RESUMEN
BACKGROUND: Diseases of the pancreas may present with extrapancreatic symptoms, such as (poly)arthritis or necrosis of subcutaneous fat. A combination of pancreatitis, panniculitis and (poly)arthritis is referred to as the PPP syndrome, which is associated with acute and chronic pancreatitis, as well as pancreatic malignancies. CASE DESCRIPTION: This article describes a patient which was admitted to our hospital with severe polyarthritis and panniculitis. A meticulous work-up revealed an underlying focal alcoholic pancreatitis. The clinical course in our patient illustrates the severity of the PPP syndrome and emphasizes the need of a multidisciplinary approach. CONCLUSION: Panniculitis and/or (poly)arthritis may be the first symptom of underlying pancreatic disease. Timely recognition and diagnosis is imperative for successful treatment and outcome. The multi-organ involvement in the PPP syndrome requires close collaboration across different medical departments.
Asunto(s)
Artritis/diagnóstico , Pancreatitis/diagnóstico , Paniculitis/diagnóstico , Adulto , Artritis/complicaciones , Artritis/fisiopatología , Humanos , Masculino , Necrosis/complicaciones , Páncreas/patología , Neoplasias Pancreáticas/diagnóstico , Pancreatitis/complicaciones , Pancreatitis/fisiopatología , Paniculitis/complicaciones , Paniculitis/fisiopatología , Síndrome , Neoplasias PancreáticasRESUMEN
Obesity is caused by a long-term imbalance between energy intake and consumption and is regulated by multiple signals. This study investigated the effect of signaling scaffolding protein Gab2 on obesity and its relevant regulation mechanism. Gab2 knockout (KO) and wild-type (WT) mice were fed with a standard diet (SD) or high-fat diet (HFD) for 12 weeks. The results showed that the a high-fat diet-induced Gab2 expression in adipose tissues, but deletion of Gab2 attenuated weight gain and improved glucose tolerance in mice fed with a high-fat diet. White adipose tissue and systemic inflammations were reduced in HFD-fed Gab2 deficiency mice. Gab2 deficiency increased the expression of Ucp1 and other thermogenic genes in brown adipose tissue. Furthermore, the regulation of Gab2 on the mature differentiation and function of adipocytes was investigated in vitro using primary or immortalized brown preadipocytes. The expression of brown fat-selective genes was found to be elevated in differentiated adipocytes without Gab2. The mechanism of Gab2 regulating Ucp1 expression in brown adipocytes involved with its downstream PI3K (p85)-Akt-FoxO1 signaling pathway. Our research suggests that deletion of Gab2 suppresses diet-induced obesity by multiple pathways and Gab2 may be a novel therapeutic target for the treatment of obesity and associated complications.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Metabolismo Energético , Obesidad/prevención & control , Paniculitis/prevención & control , Proteínas Adaptadoras Transductoras de Señales/genética , Tejido Adiposo Pardo/fisiopatología , Tejido Adiposo Blanco/fisiopatología , Adiposidad , Animales , Glucemia/metabolismo , Línea Celular , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Proteína Forkhead Box O1/metabolismo , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Obesidad/fisiopatología , Paniculitis/genética , Paniculitis/metabolismo , Paniculitis/fisiopatología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Proteína Desacopladora 1/metabolismo , Aumento de PesoAsunto(s)
Deficiencia GATA2/genética , Factor de Transcripción GATA2/genética , Linfohistiocitosis Hemofagocítica/genética , Paniculitis/genética , Adolescente , Enfermedades Asintomáticas , Padre , Femenino , Deficiencia GATA2/fisiopatología , Humanos , Infecciones/fisiopatología , Linfedema/fisiopatología , Linfohistiocitosis Hemofagocítica/fisiopatología , Mosaicismo , Mutación , Pancitopenia/fisiopatología , Paniculitis/fisiopatología , Linaje , Recurrencia , Choque/fisiopatología , HermanosRESUMEN
Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment in vivo remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol in vivo against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/efectos de los fármacos , Antiinflamatorios/farmacología , Fármacos Antiobesidad/farmacología , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Obesidad/tratamiento farmacológico , Paniculitis/prevención & control , Triterpenos Pentacíclicos/farmacología , Sirtuina 1/metabolismo , Tejido Adiposo/enzimología , Tejido Adiposo/fisiopatología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Mitocondrias Musculares/enzimología , Músculo Esquelético/enzimología , Músculo Esquelético/fisiopatología , Obesidad/enzimología , Obesidad/fisiopatología , Biogénesis de Organelos , Paniculitis/enzimología , Paniculitis/fisiopatología , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications.
