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1.
Mamm Genome ; 25(11-12): 549-63, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25001233

RESUMEN

Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure, and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance, and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition, and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.


Asunto(s)
Aterosclerosis/genética , Metabolismo Energético/genética , Obesidad/genética , Animales , Composición Corporal , Peso Corporal , Cromosomas de los Mamíferos/genética , Dieta Alta en Grasa/efectos adversos , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Masculino , Ratones Endogámicos C57BL , Fenotipo , Sitios de Carácter Cuantitativo
2.
Exerc Immunol Rev ; 18: 158-76, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22876727

RESUMEN

Regular exercise and physical activity provide many health benefits and are encouraged by medical professionals for the primary prevention of and adjuvant treatment of breast cancer Current consensus in the discipline of exercise oncology is that both regular physical activity and exercise training exert some protective effect against breast cancer risk, and may reduce morbidity in some advanced cases. While there is growing interest in the role of exercise and physical activity in breast cancer prevention, it is currently unclear how exercise may modulate tumor behavior. The tumor microenvironment is populated by stromal cells such as fibroblasts and adipocytes, as well as macrophages. Termed tumor-associated macrophages (TAMs), these immune cells are highly plastic and respond to different signals from the cancer microenvironment, causing them to either display tumor-promoting or tumor-suppressing phenotypes. Because of such plasticity, there has been considerable interest by immunologists to develop immunotherapies based on skewing the behavior of TAMs to become cancer-suppressive. Previous studies have indirectly shown the ability of exercise training to induce an anti-tumor effect of macrophages, although the studies did not address this in the tumor microenvironment. Nevertheless, this opens up the possibility that regular exercise training may exert a protective innate immune effect against breast cancer, potentially by inducing a cancer-suppressing phenotype of TAMs. This review will describe potential mechanisms through which exercise may modulate the behavior of TAMs.


Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/prevención & control , Ejercicio Físico/fisiología , Macrófagos/inmunología , Microambiente Tumoral/inmunología , Femenino , Humanos , Inmunidad Innata , Macrófagos/patología
3.
J Autoimmun ; 34(2): 96-104, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19664906

RESUMEN

We developed a panel of non-obese diabetic (NOD) mice deficient in major lysosomal cysteine proteases (cathepsins S, L and B) to identify protease enzymes essential for autoimmune diabetes. Null alleles for cathepsins (Cts) S, L or B were introgressed onto the NOD genetic background with 19 Idd markers at homozygosity. Diabetes onset was determined among females aged up to 6 months. We evaluated insulitis and sialadenitis in tissues using histology and computer assisted morphology. NOD mice deficient in Ctss or Ctsb were partially protected from diabetes with incidence at 33% and 28%, respectively, versus wild-type NOD (69%; p < 0.00001). NODs lacking cathepsin L (Ctsl-/-) are completely protected from IDDM, as originally shown by others. Ctsl, Ctss, or Ctsb heterozygous mice were able to develop IDDM, although incidence levels were significantly lower for Ctsb+/- (50%) and Ctsl+/- (55%) as compared to NODs (69%; p < 0.03). Ctsl-/- mice contain functional, diabetogenic T cells and an enriched Foxp3+ regulatory T cell population, and diabetes resistance was due to the presence of an expanded population of regulatory T cells. These data provide additional information about the potency of the diabetogenic T cell population in Ctsl-/- mice which were comparable in potency to wild-type NOD mice. These data illustrate the critical contribution of each of these proteases in determining IDDM in the NOD mouse and provide a useful set of models for further studies.


