms in the CYP17A1 and NT5C2 genes influence a reduction in both visceral and subcutaneous fat mass in Japanese women.
Assuntos
5'-Nucleotidase/genética , Povo Asiático/genética , Estudos de Associação Genética , Variação Genética , Gordura Intra-Abdominal/enzimologia , Esteroide 17-alfa-Hidroxilase/genética , Gordura Subcutânea/enzimologia , Adiposidade/genética , Pressão Sanguínea/genética , Índice de Massa Corporal , Feminino , Loci Gênicos/genética , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.
Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Gordura Intra-Abdominal/metabolismo , Proteínas/genética , Gordura Subcutânea/metabolismo , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Povo Asiático/genética , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tomógrafos ComputadorizadosRESUMO
BACKGROUND: Cardiac iodine-123 metaiodobenzylguanidine ((123)I-MIBG) scintigraphy is an established method of assessment of cardiovascular sympathetic function. The aim of the present study was to investigate the long-term cardiovascular predictive value of cardiac (123)I-MIBG scintigraphy parameters in Japanese type 2 diabetic patients without structural heart disease. METHODS AND RESULTS: Cardiac (123)I-MIBG scintigraphy in 108 patients with type 2 diabetes who did not have structural heart disease, was evaluated. The washout rate (WR) was considered enhanced if it was ≥40%. Accurate follow-up information for 4.6 years was obtained in 54 enhanced WR patients (27 male; mean age, 61 ± 11 years) and in 54 sex- and age-matched preserved WR patients (27 male; mean age, 61 ± 10 years). Major adverse cardiac and cerebrovascular events (MACCE) were investigated. During follow-up, 10 enhanced WR patients developed MACCE including cardiac death, coronary revascularization, stroke, and congestive heart failure, while MACCE occurred in only 3 male patients. The Kaplan-Meier curves indicated that enhanced WR patients had higher incidence of MACCE than those with preserved WR (P<0.05). Cox proportional hazards regression analysis showed that age and enhanced WR were independently associated with the incidence of MACCE (hazard ratio, 4.06; 95% confidence interval: 1.194-18.76, P = 0.0237). CONCLUSIONS: Abnormal WR of cardiac (123)I-MIBG scintigraphy at baseline has long-term cardiovascular predictive value in Japanese patients with type 2 diabetes without structural heart disease.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Infarto do Miocárdio/diagnóstico por imagem , Cintilografia/estatística & dados numéricos , Acidente Vascular Cerebral/diagnóstico por imagem , 3-Iodobenzilguanidina , Idoso , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Radioisótopos do Iodo , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Revascularização Miocárdica/mortalidade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Cintilografia/métodos , Sensibilidade e Especificidade , Acidente Vascular Cerebral/mortalidadeRESUMO
We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.
Assuntos
Imunoglobulina G/uso terapêutico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Metotrexato/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Doença de Still de Início Tardio/tratamento farmacológico , Adolescente , Sinergismo Farmacológico , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Síndrome de Ativação Macrofágica/imunologia , Síndrome de Ativação Macrofágica/patologia , Indução de Remissão , Doença de Still de Início Tardio/imunologia , Doença de Still de Início Tardio/patologiaRESUMO
Metabolic syndrome is defined as a cluster of multiple risk factors, including central obesity, dyslipidemia, hypertension and impaired glucose tolerance, that increase cardiovascular disease morbidity and mortality. Genetic factors are important in the development of metabolic syndrome, as are environmental factors. However, the genetic background of metabolic syndrome is not yet fully clarified. There is evidence that obesity and obesity-related phenotypes are associated with variations in several genes, including NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, SH2B1, FTO, MAF, MC4R, KCTD15, SCG3, MTMR9, TFAP2B, MSRA, LYPLAL1, GCKR and FADS1. To investigate the relationship between metabolic syndrome and variations in these genes in the Japanese population, we genotyped 33 single-nucleotide polymorphisms (SNPs) in 19 genes from 1096 patients with metabolic syndrome and 581 control individuals who had no risk factors for metabolic syndrome. Four SNPs in the FTO gene were significantly related to metabolic syndrome: rs9939609 (P=0.00013), rs8050136 (P=0.00011), rs1558902 (P=6.6 × 10(-5)) and rs1421085 (P=7.4 × 10(-5)). rs3764220 in the SCG3 gene (P=0.0010) and rs2293855 in the MTMR9 gene (P=0.0015) were also significantly associated with metabolic syndrome. SNPs in the FTO, SCG3 and MTMR9 genes had no SNP × SNP epistatic effects on metabolic syndrome. Our data suggest that genetic variations in the FTO, SCG3 and MTMR9 genes independently influence the risk of metabolic syndrome.
