RESUMEN
Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment.
Asunto(s)
COVID-19 , Trampas Extracelulares , Humanos , Animales , Ratones , COVID-19/genética , COVID-19/patología , Trampas Extracelulares/metabolismo , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/metabolismo , Pulmón/patología , Complemento C5a/genética , Complemento C5a/metabolismoRESUMEN
Owing to its unique capacity to clear macronutrients from circulation and use them to produce heat, thermogenic fat is capable of regulating glucose, lipids, and branched-chain amino acids (BCAA) circulatory levels. At the same time, its activity yields a higher energy expenditure, thereby conferring protection against cardiometabolic diseases. Our knowledge on the mechanisms of uptake and intracellular metabolism of such energy substrates into thermogenic fat has meaningfully evolved in recent years. This has allowed us to better understand how the thermogenic machinery processes those molecules to utilize them as substrates for heating up the body. Here, we discuss recent advances in the molecular and cellular regulatory process that governs the uptake and metabolism of such substrates within thermogenic fat.
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Tejido Adiposo Pardo , Calor , Tejido Adiposo Pardo/metabolismo , Metabolismo Energético/fisiología , Humanos , Termogénesis/genética , Proteína Desacopladora 1/metabolismoRESUMEN
OBJECTIVE: To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes. DESIGN: We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate. RESULTS: Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0-6.0) days for the colchicine group and 6.5 (4.0-9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0-9.0) days for the colchicine group and 9.0 (7.0-12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26). CONCLUSION: Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19. TRIAL REGISTRATION NUMBER: RBR-8jyhxh.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Colchicina/administración & dosificación , Tiempo de Internación , Terapia por Inhalación de Oxígeno , SARS-CoV-2/genética , Índice de Severidad de la Enfermedad , Adulto , Anciano , COVID-19/mortalidad , COVID-19/virología , Colchicina/efectos adversos , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Resultado del TratamientoRESUMEN
Lipids govern vital cellular processes and drive physiological changes in response to different pathological or environmental cues. Lipid species can be roughly divided into structural and signalling lipids. The former is essential for membrane composition, while the latter are usually oxidized lipids. These mediators provide beneficial effects against cardiometabolic diseases (CMDs), including fatty-liver diseases, atherosclerosis, thrombosis, obesity, and Type 2 diabetes. For instance, several oxylipins were recently found to improve glucose homeostasis, increase insulin secretion, and inhibit platelet aggregation, while specialized pro-resolving mediators (SPMs) are able to ameliorate CMD by shaping the immune system. These lipids act mainly by stimulating GPCRs. In this review, we provide an updated and comprehensive overview of the current state of the literature on signalling lipids in the context of CMD. We also highlight the network encompassing the lipid-modifying enzymes and the lipid-binding GPCRs, as well as their interactions in health and disease.
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Aterosclerosis , Diabetes Mellitus Tipo 2 , Humanos , Lípidos , Obesidad , Unión ProteicaRESUMEN
Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.
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Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Trampas Extracelulares/fisiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Células A549 , Adulto , Enzima Convertidora de Angiotensina 2 , COVID-19 , Muerte Celular , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Células Epiteliales/patología , Células Epiteliales/virología , Femenino , Células HeLa , Humanos , Masculino , Activación Neutrófila , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/sangre , Neumonía Viral/patología , SARS-CoV-2 , Serina Proteasas/metabolismo , Succión , Tráquea/inmunologíaRESUMEN
Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9-SAM-gRNA to activate endogenous uncoupling protein 1 expression. Obese mice that received HUMBLE cell transplants showed a sustained improvement in glucose tolerance and insulin sensitivity, as well as increased energy expenditure. Mechanistically, increased arginine/nitric oxide (NO) metabolism in HUMBLE adipocytes promoted the production of NO that was carried by S-nitrosothiols and nitrite in red blood cells to activate endogenous brown fat and improved glucose homeostasis in recipient animals. Together, these data demonstrate the utility of using CRISPR-Cas9 technology to engineer human white adipocytes to display brown fat-like phenotypes and may open up cell-based therapeutic opportunities to combat obesity and diabetes.