Asunto(s)
Antiasmáticos/uso terapéutico , Complicaciones del Embarazo/fisiopatología , Enfisema Pulmonar/fisiopatología , Inhibidores de Tripsina/uso terapéutico , Deficiencia de alfa 1-Antitripsina/fisiopatología , alfa 1-Antitripsina/uso terapéutico , Acetatos/uso terapéutico , Adulto , Combinación Budesonida y Fumarato de Formoterol/uso terapéutico , Ciclopropanos/uso terapéutico , Femenino , Volumen Espiratorio Forzado , Humanos , Paniculitis/fisiopatología , Fenotipo , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Capacidad de Difusión Pulmonar , Enfisema Pulmonar/tratamiento farmacológico , Quinolinas/uso terapéutico , Espirometría , Sulfuros/uso terapéutico , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológicoRESUMEN
Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRß) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRß) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.
Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Mediadores de Inflamación/metabolismo , Obesidad/metabolismo , Subunidad beta del Receptor de Oncostatina M/metabolismo , Oncostatina M/metabolismo , Paniculitis/metabolismo , Adipocitos/inmunología , Tejido Adiposo/inmunología , Tejido Adiposo/fisiopatología , Animales , Metabolismo Energético , Homeostasis , Humanos , Resistencia a la Insulina , Obesidad/inmunología , Obesidad/fisiopatología , Paniculitis/inmunología , Paniculitis/fisiopatología , Transducción de SeñalRESUMEN
Inflammation induced by obesity contributes to insulin resistance and atherosclerosis. Indeed, high levels of proinflammatory cytokines trigger chronic low-grade inflammation and promote detrimental metabolic effects in the adipose tissue. On the other hand, inflammation seems to control fat pad expansion and to have important functions on lipolysis and glucose metabolism. Thus, it is possible that inflammation may also drive fat pad loss, as seen during long-fast periods. Herein, we have used fasting as a strategy to induce weight loss and evaluate the possible role of inflammation on adipose tissue remodeling. Male BALB-c mice were fed with chow diet (lean mice) or with high-carbohydrate refined diet (mildly obese mice) for 8 weeks. After that, animals were subjected to 24 h of fasting. There was a 63% reduction of adiposity in lean mice following fasting. Furthermore, the adipose tissue was enriched of immune cells and had a higher content of IL-6, TNF-alpha, IL-10, TGF-ß and CXCL-1. Interestingly, mildly obese mice, subjected to the same 24-h fasting period, lost only 33% of their adiposity. Following fasting, these mice did not show any increment in leukocyte recruitment and cytokine levels, as did lean mice. Our findings indicate that inflammation participates in fat mass loss induced by fasting. Although the chronic low-grade inflammation seen in obesity is associated with metabolic diseases, a lower inflammatory response triggered by fasting in mildly obese mice impairs fat pad mobilization.