Assuntos
Povo Asiático/genética , Cromograninas/genética , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudos de Casos e Controles , Dessaturase de Ácido Graxo Delta-5 , Diabetes Mellitus/genética , Dislipidemias/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Obesidade/genéticaRESUMO
Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Povo Asiático/genética , Gordura Intra-Abdominal/metabolismo , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Tomografia Computadorizada por Raios X/métodos , Adulto , Distribuição da Gordura Corporal , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Elevated total plasma homocysteine (tHcy) levels are associated with cognitive dysfunction, in which changes in the hippocampus plausibly play a pivotal role. We tested the hypothesis that elevated tHcy levels are correlated with hippocampus volume and insulin resistance in nondementia patients with type 2 diabetes. MATERIALS AND METHODS: The study included 43 nondementia patients with type 2 diabetes, who were divided into two groups: a high tHcy group (age: 65 ± 8 years, mean ± standard deviation, n = 16) and a normal tHcy group (64 ± 9 years, n = 27). Hippocampus volume was quantified with a computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease (VSRAD), which yields a Z-score as the end point for the assessment of hippocampal volume. Results The Z-score was higher in the high tHcy group compared to the normal tHcy group (P < 0·0001). The fasting plasma glucose (P < 0·01) and insulin (P < 0·0001) concentrations and the homoeostasis model assessment (HOMA) index (P < 0·0001) were higher in the high tHcy group than in the normal tHcy group. Multiple regression analysis showed that the main factors that influenced tHcy levels may be the Z-score and the HOMA index. CONCLUSIONS: Our results indicate that the elevated levels of tHcy in Japanese nondementia patients with type 2 diabetes are characterised by hippocampal atrophy and insulin resistance and that the Z-score and HOMA index may be the primary factors that influence tHcy levels.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Hipocampo/patologia , Homocisteína/sangue , Idoso , Mapeamento Encefálico/métodos , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Resistência à Insulina/fisiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
BACKGROUND: Cardiovascular autonomic neuropathy is a major complication in patients with diabetes mellitus (DM), and baroreflex sensitivity (BRS) reportedly can predict cardiovascular prognosis in type 2 DM patients. The hypothesis that cardiovascular events are associated with gender differences in BRS was tested in the present study. METHODS AND RESULTS: From 1998, we have evaluated BRS by phenylephrine methods in 185 consecutive type 2 DM patients. The long-term prognostic value of BRS was compared between 91 female (5812 years) and 94 male patients (5811 years). There was no significant difference in age or severity and duration of DM between the 2 groups. When compared to male, the BRS value in female patients was significantly lower (9.266.0 vs. 5.975.0 ms/mmHg, P < 0.0001). During a mean of 62.7 months of follow-up, 16 female patients developed cardiovascular events (17.6%) including stroke, acute myocardial infarction, angina pectoris requiring percutaneous coronary intervention or coronary artery bypass grafting and congestive heart failure requiring admission, while only 4 male patients developed events (4.3%, P < 0.005). In females, the Kaplan-Meier curves revealed that those with depressed BRS (< 6 ms/mmHg) had a higher incidence of cardiovascular events than those with preserved BRS (P < 0.05), but this relationship was not observed in male patients. CONCLUSIONS: Although the reason why females had a more depressed BRS remains unclear, our findings demonstrated that a depressed BRS value can accurately predict cardiovascular events, especially in female patients with type 2 DM.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo , Transtornos Cerebrovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Cardiopatias/etiologia , Idoso , Análise de Variância , Transtornos Cerebrovasculares/mortalidade , Transtornos Cerebrovasculares/fisiopatologia , Distribuição de Qui-Quadrado , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Neuropatias Diabéticas/mortalidade , Neuropatias Diabéticas/fisiopatologia , Feminino , Cardiopatias/mortalidade , Cardiopatias/fisiopatologia , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de TempoRESUMO
Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu(-/-) mice) develop obesity. Nmu(-/-) mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu(-/-) mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu(-/-) mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity.