Asunto(s)
Catepsina B/metabolismo , Catepsina L/metabolismo , Catepsinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Edad de Inicio , Animales , Antígenos CD4/biosíntesis , Catepsina B/genética , Catepsina B/inmunología , Catepsina L/genética , Catepsina L/inmunología , Catepsinas/genética , Catepsinas/inmunología , Movimiento Celular/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Factores de Transcripción Forkhead/biosíntesis , Linfopenia , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Pancreatitis , Sialadenitis , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/patología
4.
Arterioscler Thromb Vasc Biol ; 28(4): 685-91, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18239153

RESUMEN

OBJECTIVE: Chronic systemic inflammation accompanies obesity and predicts development of cardiovascular disease. Dietary cholesterol has been shown to increase inflammation and atherosclerosis in LDL receptor-deficient (LDLR(-/-)) mice. This study was undertaken to determine whether dietary cholesterol and obesity have additive effects on inflammation and atherosclerosis. METHODS AND RESULTS: LDLR(-/-) mice were fed chow, high-fat, high-carbohydrate (diabetogenic) diets without (DD) or with added cholesterol (DDC) for 24 weeks. Effects on adipose tissue, inflammatory markers, and atherosclerosis were studied. Despite similar weight gain between DD and DDC groups, addition of dietary cholesterol increased insulin resistance relative to DD. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were observed in intraabdominal adipose tissue in DD and DDC, but were significantly higher in the DDC group. Circulating levels of the inflammatory protein serum amyloid A (SAA) were 4.4-fold higher in DD animals and 15-fold higher in DDC animals than controls, suggesting chronic systemic inflammation. Hepatic SAA mRNA levels were similarly elevated. Atherosclerosis was increased in the DD-fed animals and further increased in the DDC group. CONCLUSIONS: Obesity-induced macrophage accumulation in adipose tissue is exacerbated by dietary cholesterol. These local inflammatory changes in adipose tissue are associated with insulin resistance, systemic inflammation, and increased atherosclerosis in this mouse model.


Asunto(s)
Aterosclerosis/etiología , Colesterol en la Dieta/efectos adversos , Macrófagos/patología , Obesidad/complicaciones , Receptores de LDL/deficiencia , Grasa Abdominal/metabolismo , Grasa Abdominal/patología , Adipocitos/patología , Animales , Aterosclerosis/metabolismo , Secuencia de Bases , Colesterol en la Dieta/administración & dosificación , Cartilla de ADN/genética , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Obesidad/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de LDL/genética , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/metabolismo
5.
Arterioscler Thromb Vasc Biol ; 28(11): 1982-8, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18772497

RESUMEN

OBJECTIVE: Obesity causes inflammation and insulin resistance in the vasculature as well as in tissues involved in glucose metabolism such as liver, muscle, and adipose tissue. To investigate the relative susceptibility of vascular tissue to these effects, we determined the time course over which inflammation and insulin resistance develops in various tissues of mice with diet-induced obesity (DIO) and compared these tissue-based responses to changes in circulating inflammatory markers. METHODS AND RESULTS: Adult male C57BL/6 mice were fed either a control low-fat diet (LF; 10% saturated fat) or a high-fat diet (HF, 60% saturated fat) for durations ranging between 1 to 14 weeks. Cellular inflammation and insulin resistance were assessed by measuring phospho-IkappaBalpha and insulin-induced phosphorylation of Akt, respectively, in extracts of thoracic aorta, liver, skeletal muscle, and visceral fat. As expected, HF feeding induced rapid increases of body weight, fat mass, and fasting insulin levels compared to controls, each of which achieved statistical significance within 4 weeks. Whereas plasma markers of inflammation became elevated relatively late in the course of DIO (eg, serum amyloid A [SAA], by Week 14), levels of phospho-IkappaBalpha in aortic lysates were elevated by 2-fold within the first week. The early onset of vascular inflammation was accompanied by biochemical evidence of both endothelial dysfunction (reduced nitric oxide production; induction of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) and insulin resistance (impaired insulin-induced phosphorylation of Akt and eNOS). Although inflammation and insulin resistance were also detected in skeletal muscle and liver of HF-fed animals, these responses were observed much later (between 4 and 8 weeks of HF feeding), and they were not detected in visceral adipose tissue until 14 weeks. CONCLUSIONS: During obesity induced by HF feeding, inflammation and insulin resistance develop in the vasculature well before these responses are detected in muscle, liver, or adipose tissue. This observation suggests that the vasculature is more susceptible than other tissues to the deleterious effects of nutrient overload.


