RESUMEN

Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL-6), IL-1ß, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IκBα degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation.

Asunto(s)

Hemo-Oxigenasa 1/metabolismo , Hipotálamo/patología , Inflamación/inducido químicamente , Proteínas de la Membrana/metabolismo , Microglía/efectos de los fármacos , Obesidad/complicaciones , Quercetina/farmacología , Animales , Técnicas de Cultivo de Célula , Línea Celular , Medios de Cultivo Condicionados , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Inflamación/tratamiento farmacológico , Masculino , Proteínas de la Membrana/genética , Ratones , Obesidad/inducido químicamente , Distribución Aleatoria

RESUMEN

BACKGROUND: Obesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism. METHODS: Male C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting. RESULTS: Quercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2. CONCLUSION: These findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

RESUMEN

Obesity-induced inflammation is characterized by recruitment of adipose tissue macrophages that release inflammatory cytokines and chemokines. MIP-1α (macrophage inflammatory protein 1α)/CCL3, a CC chemokine, induces monocyte/macrophage infiltration and thus is implicated in obesity-induced adipose inflammation. Quercetin has been shown to modulate obesity-induced inflammation, but the mechanism of its action remains unclear. Here we demonstrate that quercetin decreases MIP-1α release from adipocytes and macrophages and from cocultured adipocytes/macrophages; it also opposes MIP-1α-induced macrophage infiltration and activation. The inhibitory action of quercetin on the MIP-1α-induced inflammatory responses of macrophages is mediated by downregulation of CCR1/CCR5, and inhibition of activation of JNK, p38 mitogen-activated-protein kinase (MAPK), and IKK as well as IκBα degradation. These findings suggest that quercetin may be a useful agent against obesity-induced adipose tissue inflammation.

Asunto(s)

Tejido Adiposo , Quimiocina CCL3/antagonistas & inhibidores , Inflamación/prevención & control , Quercetina/farmacología , Receptores CCR/genética , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo/química , Animales , Línea Celular , Quimiocina CCL3/genética , Quimiocina CCL3/fisiología , Quimiotaxis/efectos de los fármacos , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Regulación hacia Abajo/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Inflamación/etiología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Obesidad/complicaciones , ARN Mensajero/análisis , Receptores CCR1/genética , Receptores CCR5/genética , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos

RESUMEN

Skeletal muscle inflammation and atrophy are closely associated with metabolic impairment such as insulin resistance. Quercetin, a natural polyphenol flavonoid, is known to elicit anti-inflammatory and antioxidant activities. In this study, we investigated its effect on obesity-induced skeletal muscle inflammation and atrophy in mice. Male C57BL/6 mice were fed a regular diet, a high-fat diet (HFD), and an HFD supplemented with quercetin for nine weeks. Quercetin reduced levels of inflammatory cytokines and macrophage accumulation in the skeletal muscle of the HFD-fed obese mice. It also reduced transcript and protein levels of the specific atrophic factors, Atrogin-1 and MuRF1, in the skeletal muscle of the HFD-fed obese mice, and protected against the reduction of muscle mass and muscle fiber size. In vitro, quercetin markedly diminished transcript levels of inflammatory receptors and activation of their signaling molecules (ERK, p38 MAPK, and NF-κB) in cocultured myotubes/macrophages, and this was accompanied by reduced expression of the atrophic factors. Together, these findings suggest that quercetin reduces obesity-induced skeletal muscle atrophy by inhibiting inflammatory receptors and their signaling pathway. Quercetin may be useful for preventing obesity-induced muscle inflammation and sarcopenia.

Asunto(s)

Antioxidantes/química , Atrofia/patología , Inflamación/patología , Músculo Esquelético/patología , Obesidad/complicaciones , Quercetina/química , Animales , Secuencia de Bases , Línea Celular , Citocinas/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas Ligasas SKP Cullina F-box/metabolismo , Sarcopenia/metabolismo , Transducción de Señal , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/metabolismo

RESUMEN

Metabolic dysregulation (e.g., hyperglycemia, hyperinsulinemia, hyperlipidemia, etc.) is a hallmark of obesity-related diseases such as insulin resistance, type 2 diabetes, and fatty liver disease. In this study, we assessed whether dietary capsaicin attenuated the metabolic dysregulation in genetically obese diabetic KKAy mice, which have severe diabetic phenotypes. Male KKAy mice fed a high-fat diet for 2 weeks received a 0.015% capsaicin supplement for a further 3 weeks and were compared with nonsupplemented controls. Dietary capsaicin markedly decreased fasting glucose/insulin and triglyceride levels in the plasma and/or liver, as well as expression of inflammatory adipocytokine genes (e.g., monocyte chemoattractant protein-1 and interleukin-6) and macrophage infiltration. At the same time expression of the adiponectin gene/protein and its receptor, AdipoR2, increased in adipose tissue and/or plasma, accompanied by increased activation of hepatic AMP-activated protein kinase, a marker of fatty acid oxidation. These findings suggest that dietary capsaicin reduces metabolic dysregulation in obese/diabetic KKAy mice by enhancing expression of adiponectin and its receptor. Capsaicin may be useful as a dietary factor for reducing obesity-related metabolic dysregulation.