Asunto(s)
Tejido Adiposo , Adiposidad/fisiología , Ayuno/fisiología , Obesidad/fisiopatología , Paniculitis/fisiopatología , Animales , Peso Corporal , Quimiocina CXCL1/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones Endogámicos BALB C , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Lavatera critica, a leafy green herb, is reported to have many pharmacological activities; but, the improvement of insulin sensitivity against the high gram-fat diet (HGFD)-caused insulin resistance (IR) has not yet been studied. OBJECTIVE: This study evaluated the role of Lavatera critica leaf extract (LCE) in systemic insulin resistance through the alleviation of adipose tissue inflammation and oxidative damage in HGFD fed mice. METHODS: The mice were fed with HGFD for 10 weeks and the diet was supplemented with LCE each day for the next five weeks. Body weight, food intake, leptin, blood glucose, insulin, insulin resistance, and pro- and anti-inï¬ammatory genes expression were assessed on day 106. RESULTS: The HGFD control mice displayed markedly elevated adipose tissue inflammation, oxidative stress, insulin inactivity, and hyperglycemia. Administration of LCE in the HGFD mice, especially a dose of 100â¯mg/kg, lowered the body weight, food intake, plasma leptin, plasma glucose, plasma insulin, insulin resistance, and increased the food efficacy ratio when compared with the HGFD control mice. The oral glucose tolerance test (OGTT) revealed that LCE prevented further increase in the circulating levels after the glucose load. LCE-treated mice demonstrated a marked suppression of pro-inflammatory cytokines mRNA expression. On the other hand, the mice showed a higher anti-inï¬ammatory genes mRNA expression in the adipose tissue. In addition, LCE treatment improved the oxidative damage as evidenced by the reduced levels of lipid hydroperoxides and thiobarbituric acid reactive substances coupled with the increased antioxidants (superoxide dismutase, total glutathione, glutathione/glutathione disulï¬de ratio and glutathione peroxidase) in the adipose tissue, plasma and erythrocytes. Gas chromatography-mass spectrometry analysis of the bioactive compounds revealed the presence of 9, 12, 15-octadecatrienoic acid, vitamin E, phytol, hexadecanoic acid, benzenepropanoic acid, and stigmasterol. CONCLUSIONS: These findings prove that LCE improves the insulin-sensitizing activity in the mouse model of HGFD-caused IR, probably due to the amelioration of adipose tissue inflammation and oxidative damage. Hence, the LCE could serve as a useful anti-diabetic agent.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Cromatografía de Gases y Espectrometría de Masas , Hipoglucemiantes/farmacología , Mediadores de Inflamación/sangre , Resistencia a la Insulina , Malvaceae , Estrés Oxidativo/efectos de los fármacos , Paniculitis/tratamiento farmacológico , Extractos Vegetales/farmacología , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatología , Ingestión de Alimentos/efectos de los fármacos , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/aislamiento & purificación , Insulina/sangre , Resistencia a la Insulina/genética , Leptina/sangre , Masculino , Malvaceae/química , Ratones Endogámicos C57BL , Paniculitis/sangre , Paniculitis/fisiopatología , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Plantas Medicinales , Factores de Tiempo , Aumento de Peso/efectos de los fármacosRESUMEN
Panniculitides represent a heterogeneous group of inflammatory diseases that are traditionally considered one of the most difficult challenge for clinicians and pathologists. They may occur in a variety of dermato/rheumatologic diseases and are of particular relevance for clinicians dealing with such pathologies, including immune-mediated/autoimmune and autoinflammatory disorders. In fact, panniculitides can be the initial sign of presentation of a dermato/rheumatologic disease, thereby providing the physician with important clues to the correct diagnosis. Then, panniculitides may serve as an easy-to-access indicator of both systemic involvement and prognostic outcome in dermato/rheumatologic disorders. This review will focus on clinical and histopathological findings of panniculitides in the setting of dermato/rheumatologic disorders and discusses the value of skin biopsies and consequent histopathological examination in the diagnosis of these disorders with the help of a logarithmic table.
Asunto(s)
Paniculitis/diagnóstico , Enfermedades Reumáticas/diagnóstico , Enfermedades de la Piel/diagnóstico , Biopsia , Humanos , Paniculitis/etiología , Paniculitis/fisiopatología , Pronóstico , Enfermedades Reumáticas/fisiopatología , Enfermedades de la Piel/fisiopatologíaRESUMEN
Sleep disturbances are associated with various metabolic diseases such as hypertension and diabetes. We had previously established a mouse model of a psychophysiological stress-induced chronic sleep disorder (CSD) characterized by disrupted circadian rhythms of wheel-running activity, core body temperature, and sleep-wake cycles. To evaluate the underlying mechanisms of metabolic disorders induced by CSD, we created mice with CSD for six weeks and fed them with a high-fat diet. Glucose intolerance with hyperglycemia resulted, although plasma insulin levels and body weight increases were identical between control and CSD mice. Gluconeogenesis and glycolysis were enhanced and suppressed, respectively, in the livers of CSD mice, because the mRNA expression of Pck1 was significantly increased, whereas that of Gck and Pklr were significantly decreased in the CSD mice. Adipose inflammation induced by the high-fat diet seemed suppressed by the CSD, because the mRNA expression levels of Adgre1, Ccl2, and Tnf were significantly downregulated in the adipose tissues of CSD mice. These findings suggest that CSD impair glucose tolerance by inducing gluconeogenesis and suppressing glycolysis. Hyperphasia with hypoleptinemia, hypercorticosteronemia, and increased plasma free fatty acids might be involved in the impaired glucose metabolism under a CSD. Further studies are needed to elucidate the endocrine and molecular mechanisms underlying the associations between sleep disorders and impaired glucose homeostasis that consequently causes diabetes.