Asunto(s)
Endotelio Vascular/metabolismo , Glucosa/metabolismo , Inflamación/etiología , Resistencia a la Insulina , Óxido Nítrico/metabolismo , Obesidad/complicaciones , Enfermedades Vasculares/etiología , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Adiposidad , Animales , Peso Corporal , Grasas de la Dieta , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endotelio Vascular/fisiopatología , Quinasa I-kappa B/metabolismo , Inflamación/metabolismo , Inflamación/fisiopatología , Mediadores de Inflamación/sangre , Insulina/metabolismo , Hígado/metabolismo , Hígado/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Fosforilación , Transducción de Señal , Factores de Tiempo , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/fisiopatología
6.
Immunology ; 123(4): 547-54, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18005036

RESUMEN

Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne.


Asunto(s)
Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales/uso terapéutico , Diabetes Mellitus Tipo 1/prevención & control , Glutamato Descarboxilasa/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Unión Competitiva , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Epítopos/inmunología , Femenino , Inmunoglobulina G/sangre , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos NOD , Datos de Secuencia Molecular , Alineación de Secuencia , Índice de Severidad de la Enfermedad , Pérdida de Peso
7.
Am J Clin Nutr ; 86(5): 1445-55, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17991658

RESUMEN

BACKGROUND: The link between poor nutritional status and impaired immune function is well established; however, most studies have focused on individual nutrients instead of overall dietary patterns. OBJECTIVE: Our objective was to investigate associations between 3 indexes of overall diet quality [the Diet Quality Index (DQI), the DQI including supplementary calcium (DQI-Ca), and the Healthy Eating Index (HEI)] and biomarkers of inflammation and immunity. DESIGN: This cross-sectional study included 110 overweight or obese postmenopausal women. Dietary intake measured by food-frequency questionnaire was used to calculate diet quality scores. C-reactive protein (CRP) and serum amyloid A (SAA) were measured by latex-enhanced nephelometry. Flow cytometry was used to measure natural killer (NK) cell cytotoxicity and to enumerate and phenotype lymphocyte subsets. T lymphocyte proliferation was assessed by (3)H-thymidine incorporation as well as by the carboxyfluorescein-succinimidyl ester method of cell division tracking. Multivariable-adjusted linear regression analysis was used to investigate associations between diet quality scores and markers of inflammation and immune function. RESULTS: Higher diet quality was associated with increased proportions of cytotoxic and decreased proportions of helper T lymphocytes. CRP and SAA concentrations were higher among women with a lower-quality diet; these associations became nonsignificant after adjustment for body mass index or percentage body fat. We observed limited evidence for an association between healthy eating patterns and greater lymphocyte proliferation and no evidence for an association with NK cell cytotoxicity. CONCLUSION: Our results provide limited evidence that healthy eating patterns contribute to enhanced immune function and reduced inflammation in overweight and obese postmenopausal women.


Asunto(s)
Dieta , Inmunidad , Inflamación/prevención & control , Obesidad/inmunología , Sobrepeso/inmunología , Posmenopausia/inmunología , Anciano , Proteína C-Reactiva/análisis , Estudios Transversales , Femenino , Humanos , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Recuento de Linfocitos , Persona de Mediana Edad , Proteína Amiloide A Sérica/análisis
8.
Arterioscler Thromb Vasc Biol ; 26(9): 2117-24, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16840715

RESUMEN

OBJECTIVE: Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice. METHODS AND RESULTS: Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. CONCLUSIONS: OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.