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Adipocitos Marrones , Síndrome Metabólico , Tejido Adiposo Pardo/metabolismo , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Dieta Alta en Grasa , Metabolismo Energético , Humanos , Síndrome Metabólico/terapia , Ratones , Ratones Obesos , Obesidad/metabolismo , Obesidad/terapia , TermogénesisRESUMEN
Adipose tissue exerts multiple vital functions that critically maintain energy balance, including storing and expending energy, as well as secreting factors that systemically modulate nutrient metabolism. Since lipids are the major constituents of the adipocytes, it is unsurprising that the lipid composition of these cells plays a critical role in maintaining their functions and communicating with other organs and cells. In both positive and negative energy balance conditions, lipids and free fatty acids secreted from adipocytes exert either beneficial or detrimental effects in other tissues, such as the liver, pancreas and muscle. The way the adipocytes communicate with other organs tightly depends on the nature of their lipidome composition. Notwithstanding, the lipidome composition of the adipocytes is affected by physiological factors such as adipocyte type, gender and age, but also by environmental cues such as diet composition, thermal stress and physical activity. Here we provide an updated overview on how the adipose tissue lipidome profile is shaped by different physiological and environmental factors and how these changes impact the way the adipocytes regulate whole-body energy metabolism.
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Metabolismo Energético/genética , Lipidómica , Lípidos/genética , Termogénesis/genética , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Humanos , Hígado/metabolismo , Obesidad/genética , Obesidad/metabolismo , Obesidad/patologíaRESUMEN
Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally long-lived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice. We observed distinct lipid profiles in brown versus white adipose tissue of Ames dwarf mice that are consistent with increased thermogenesis and insulin sensitivity, such as increased cardiolipin and decreased ceramide concentrations. Moreover, we identified 5-hydroxyeicosapentaenoic acid (5-HEPE), an ω-3 fatty acid metabolite, to be increased in Ames dwarf brown adipose tissue (BAT), as well as in circulation. Importantly, 5-HEPE is increased in other models of BAT activation and is negatively correlated with body weight, insulin resistance, and circulating triglyceride concentrations in humans. Together, these data represent a novel lipid signature of adipose tissue in a mouse model of extreme longevity.
Asunto(s)
Metabolismo de los Lípidos , Longevidad , Tejido Adiposo Pardo , Animales , Metabolómica , Ratones , TermogénesisRESUMEN
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.
Asunto(s)
Adipocitos Marrones/metabolismo , Adipogénesis , Factor 6 de Crecimiento de Fibroblastos/metabolismo , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Obesidad/metabolismo , Proteína Desacopladora 1/metabolismo , Adipocitos Marrones/citología , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Animales , Factor 6 de Crecimiento de Fibroblastos/genética , Factor 9 de Crecimiento de Fibroblastos/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/fisiopatología , Termogénesis , Proteína Desacopladora 1/genéticaRESUMEN
Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders.
Asunto(s)
Adipocitos Marrones/metabolismo , Metabolismo Energético , Opsinas de Bastones/metabolismo , Tejido Adiposo Pardo/inervación , Animales , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica , Glucosa/metabolismo , Resistencia a la Insulina , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Mutación , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Opsinas de Bastones/genética , Transducción de Señal , TermogénesisRESUMEN
Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold-activated lipid landscapes in circulation and in adipose tissue by MS/MSALL shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio-signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Cardiolipinas/metabolismo , Frío , Lípidos/sangre , Termogénesis , Animales , Biomarcadores/sangre , Humanos , Metabolómica , Ratones , Modelos Animales , Fosfatidilgliceroles/metabolismoRESUMEN
Adipocytes possess remarkable adaptive capacity to respond to nutrient excess, fasting or cold exposure, and they are thus an important cell type for the maintenance of proper metabolic health. Although the endoplasmic reticulum (ER) is a critical organelle for cellular homeostasis, the mechanisms that mediate adaptation of the ER to metabolic challenges in adipocytes are unclear. Here we show that brown adipose tissue (BAT) thermogenic function requires an adaptive increase in proteasomal activity to secure cellular protein quality control, and we identify the ER-localized transcription factor nuclear factor erythroid 2-like 1 (Nfe2l1, also known as Nrf1) as a critical driver of this process. We show that cold adaptation induces Nrf1 in BAT to increase proteasomal activity and that this is crucial for maintaining ER homeostasis and cellular integrity, specifically when the cells are in a state of high thermogenic activity. In mice, under thermogenic conditions, brown-adipocyte-specific deletion of Nfe2l1 (Nrf1) resulted in ER stress, tissue inflammation, markedly diminished mitochondrial function and whitening of the BAT. In mouse models of both genetic and dietary obesity, stimulation of proteasomal activity by exogenously expressing Nrf1 or by treatment with the proteasome activator PA28α in BAT resulted in improved insulin sensitivity. In conclusion, Nrf1 emerges as a novel guardian of brown adipocyte function, providing increased proteometabolic quality control for adapting to cold or to obesity.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Retículo Endoplásmico/genética , Factor 1 Relacionado con NF-E2/genética , Obesidad/genética , Complejo de la Endopetidasa Proteasomal/genética , Aclimatación/genética , Aclimatación/fisiología , Animales , Frío , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/genética , Eliminación de Gen , Homeostasis , Humanos , Inflamación/genética , Inflamación/fisiopatología , Resistencia a la Insulina/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Animales , Obesidad/fisiopatología , Complejo de la Endopetidasa Proteasomal/metabolismo , Termogénesis/genéticaRESUMEN
This corrects the article DOI: 10.1038/nm.4297.