Assuntos
Metabolismo Energético/genética , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica , Leptina/metabolismo , Neuropeptídeos/metabolismo , Obesidade/fisiopatologia , Transdução de Sinais/fisiologia , Tecido Adiposo/patologia , Análise de Variância , Animais , Análise Química do Sangue , Northern Blotting , Composição Corporal/genética , Composição Corporal/fisiologia , Regulação da Temperatura Corporal/genética , Peso Corporal/genética , Peso Corporal/fisiologia , Proteínas de Transporte/metabolismo , Metabolismo Energético/fisiologia , Técnicas Histológicas , Hipotálamo/patologia , Imuno-Histoquímica , Hibridização In Situ , Canais Iônicos , Leptina/sangue , Fígado/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Proteínas Mitocondriais , Neuropeptídeos/genética , Obesidade/genética , Proteína Desacopladora 1RESUMO
BACKGROUND: Cardiac autonomic dysfunction is associated with a poor prognosis in patients with heart failure (HF). Systemic inflammation is elevated in patients with HF. We hypothesized that cardiac resynchronization therapy (CRT) improves cardiac sympathetic nervous dysfunction and systemic inflammation. To test our hypothesis, we evaluated cardiac sympathetic activity and serum levels of high sensitive C-reactive protein (hs-CRP) before and after CRT. METHODS: Twenty-seven patients with chronic HF (19 men, eight women; mean age 67 ± 10 years) with nonischemic cardiomyopathy who underwent CRT were evaluated. Each patient was evaluated before and 6 months after CRT. Responders were defined as patients showing ≥15% absolute decrease in left ventricular end-systolic volume. Cardiac sympathetic activity was estimated with cardiac (123) I-metaiodobenzylguanidine (MIBG) scintigrams. RESULTS: Patients were categorized as responders (n = 19) and nonresponders (n = 8) according to echocardiographic findings. In responders, the mean heart-to-mediastinum (H/M) ratio at the delayed phase in cardiac (123) I-MIBG scintigraphic findings was significantly increased (P<0.05) and serum levels of hs-CRP were decreased (P <0.01). Such improvements were not observed in nonresponders. Stepwise multiple regression analysis showed that the reduction in hs-CRP level was independently associated with the increase in the H/M ratio at delayed phase. CONCLUSIONS: Our results demonstrated that cardiac sympathetic nervous dysfunction and systemic inflammation were improved in responder HF patients to CRT. Furthermore, the reduction in systemic inflammation was associated with the improvement in cardiac sympathetic nervous dysfunction.
Assuntos
Proteína C-Reativa/metabolismo , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/terapia , Coração/inervação , Sistema Nervoso Simpático/fisiopatologia , Idoso , Doença Crônica , Feminino , Coração/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Resultado do Tratamento , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapiaRESUMO
Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.
Assuntos
Regulação do Apetite/fisiologia , Peso Corporal , Grelina/metabolismo , Grelina/fisiologia , Intestino Delgado/metabolismo , Parabiose , Animais , Regulação do Apetite/genética , Peso Corporal/genética , Peso Corporal/fisiologia , Comportamento Alimentar/fisiologia , Mucosa Gástrica/metabolismo , Grelina/genética , Mucosa Intestinal/metabolismo , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Intestinos/patologia , Intestinos/cirurgia , Masculino , Modelos Biológicos , Ratos , Ratos Endogâmicos Lew , Estômago/fisiologiaRESUMO
It has been demonstrated the involvement of branched-chain amino acids (BCAA) on obesity and related metabolic disorder. We investigated the effects of branched-chain amino acids (BCAA) on obesity and on glucose/fat homeostasis in mice fed on a high-fat (45%) diet. BCAA was dissolved in 0.5% methylcellulose and added to the drinking water (BCAA-treated group). A high-fat diet was provided for 6 weeks and BCAA was given for 2 weeks. The BCAA-treated group gained almost 7% less body weight and had less epididymal adipose tissue (WAT) mass than the control group (p<0.05). BCAA supplementation also reduced the hepatic and skeletal muscle triglyceride (TG) concentrations (p<0.05). The hepatic levels of PPAR-alpha and uncoupling protein (UCP) 2, and the level of PPAR-alpha and UCP3 in the skeletal muscle were greater in the BCAA-treated group than in the control mice (p<0.05). These results demonstrate that the liver and muscle TG concentration are less in BCAA-treated group. BCAA affects PPAR-alpha and UCP expression in muscle and liver tissue.