Asunto(s)
Envejecimiento , Aterosclerosis/metabolismo , Aterosclerosis/patología , Calcinosis/metabolismo , Calcinosis/patología , Glicoproteínas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Tronco Braquiocefálico/metabolismo , Tronco Braquiocefálico/patología , Calcinosis/prevención & control , Calcio/metabolismo , Proteínas Portadoras/metabolismo , Supervivencia Celular , Progresión de la Enfermedad , Femenino , Glicoproteínas/sangre , Glicoproteínas/genética , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados/genética , Miocitos del Músculo Liso/metabolismo , Osteoprotegerina , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B , Receptores Citoplasmáticos y Nucleares/sangre , Receptores Citoplasmáticos y Nucleares/genética , Receptores del Factor de Necrosis Tumoral/sangre , Receptores del Factor de Necrosis Tumoral/genética
9.
Arterioscler Thromb Vasc Biol ; 25(7): 1420-5, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15845913

RESUMEN

OBJECTIVE: Advanced atherosclerotic lesions in the innominate arteries of chow-fed apolipoprotein E-deficient mice become highly calcified with 100% frequency by 75 weeks of age. The time course, cell types, and mechanism(s) associated with calcification were investigated. METHODS AND RESULTS: The deposition of hydroxyapatite is preceded by the formation of fibro-fatty nodules that are populated by cells that morphologically resemble chondrocytes. These cells are spatially associated with small deposits of hydroxyapatite in animals between 45 and 60 weeks of age. Immunocytochemical analyses with antibodies recognizing known chondrocyte proteins show that these cells express the same proteins as chondrocytes within developing bone. Histological and electron microscopic analyses of lesions from animals between 45 and 60 weeks of age show that the chondrocyte-like cells are surrounded by dense connective tissue that stains positive for type II collagen. Nanocrystals of hydroxyapatite can be seen within matrix vesicles derived from the chondrocyte-like cells. In mice between 75 and 104 weeks of age, the lesions have significantly reduced cellularity and contain large calcium deposits. The few remaining chondrocyte-like cells are located adjacent to or within the large areas of calcification. CONCLUSIONS: Calcification of advanced lesions in chow-fed apolipoprotein E-deficient mice occurs reproducibly in mice between 45 and 75 weeks of age. The deposition of hydroxyapatite is mediated by chondrocytes, which suggests that the mechanism of calcification may in part recapitulate the process of endochondral bone formation.


Asunto(s)
Apolipoproteínas E/genética , Aterosclerosis/patología , Calcinosis/patología , Condrocitos/patología , Fosfatasa Alcalina/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Calcinosis/genética , Calcinosis/metabolismo , Condrocitos/metabolismo , Condrocitos/ultraestructura , Durapatita/metabolismo , Femenino , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Microscopía Electrónica , Osificación Heterotópica/genética , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología
10.
Arterioscler Thromb Vasc Biol ; 25(4): 785-90, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15692094

RESUMEN

OBJECTIVE: Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. METHODS AND RESULTS: Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)-/- and apoE-/- mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE-/-, r=0.76; LDLR-/-, r=0.86), apoA-I areas (apoE-/-, r=0.88; LDLR-/-, r=0.80), apoB areas (apoE-/-, r=0.74; LDLR-/-, r=0.89), and perlecan areas (apoE-/-, r=0.83; LDLR-/-, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE-/- and LDLR-/- mice demonstrated that SAA was present on both apoA-I-containing and apoB-containing lipoproteins. CONCLUSIONS: In chow-fed apoE-/- and LDLR-/- mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.


Asunto(s)
Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Arteriosclerosis/metabolismo , Proteína Amiloide A Sérica/metabolismo , Animales , Apolipoproteínas E/genética , Arteriosclerosis/patología , Colesterol/sangre , Modelos Animales de Enfermedad , Femenino , Proteoglicanos de Heparán Sulfato/metabolismo , Inmunohistoquímica , Lipoproteínas HDL/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores de LDL/genética , Seno Aórtico/patología
11.
J Neurosci ; 24(19): 4698-708, 2004 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-15140941