RESUMEN
Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
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Tejido Adiposo Pardo/metabolismo , Frío , Ácidos Grasos/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Ácidos Oléicos/metabolismo , Termogénesis , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Transporte Biológico/efectos de los fármacos , Antígenos CD36/efectos de los fármacos , Antígenos CD36/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Metabolismo Energético/efectos de los fármacos , Proteínas de Transporte de Ácidos Grasos/efectos de los fármacos , Proteínas de Transporte de Ácidos Grasos/metabolismo , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Ratones , Ácidos Oléicos/biosíntesis , Ácidos Oléicos/farmacología , Sobrepeso/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , ARN Mensajero/metabolismo , Radiofármacos , Triglicéridos/metabolismoRESUMEN
Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.
Asunto(s)
Antioxidantes/uso terapéutico , Asma/tratamiento farmacológico , Eosinófilos/fisiología , Pulmón/efectos de los fármacos , Obesidad/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Estilbenos/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Progresión de la Enfermedad , Pulmón/patología , Ratones , Ratones Endogámicos , ResveratrolRESUMEN
Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.
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Tronco Encefálico/enzimología , Hiperreactividad Bronquial/complicaciones , Neuronas Colinérgicas/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hiperinsulinismo/complicaciones , Sistema de Señalización de MAP Quinasas , Animales , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/fisiopatología , Broncoconstricción , Neuronas Colinérgicas/patología , Dieta Alta en Grasa , Activación Enzimática , Hiperinsulinismo/enzimología , Hiperinsulinismo/fisiopatología , Inflamación/patología , Inyecciones Intraventriculares , Insulina/metabolismo , Cloruro de Metacolina , Ratones Endogámicos C57BL , Ratones Obesos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Receptor de Insulina/metabolismoRESUMEN
Obesity is a major risk factor for asthma. Likewise, obesity is known to increase disease severity in asthmatic subjects and also to impair the efficacy of first-line treatment medications for asthma, worsening asthma control in obese patients. This concept is in agreement with the current understanding that some asthma phenotypes are not accompanied by detectable inflammation, and may not be ameliorated by classical anti-inflammatory therapy. There are growing evidences suggesting that the obesity-related asthma phenotype does not necessarily involve the classical T(H)2-dependent inflammatory process. Hormones involved in glucose homeostasis and in the pathogeneses of obesity likely directly or indirectly link obesity and asthma through inflammatory and non-inflammatory pathways. Furthermore, the endocrine regulation of the airway-related pre-ganglionic nerves likely contributes to airway hyperreactivity (AHR) in obese states. In this review, we focused our efforts on understanding the mechanism underlying obesity-related asthma by exploring the T(H)2-independent mechanisms leading to this disease.
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Tejido Adiposo/inmunología , Adiposidad , Asma/etiología , Modelos Biológicos , Obesidad/fisiopatología , Células Th2/inmunología , Adiponectina/sangre , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Resistencia de las Vías Respiratorias , Animales , Asma/sangre , Asma/inmunología , Asma/metabolismo , Humanos , Leptina/sangre , Leptina/metabolismo , Obesidad/sangre , Obesidad/inmunología , Obesidad/metabolismo , Células Th2/metabolismoRESUMEN
INTRODUCTION: Cardiovascular and endocrine-metabolic diseases associated with increased oxidative stress such as obesity lead to erectile dysfunction (ED). Activators of soluble guanylyl cyclase (sGC) such as BAY 60-2770 reactivate the heme-oxidized sGC in vascular diseases. AIM: This study aimed to evaluate the effects of 2-week oral intake with BAY 60-2270 on a murine model of obesity-associated ED. METHODS: C57BL/6 male mice were fed for 12 weeks with standard chow or high-fat diet. Lean and obese mice were treated with BAY 60-2770 (1 mg/kg/day, 2 weeks). MAIN OUTCOME MEASURES: Measurements of intracavernosal pressure (ICP), along with acetylcholine (10(-9) to 10(-5) M) and electrical field stimulation (EFS; 4-10 Hz)-induced corpus cavernosum relaxations in vitro, were obtained. Levels of cyclic guanosine monophosphate (cGMP), reactive oxygen species (ROS), and sGC protein expressions in cavernosal tissues were measured. RESULTS: Cavernous nerve stimulation caused frequency-dependent ICP increases, which were significantly lower in obese compared with lean mice (P < 0.05). Two-week therapy with BAY 60-2770 fully reversed the decreased ICP in obese group. Acetylcholine-induced cavernosal relaxations were 45% lower (P < 0.001) in obese mice, which were fully restored by BAY 60-2770 treatment. Likewise, the EFS-induced relaxations in obese mice were restored by BAY 60-2770. Basal cGMP content in erectile tissue was 68% lower (P < 0.05) in obese mice, an effect normalized by BAY 60-2770. Levels of ROS were 52% higher (P < 0.05) whereas protein expression of α1 sGC subunit was reduced in cavernosal tissue of obese mice, both of which were normalized by BAY 60-2770. In lean group, BAY 60-2770 did not significantly affect any functional, biochemical, or molecular parameter analyzed. CONCLUSIONS: Two-week therapy with BAY 60-2770 restores the erectile function in obese mice that is associated with reduced ROS levels, up-regulation of α1 sGC subunit, and increased cGMP levels in the erectile tissue.