Asunto(s)

Adiponectina/metabolismo , Capsaicina/uso terapéutico , Capsicum/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Adipoquinas/metabolismo , Adiponectina/genética , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Capsaicina/farmacología , Diabetes Mellitus Experimental/metabolismo , Suplementos Dietéticos , Insulina/sangre , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Obesos , Obesidad/metabolismo , Extractos Vegetales/farmacología , Receptores de Adiponectina/metabolismo , Triglicéridos/metabolismo

RESUMEN

Human monocytes and neutrophils play major roles in clearing bacteria from human blood and tissues. We found that the herpes virus entry mediator (HVEM) was highly expressed in monocytes and neutrophils, and its interaction with "homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM/tumor necrosis factor (TNF)-related 2" (LIGHT) enhanced bactericidal activity against Listeria monocytogenes and Staphylococcus aureus. The LIGHT-HVEM interaction increased levels of phagocytosis, interleukin (IL)-8, TNF-alpha, nitric oxide (NO), and reactive oxygen species (ROS) in monocytes and neutrophils. Anti-HVEM monoclonal antibody was able to block LIGHT-induced bactericidal activity, cytokine production (IL-8 and TNF-alpha), and ROS generation. Moreover, inhibition of ROS and NO production blocked LIGHT-induced bactericidal activity. Our results indicate that the LIGHT/HVEM interaction in monocytes and neutrophils contributes to antibacterial activity.

Asunto(s)

Linfotoxina-alfa/farmacología , Proteínas de la Membrana/fisiología , Monocitos/inmunología , Neutrófilos/inmunología , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores Virales/inmunología , Factor 2 Asociado a Receptor de TNF/farmacología , Factor de Necrosis Tumoral alfa/fisiología , Proteínas del Envoltorio Viral/farmacología , Anticuerpos Monoclonales/farmacología , Humanos , Interleucina-8/biosíntesis , Listeria monocytogenes/efectos de los fármacos , Listeria monocytogenes/inmunología , Linfotoxina-alfa/antagonistas & inhibidores , Linfotoxina-alfa/inmunología , Monocitos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Fagocitosis/efectos de los fármacos , Fagocitosis/inmunología , Especies Reactivas de Oxígeno/inmunología , Receptores del Factor de Necrosis Tumoral/antagonistas & inhibidores , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Receptores Virales/antagonistas & inhibidores , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/inmunología , Factor 2 Asociado a Receptor de TNF/antagonistas & inhibidores , Factor 2 Asociado a Receptor de TNF/inmunología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas del Envoltorio Viral/inmunología

RESUMEN

We have employed an estrogen receptor dependent transcriptional expression assay and E-Screen assay systems to evaluate the estrogenicity of various heavy metals and their species. Using the former, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>barium chloride=chromium chloride>lithium hydroxide>sodium selenate=lead acetate>stannous chloride. Using the latter, the following estrogenicity ranking was measured: bis(tri-n-butyltin)>cadmium chloride>antimony chloride>lithium hydroxide>barium chloride>sodium selenate>chromium chloride. Especially, bis(tri-n-butyltin), cadmium chloride, antimony chloride, lithium hydroxide, barium chloride, and chromium chloride showed estrogenicity in both assay systems. Recent studies suggesting that bis(tri-n-butyltin), cadmium chloride, and lithium hydroxide have estrogenicities are compatible with the present findings. Furthermore, our studies are the first to suggest that antimony, barium, chromium may be estrogenic. A range of estrogenicity was observed for different species of the same heavy metal. The results demonstrate that an estrogen receptor dependent transcriptional expression assay and the E-Screen assay systems could serve as a useful method to assess the estrogenicity of heavy metals.

Asunto(s)

Contaminantes Ambientales/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Metales Pesados/efectos adversos , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/efectos de los fármacos , Bioensayo , Neoplasias de la Mama/patología , Genes Reporteros , Humanos , Luciferasas/farmacología , Valores de Referencia , Células Tumorales Cultivadas

RESUMEN

Capsaicin, a major ingredient of hot pepper, was considered to exhibit an anti-inflammatory property. In order to clarify the signalling mechanism underlying the anti-inflammatory action of capsaicin, we investigated the effect of capsaicin on the production of inflammatory molecules in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The level of PGE2 was measured by EIA. The expression levels of COX-2, iNOS, IkB-a, and vanilloid receptor-1 (VR-1) were determined at the protein and mRNA levels. Significant inhibition of the production of LPS-induced PGE2 by capsaicin was observed in a dose-dependent manner. Capsaicin did not affect the COX-2 expression at either the protein or mRNA level, but inhibited the enzyme activity of COX-2 and the expression of the iNOS protein. Capsaicin completely blocked LPS-induced disappearance of IkB-a and therefore inactivated NF-kB. The inhibitory action of capsaicin on PGE2 production was not abolished by capsazepine, a specific antagonist to VR-1. A high expression level of the VR-1 like protein (VRL-1) was observed in peritoneal macrophages, while the expression of VR-1 was not detected. These findings suggest that the anti-inflammatory action of capsaicin may occur through a novel mechanism, not by a VR-1 receptor-mediated one. Both capsaicin and capsazepine may be a promising drug candidates for ameliorating inflammatory diseases and cancer.

Asunto(s)

Capsaicina/farmacología , Proteínas I-kappa B/metabolismo , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Animales , Antiinflamatorios/farmacología , Ciclooxigenasa 2 , Dinoprostona/metabolismo , Activación Enzimática/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Isoenzimas/genética , Isoenzimas/metabolismo , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/análisis , Receptores de Droga/genética , Receptores de Droga/metabolismo , Canales Catiónicos TRPV