RESUMEN

Ca2+-binding protein-1 (CaBP1) is a Ca2+-binding protein that is closely related to calmodulin (CaM) and localized in somatodendritic regions of principal neurons throughout the brain, but how CaBP1 participates in postsynaptic Ca2+ signaling is not known. Here, we describe a novel role for CaBP1 in the regulation of Ca2+ influx through Ca(v)1.2 (L-type) Ca2+ channels. CaBP1 interacts directly with the alpha1 subunit of Ca(v)1.2 at sites that also bind CaM. CaBP1 binding to one of these sites, the IQ domain, is Ca2+ dependent and competitive with CaM binding. The physiological significance of this interaction is supported by the association of Ca(v)1.2 and CaBP1 in postsynaptic density fractions purified from rat brain. Moreover, in double-label immunofluorescence experiments, CaBP1 and Ca(v)1.2 colocalize in numerous cell bodies and dendrites of neurons, particularly in pyramidal cells in the CA3 region of the hippocampus and in the dorsal cortex. In electrophysiological recordings of cells transfected with Ca(v)1.2, CaBP1 greatly prolonged Ca2+ currents, prevented Ca2+-dependent inactivation, and caused Ca2+-dependent facilitation of currents evoked by step depolarizations and repetitive stimuli. These effects contrast with those of CaM, which promoted strong Ca2+-dependent inactivation of Ca(v)1.2 with these same voltage protocols. Our findings reveal how Ca2+-binding proteins, such as CaM and CaBP1, differentially adjust Ca2+ influx through Ca(v)1.2 channels, which may specify diverse modes of Ca2+ signaling in neurons.


Asunto(s)
Canales de Calcio Tipo L/metabolismo , Proteínas de Unión al Calcio/metabolismo , Isomerasas de Vínculo Azufre-Azufre/metabolismo , Sinapsis/metabolismo , Animales , Unión Competitiva/fisiología , Química Encefálica , Calcio/metabolismo , Canales de Calcio Tipo L/genética , Señalización del Calcio/fisiología , Calmodulina/metabolismo , Línea Celular , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Sustancias Macromoleculares , Masculino , Técnicas de Placa-Clamp , Unión Proteica/fisiología , Estructura Terciaria de Proteína/fisiología , Células Piramidales/metabolismo , Ratas , Ratas Sprague-Dawley , Sinapsis/química , Transfección
12.
Circulation ; 110(5): 540-5, 2004 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-15277327

RESUMEN

BACKGROUND: Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk. SAA levels can be increased by dietary fat and cholesterol. Moreover, SAA can cause lipoproteins to bind extracellular vascular proteoglycans, a process that is critical in atherogenesis. Therefore, we hypothesized that diet-induced increases in SAA would increase atherosclerosis independent of their effect on plasma cholesterol levels. METHODS AND RESULTS: Female LDL-receptor-null (LDLR-/-) mice were fed high-saturated fat diets (21%, wt/wt), with or without added cholesterol (0.15%, wt/wt), for 10 weeks. Compared with chow-fed controls, the high-fat diets increased plasma SAA levels. Addition of cholesterol further increased SAA levels 2-fold (P<0.05) without further increasing plasma cholesterol levels. Addition of dietary cholesterol also increased atherosclerosis (P<0.05). Four lines of evidence suggest that SAA actually might cause atherosclerosis: (1) SAA levels when mice were euthanized correlated with the extent of atherosclerosis (r=0.49; P<0.02); (2) SAA levels after 5 weeks of diet correlated with the extent of atherosclerosis at 10 weeks (r=0.66; P<0.01); (3) binding of HDL from these animals to proteoglycans in vitro was related to the HDL-SAA content (r=0.65; P<0.01); and (4) immunoreactive SAA was present in lesion areas enriched with both proteoglycans and apolipoprotein A-I, the major HDL apolipoprotein. CONCLUSIONS: Addition of cholesterol to a high-fat diet increased plasma SAA levels and atherosclerosis independent of an adverse effect on plasma lipoproteins, consistent with the hypothesis that SAA may promote atherosclerosis directly by mediating retention of SAA-enriched HDL to vascular proteoglycans.