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Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/fisiopatología , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/fisiopatología , Estrés Psicológico/complicaciones , Estrés Psicológico/fisiopatología , Animales , Enfermedad Crónica , Citocinas/metabolismo , Masculino , Ratones , Paniculitis/etiología , Paniculitis/fisiopatologíaRESUMEN
The main goal of the present study was to evaluate the metabolic profile, inflammatory markers and the gene expression of the renin-angiotensin system (RAS) components in the visceral adipose tissue of eutrophic, obese and malnourished individuals and mice models of obesity and food restriction. Male Swiss mice were divided into eight groups and fed different levels of food restriction (20%, 40%, or 60%) using standard or high-fat diet. Metabolic profile and adipose tissues were assessed. The expression of AGT (Angiotensinogen), ACE (Angiotensin-converting enzyme), ACE2 (Angiotensin-converting enzyme 2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in the mice epididymal adipose tissue and the human visceral adipose tissue was assessed. The main findings showed reduced body weight, improved metabolism, decreased adipose tissues weight and reduced adipocyte area in mice submitted to food restriction. Diminished expression of IL-6, TNF-α, AGT, AT1 and ACE was detected in the 20% and 40% food restriction animal groups, although they were increased in the 60% malnourished group. Increased expression of IL-6, TNF-α, AGT and ACE in obese and malnourished individuals was observed. Adipocytes size was increased in obese individuals and reduced in malnutrition. In conclusion, we found that food restriction of 20% and 40% improved the metabolic profile, ameliorated the inflammatory status and down-regulated the RAS in mice. Severe 60% food restriction (malnutrition), however, stimulated a proinflammatory state and increased AGT and ACE expression in the adipose tissue of mice. A similar profile was observed in the adipose tissue of obese and malnourished humans, supporting the critical role of inflammation and RAS as mediators of metabolic disorders.
Asunto(s)
Biomarcadores/metabolismo , Desnutrición/fisiopatología , Obesidad/fisiopatología , Paniculitis/fisiopatología , Sistema Renina-Angiotensina/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Glucemia/metabolismo , Estudios de Casos y Controles , Colesterol/sangre , Femenino , Humanos , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/fisiopatología , Masculino , Desnutrición/metabolismo , Ratones , Persona de Mediana Edad , Paniculitis/etiologíaRESUMEN
PURPOSE OF REVIEW: Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review. RECENT FINDINGS: Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed.
Asunto(s)
Artritis/fisiopatología , Enfermedades Pancreáticas/fisiopatología , Paniculitis/fisiopatología , Artritis/diagnóstico , Artritis/epidemiología , Artritis/terapia , Humanos , Lipasa/sangre , Enfermedades Pancreáticas/diagnóstico , Enfermedades Pancreáticas/epidemiología , Enfermedades Pancreáticas/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/fisiopatología , Neoplasias Pancreáticas/terapia , Paniculitis/diagnóstico , Paniculitis/epidemiología , Paniculitis/terapia , PronósticoRESUMEN
White adipose tissue plays an important role in the development of metabolic disturbance, which is a common feature in patients with chronic kidney disease (CKD). The effect of CKD on white adipose tissue remains poorly appreciated. Here, we evaluated the inflammatory potential of visceral white adipose tissue in a rat model of CKD. The results showed that production of proinflammatory cytokines and infiltration of macrophage in the tissue were increased significantly in CKD rats compared with sham rats. Moreover, the primary adipocytes and stromal vascular fraction under the condition of CKD could trigger the inflammatory response in each other. Free fatty acid induced robust inflammatory response in ex vivo peritoneal-derived macrophages from CKD rats, which was associated with reduced activity of silent information regulator T1 (SIRT1). Improvement of SIRT1 activity by an activator could alleviate free fatty acid-induced inflammatory response in the macrophages and inflammation in the white adipose tissue. Moreover, oxidative stress occurred in the tissue and linked with the reduced activity of SIRT1 in macrophages and enhanced release of free fatty acid in the tissue. We thus identified CKD as a risk factor for chronic inflammation in white adipose tissue. These observations might open up new therapeutic strategies for metabolic disturbance in CKD via the modulation of adipose tissue-related pathways.