Asunto(s)
Arteriosclerosis/inducido químicamente , Colesterol en la Dieta/farmacología , Proteína Amiloide A Sérica/análisis , Animales , Aorta/química , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/inducido químicamente , Enfermedades de la Aorta/patología , Apolipoproteína A-I/análisis , Arteriosclerosis/sangre , Arteriosclerosis/patología , Biglicano , Colesterol/sangre , Colesterol en la Dieta/toxicidad , Dieta Aterogénica , Proteínas de la Matriz Extracelular , Femenino , Lipoproteínas HDL/metabolismo , Ratones , Ratones Noqueados , Proteoglicanos/análisis , Proteoglicanos/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Componente Amiloide P Sérico/análisis , Triglicéridos/sangre
13.
Obes Surg ; 25(12): 2321-7, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25910981

RESUMEN

BACKGROUND: Patients who undergo bariatric surgery are at risk for micronutrient deficiencies. The aims of this study were to determine the prevalence and predictors of vitamin D deficiency in obese patients residing in the northern climate, and to evaluate the effectiveness of a daily maintenance dose of vitamin D 2000 IU in preventing hypovitaminosis D within 1 year after bariatric surgery. METHODS: A cohort study involving adult patients undergoing RYGB was conducted. Longitudinal changes in serum vitamin D concentrations and clinical parameters were measured and collected. RESULTS: Data from 134 recipients of RYGB were analyzed. Hypovitaminosis D was identified in 86 patients (64 %), and was significantly affected by seasonal change and the number of comorbidities. Follow-up data were available in 60 patients. Vitamin D sufficiency was achieved in 62.5 % of those patients with baseline vitamin D insufficiency. A dose-response relationship of vitamin D intake was observed, with the most significant increase in 25(OH)D associated with daily vitamin D intakes ≥ 2000 IU. CONCLUSIONS: The prevalence of hypovitaminosis D before RYGB was comparable to patients living in the non-northern climate. Daily vitamin D intake meeting at least 2000 IU is associated with greater improvement in serum vitamin D concentration.


Asunto(s)
Clima , Derivación Gástrica , Obesidad Mórbida/sangre , Obesidad Mórbida/cirugía , Vitamina D/sangre , Adulto , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/estadística & datos numéricos , Frío , Femenino , Derivación Gástrica/efectos adversos , Derivación Gástrica/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/epidemiología , Prevalencia , Estudios Retrospectivos , Estaciones del Año , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/epidemiología , Adulto Joven
14.
Endocrinology ; 155(9): 3409-20, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24914938

RESUMEN

Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14(+)CD206(+) macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b(+)F4/80(+)CD11c(-) macrophages accumulated to a greater extent in MMP12-deficient (Mmp12(-/-)) mice than in wild-type mice (Mmp12(+/+)). Despite being markedly more obese, fat-fed Mmp12(-/-) mice were more insulin sensitive than fat-fed Mmp12(+/+) mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12(-/-) macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion.


Asunto(s)
Tejido Adiposo/enzimología , Insulina/metabolismo , Macrófagos/enzimología , Metaloproteinasa 12 de la Matriz/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Obesidad/enzimología , Tejido Adiposo/crecimiento & desarrollo , Tejido Adiposo/metabolismo , Adulto , Animales , Femenino , Humanos , Técnicas In Vitro , Resistencia a la Insulina , Macrófagos/metabolismo , Masculino , Metaloproteinasa 12 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/metabolismo , Obesidad/genética , Obesidad/metabolismo , Adulto Joven
15.
Obesity (Silver Spring) ; 18(11): 2204-11, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20111023

RESUMEN

Persons diagnosed with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EA). Obesity is a major risk factor for both BE and EA. The primary purposes of this study were to determine whether circulating levels of leptin and adiponectin, both of which are deregulated in obese states, predict risk of specialized intestinal metaplasia (SIM) occurring in the esophagus (BE) and/or gastroesophageal junction, and evaluate the extent to which they mediate the relationship between obesity and these conditions. In this case-control study, 177 persons newly diagnosed with SIM were compared with 173 general population controls using unconditional logistic regression. Females in the highest tertiles of BMI and waist circumference were at the greatest risk (adjusted odds ratio (OR) = 4.6 (95% confidence interval (CI) = 1.9, 11.6), P(trend) = 0.002; OR = 5.1 (95% CI = 2.0, 13.0), P(trend) = 0.002, respectively) compared to females in the lowest tertiles. Adjustment for leptin and adiponectin attenuated these associations by 52 and 42%, respectively. Males in the highest tertile of waist-to-hip ratio were at the greatest risk (adjusted OR = 2.8 (95% CI = 1.3, 5.9), P(trend) = 0.014) compared to males in the lowest tertile. However, adjustment for leptin and adiponectin did not attenuate these associations. Our study results are consistent with the notion that circulating leptin and adiponectin partially mediate the obesity-BE relationship in women. Leptin and adiponectin's role in the progression from normal epithelium to SIM/BE and on to EA should be further elucidated.


Asunto(s)
Adiponectina/sangre , Esófago de Barrett/sangre , Unión Esofagogástrica/patología , Leptina/sangre , Obesidad/sangre , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/etiología , Esófago de Barrett/patología , Índice de Masa Corporal , Estudios de Casos y Controles , Unión Esofagogástrica/citología , Femenino , Humanos , Modelos Logísticos , Masculino , Metaplasia , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/patología , Oportunidad Relativa , Factores de Riesgo , Factores Sexuales , Relación Cintura-Cadera , Adulto Joven
16.
Am J Clin Nutr ; 89(3): 890-6, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19144726

RESUMEN

BACKGROUND: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma. Modifiable risk factors for BE are largely unknown. OBJECTIVE: The purpose of this study was to determine whether vegetable and fruit intakes are associated with BE risk. DESIGN: In a case-control study based in western Washington State, we compared the vegetable and fruit intakes of 170 patients with newly diagnosed BE with those of 182 controls from the general population. Relations between vegetable and fruit intakes and BE were examined by using unconditional logistic regression to compute odds ratios (ORs) and corresponding 95% CIs. RESULTS: Participants in the second (adjusted OR: 0.40; 95% CI: 0.23, 0.71) and third (adjusted OR: 0.33; 95% CI: 0.17, 0.63) tertiles of vegetable intake appeared to have a lower risk of BE (P for trend = 0.048) than did participants in the first tertile of vegetable intake. Similarly, participants in the second (adjusted OR: 0.49; 95% CI: 0.28, 0.86) and third (adjusted OR: 0.39; 95% CI: 0.21, 0.75) tertiles of combined vegetable and fruit intakes had a lower risk of BE (P for trend = 0.047) than did participants in the first tertile of vegetable and fruit intakes. Similar results were obtained in subanalyses limited to patients with visible and with long-segment BE. CONCLUSIONS: The results support previous findings that increased intakes of vegetables and of vegetables and fruit are associated with a lower risk of BE in men and women. Prospective data that examine relations between diet and BE are needed.


Asunto(s)
Esófago de Barrett/epidemiología , Frutas , Verduras , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/prevención & control , Estudios de Casos y Controles , Ingestión de Alimentos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven
17.
Atherosclerosis ; 203(1): 82-8, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18667203

RESUMEN

Supplements and diets enriched in antioxidants and soy isoflavones are purported to reduce cardiovascular disease risk. Many experimental studies have demonstrated inhibitory effects of antioxidants and soy isoflavones on the development of fatty streaks in animal models. However, it is still unknown whether antioxidants and isoflavones have comparable inhibitory effects on the progression of advanced stages of atherosclerosis. This is an important question because clinical trials in humans have not supported a cardio-protective role for antioxidants or isoflavones. Thus, we examined the effects of antioxidants and genistein on the progression and composition of established, advanced atherosclerotic lesions in the innominate arteries (IA) of older apolipoprotein E-deficient (apoE(-/-)) mice. Thirty-week-old male apoE(-/-) mice were fed chow with or without genistein (0.27%, w/w) for 6, 12 and 24 weeks. Twenty-week-old male apoE(-/-) mice were fed chow with or without a cocktail of antioxidants (vitamin E 0.2%, w/w; vitamin C 0.05%, w/w; and beta carotene 0.5%, w/w) for 10, 16, and 22 weeks. There were no significant differences in total plasma cholesterol, body weight, average lesion or medial area, or changes in lesion composition with either treatment in comparison to control mice.