Asunto(s)
Adipocitos/metabolismo , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Grasa Intraabdominal/metabolismo , Macrófagos/metabolismo , Paniculitis/etiología , Insuficiencia Renal Crónica/complicaciones , Animales , Comunicación Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/genética , Modelos Animales de Enfermedad , Metabolismo Energético , Ácidos Grasos no Esterificados/metabolismo , Grasa Intraabdominal/fisiopatología , Masculino , Estrés Oxidativo , Paniculitis/genética , Paniculitis/metabolismo , Paniculitis/fisiopatología , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Transducción de Señal , Sirtuina 1/metabolismo , Factores de TiempoRESUMEN
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients' fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
Asunto(s)
Alelos , Endopeptidasas/genética , Fibroblastos/patología , Enfermedades Autoinflamatorias Hereditarias/genética , Leucocitos Mononucleares/patología , Mutación , Edad de Inicio , Niño , Preescolar , Consanguinidad , Citocinas/genética , Citocinas/inmunología , Dermatitis/fisiopatología , Endopeptidasas/deficiencia , Endopeptidasas/inmunología , Insuficiencia de Crecimiento/fisiopatología , Femenino , Fiebre/fisiopatología , Fibroblastos/enzimología , Fibroblastos/inmunología , Regulación de la Expresión Génica , Células HEK293 , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/enzimología , Enfermedades Autoinflamatorias Hereditarias/patología , Humanos , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/inmunología , Masculino , FN-kappa B/genética , FN-kappa B/inmunología , Paniculitis/fisiopatología , Linaje , Transducción de Señal , Ubiquitina/genética , Ubiquitina/inmunologíaRESUMEN
α1-Antitrypsin deficiency is an autosomal codominant condition that predisposes to emphysema and cirrhosis. The condition is common but grossly under-recognized. Identifying patients' α1-antitrypsin deficiency has important management implications (ie, smoking cessation, genetic and occupational counseling, and specific treatment with the infusion of pooled human plasma α1-antitrypsin). The weight of evidence suggests that augmentation therapy slows the progression of emphysema in individuals with severe α1-antitrypsin deficiency.
Asunto(s)
Cirrosis Hepática/fisiopatología , Enfisema Pulmonar/fisiopatología , alfa 1-Antitripsina/genética , Progresión de la Enfermedad , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Paniculitis/etiología , Paniculitis/genética , Paniculitis/fisiopatología , Enfisema Pulmonar/tratamiento farmacológico , Enfisema Pulmonar/etiología , Enfisema Pulmonar/genética , Inhibidores de Serina Proteinasa/uso terapéutico , Vasculitis/etiología , Vasculitis/genética , Vasculitis/fisiopatología , alfa 1-Antitripsina/uso terapéutico , Deficiencia de alfa 1-Antitripsina/complicaciones , Deficiencia de alfa 1-Antitripsina/tratamiento farmacológico , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/fisiopatologíaRESUMEN
Adipose tissue (AT) inflammation is a hallmark characteristic of obesity and an important determinant of insulin resistance and cardiovascular disease; therefore, a better understanding of factors regulating AT inflammation is critical. It is well established that reduced vascular endothelial nitric oxide (NO) bioavailability promotes arterial inflammation; however, the role of NO in modulating inflammation in AT remains disputed. In the present study, 10-wk-old C57BL6 wild-type and endothelial nitric oxide synthase (eNOS) knockout male mice were randomized to either a control diet (10% kcal from fat) or a Western diet (44.9% kcal from fat, 17% sucrose, and 1% cholesterol) for 18 wk (n= 7 or 8/group). In wild-type mice, Western diet-induced obesity led to increased visceral white AT expression of inflammatory genes (e.g., MCP1, TNF-α, and CCL5 mRNAs) and markers of macrophage infiltration (e.g., CD68, ITGAM, EMR1, CD11C mRNAs, and Mac-2 protein), as well as reduced markers of mitochondrial content (e.g., OXPHOS complex I and IV protein). Unexpectedly, these effects of Western diet on visceral white AT were not accompanied by decreases in eNOS phosphorylation at Ser-1177 or increases in eNOS phosphorylation at Thr-495. Also counter to expectations, eNOS knockout mice, independent of the diet, were leaner and did not exhibit greater white or brown AT inflammation compared with wild-type mice. Collectively, these findings do not support the hypothesis that reduced NO production from eNOS contributes to obesity-related AT inflammation.
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Grasa Intraabdominal/enzimología , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico/metabolismo , Obesidad/enzimología , Paniculitis/enzimología , Tejido Adiposo Pardo/enzimología , Adiposidad , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Obesidad/genética , Obesidad/fisiopatología , Paniculitis/genética , Paniculitis/fisiopatología , Fenotipo , Fosforilación , Serina , Transducción de Señal , TreoninaRESUMEN
Obesity is often associated with the development of adipose tissue (AT) inflammation, resulting in metabolic dysfunction and an increased risk for developing type 2 diabetes. It is also associated with multiple chronic diseases, including cardiovascular, liver, and kidney disease, and thus can contribute to organ failure. Several studies have investigated whether there is a correlation between obesity and outcomes in transplantation, but there is currently very limited information on the specific role of AT inflammation in the rejection process or on the overall function of the transplanted organ. Here, we provide a brief review of the current understanding of the cellular mechanisms that control obesity-associated AT inflammation and summarize knowledge about how obesity affects clinical outcomes following solid organ or hematopoietic stem cell transplantation. We also highlight opportunities for more research to better understand how obesity affects outcomes of transplantation.
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Tejido Adiposo/inmunología , Obesidad/complicaciones , Trasplante de Órganos , Paniculitis/etiología , Animales , Rechazo de Injerto , Humanos , Obesidad/fisiopatología , Paniculitis/fisiopatologíaRESUMEN
SCOPE: Diet-induced obesity (DIO) is proposed to cause impairments in intestinal barrier integrity, but contradictory results have been published and it appears that the outcomes depend on other environmental factors. We therefore assessed whether the hygienic status of animal facilities alters the gut barrier in DIO mice. METHODS AND RESULTS: Male C57BL/6N mice were housed in a conventional (CV) or a specific pathogen-free (SPF) animal facility and were fed identical diets represented by a high-fat (60kJ% fat) or control diet (11kJ% fat) for 12 wks. Intestinal barrier function in small and large intestine was evaluated in Ussing chambers by electrical resistance and permeability measurements. Jejunal (p < 0.01) and proximal colonic (p < 0.05) barrier function was altered in CV DIO mice, but not in SPF DIO mice. Moreover, only CV DIO mice were characterized by metabolic endotoxemia and low-grade inflammation. High-throughput 16S rRNA gene sequencing revealed significant differences in fecal bacterial diversity and composition between the two animal facilities, but only in mice fed the HFD. Moreover, cecal DCA concentrations correlated positively with two yet uncultivated Clostridiales species. CONCLUSIONS: We demonstrated that housing conditions and associated changes in gut bacterial colonization are pivotal for maintenance of gut barrier integrity in DIO mice.
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Dieta Alta en Grasa/efectos adversos , Microbioma Gastrointestinal/fisiología , Vivienda para Animales , Intestinos/fisiopatología , Obesidad/etiología , Animales , Ácidos y Sales Biliares/metabolismo , Endotoxemia/fisiopatología , Heces/microbiología , Microbioma Gastrointestinal/genética , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/fisiopatología , Paniculitis/fisiopatología , Proteínas de Uniones Estrechas/metabolismoRESUMEN
OBJECTIVE: The Ossabaw pig is emerging as an attractive model of human cardiometabolic disease because of its size and susceptibility to atherosclerosis, among other characteristics. The relationship between adipose tissue inflammation and metabolic dysfunction in this model was investigated here. METHODS: Young female Ossabaw pigs were fed a Western-style high-fat diet (HFD) (n = 4) or control low-fat diet (LFD) (n = 4) for a period of 9 months and compared for cardiometabolic outcomes and adipose tissue inflammation. RESULTS: The HFD-fed "OBESE" pigs were 2.5 times heavier (P < 0.001) than LFD-fed "LEAN" pigs and developed severe obesity. HFD feeding caused pronounced dyslipidemia, hypertension, and insulin resistance (systemic and adipose), as well as induction of inflammatory genes, impairments in vasomotor reactivity to insulin, and atherosclerosis in the coronary arteries. Remarkably, visceral, subcutaneous, and perivascular adipose tissue inflammation (via FACS analysis and RT-PCR) was not increased in OBESE pigs, nor were circulating inflammatory cytokines. CONCLUSIONS: These findings reveal a disconnect between adipose tissue inflammation and cardiometabolic dysfunction induced by Western diet feeding in the Ossabaw pig model.