Asunto(s)
Antioxidantes/metabolismo , Apolipoproteínas E/genética , Aterosclerosis/genética , Genisteína/farmacología , Envejecimiento , Animales , Aterosclerosis/patología , Peso Corporal , Progresión de la Enfermedad , Isoflavonas/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Glycine max , Factores de Tiempo
18.
Diabetes ; 57(5): 1254-61, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18268047

RESUMEN

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1), a CC-motif chemokine, has been proposed to play critical roles in insulin resistance and recruitment of monocytes into adipose tissue. We hypothesized that the absence of MCP-1 would improve the former and diminish the latter. RESEARCH DESIGN AND METHODS: We investigated these two hypotheses by quantifying glucose metabolism and the accumulation of macrophages in adipose tissue of control and MCP-1-deficient (Mcp1(-)(/)(-)) mice after feeding the animals a high-fat diet for 10 or 16 weeks. RESULTS: We first established that the two strains were in the same genetic background and that macrophage recruitment into inflamed peritoneum was markedly reduced in the MCP-1-deficient animals. In striking contrast, independent studies at two different facilities at either an early or late time point failed to detect any impairment in macrophage accumulation in adipose tissue of fat-fed Mcp1(-/-) mice. Immunoblot analysis revealed higher levels of Mac2, a macrophage-specific protein, in multiple fat depots of Mcp1(-/-) mice fed a high-fat diet. These mice also had significantly more adipose tissue than control mice, but their glucose metabolism was similar. CONCLUSIONS: Our observations suggest that MCP-1 does not play a prominent a role in promoting macrophage recruitment into adipose tissue or in systemic insulin resistance.


Asunto(s)
Tejido Adiposo/fisiología , Quimiocina CCL2/fisiología , Macrófagos Peritoneales/fisiología , Alimentación Animal , Animales , Glucemia/metabolismo , Quimiocina CCL2/deficiencia , Quimiocina CCL2/genética , Dieta con Restricción de Grasas , Grasas de la Dieta , Humanos , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Noqueados , Valores de Referencia , Triglicéridos/sangre
19.
J Nutr ; 136(11): 2856-61, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17056813

RESUMEN

Glucosamine, commonly consumed for the treatment of osteoarthritis, is classified as a nutritional supplement; however, there are few data regarding its metabolic or vascular effects. Glucosamine is a component of the hexosamine pathway, which has been implicated in the development of insulin resistance. Anecdotal reports suggest that glucosamine consumption can increase circulating cholesterol concentrations. To investigate the metabolic and vascular effects of glucosamine supplementation, we studied male and female LDL receptor-deficient mice fed a Western diet (21% fat, 0.15% cholesterol). Three groups of 6-10 mice of each gender received either no supplement, 15 mg . kg(-1) . d(-1) glucosamine (equivalent to an average human dose), or 50 mg . kg(-1) . d(-1) glucosamine added to their drinking water for 5, 10, or 20 wk. Plasma cholesterol and triglyceride concentrations increased in all mice with the addition of the Western diet. However, after 20 wk of treatment, cholesterol and triglyceride concentrations increased further in male mice consuming glucosamine compared with control groups. Glucosamine-supplemented mice had increased initiation of atherosclerosis after 5 wk; however, there was no effect on progression of atherosclerosis in either gender after longer periods of glucosamine supplementation (10 or 20 wk). Although long-term glucosamine supplementation exacerbated the hyperlipidemia in male mice, no increase in atherosclerosis occurred. Thus, glucosamine supplementation appears to be safe, with no adverse vascular consequences.


Asunto(s)
Aterosclerosis/etiología , Suplementos Dietéticos , Glucosamina/administración & dosificación , Receptores de LDL/fisiología , Animales , Colesterol/sangre , Femenino , Glucosamina/efectos adversos , Masculino , Ratones , Proteoglicanos/biosíntesis , Receptores de LDL/deficiencia , Factores de Tiempo , Triglicéridos/sangre
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