Asunto(s)
Benzoatos/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Activadores de Enzimas/administración & dosificación , Disfunción Eréctil/tratamiento farmacológico , Disfunción Eréctil/fisiopatología , Hidrocarburos Fluorados/administración & dosificación , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , GMP Cíclico/metabolismo , Dieta Alta en Grasa/efectos adversos , Disfunción Eréctil/enzimología , Disfunción Eréctil/etiología , Guanilato Ciclasa/genética , Guanilato Ciclasa/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Erección Peniana/efectos de los fármacos , Pene/irrigación sanguínea , Especies Reactivas de Oxígeno/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Guanilil Ciclasa Soluble , Regulación hacia ArribaRESUMEN
Obesity has emerged as a major contributing risk factor for overactive bladder (OAB), but no study examined urethral smooth muscle (USM) dysfunction as a predisposing factor to obesity-induced OAB. This study investigated the USM relaxant machinery in obese mice and whether soluble guanylyl cyclase (sGC) activation with BAY 60-2770 [acid 4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4-(trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} methyl) benzoic] rescues the urethral reactivity through improvement of sGC-cGMP (cyclic guanosine monophosphate) signaling. Male C57BL/6 mice were fed for 12 weeks with a high-fat diet to induce obesity. Separate groups of animals were treated with BAY 60-2770 (1 mg/kg per day for 2 weeks). Functional assays and measurements of cGMP, reactive-oxygen species (ROS), and sGC protein expression in USM were determined. USM relaxations induced by NO (acidified sodium nitrite), NO donors (S-nitrosoglutathione and glyceryl trinitrate), and BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] (sGC stimulator) were markedly reduced in obese compared with lean mice. In contrast, USM relaxations induced by BAY 60-2770 (sGC activator) were 43% greater in obese mice (P < 0.05), which was accompanied by increases in cGMP levels. Oxidation of sGC with ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one] (10 µM) potentiated BAY 60-2770-induced USM responses in the lean group. Long-term oral BAY 60-2770 administration fully prevented the impairment of USM relaxations in obese mice. Reactive-oxygen species (ROS) production was enhanced, but protein expression of ß1 second guanylate cyclase subunit was reduced in USM from obese mice, both of which were restored by BAY 60-2770 treatment. In conclusion, impaired USM relaxation in obese mice is associated with ROS generation and down-regulation of sGC-cGMP signaling. Prevention of sGC degradation by BAY 60-2770 ameliorates the impairment of urethral relaxations in obese mice.
Asunto(s)
Benzoatos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Activadores de Enzimas/uso terapéutico , Guanilato Ciclasa/metabolismo , Hidrocarburos Fluorados/uso terapéutico , Óxido Nítrico/metabolismo , Obesidad/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/metabolismo , Uretra/efectos de los fármacos , Animales , Benzoatos/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Relación Dosis-Respuesta a Droga , Activación Enzimática , Activadores de Enzimas/administración & dosificación , Hidrocarburos Fluorados/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Relajación Muscular/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/enzimología , Músculo Liso/metabolismo , Obesidad/complicaciones , Obesidad/enzimología , Obesidad/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Guanilil Ciclasa Soluble , Uretra/enzimología , Uretra/metabolismo , Vejiga Urinaria Hiperactiva/enzimología , Vejiga Urinaria Hiperactiva/etiología , Vejiga Urinaria Hiperactiva/fisiopatología , Vejiga Urinaria Hiperactiva/prevención & controlRESUMEN
PURPOSE: Activators of soluble guanylyl cyclase are of potential interest as treatment for cardiovascular diseases but to our knowledge they have never been proposed to treat overactive bladder. We evaluated the effects of the soluble guanylyl cyclase activator BAY 60-2270 on voiding dysfunction and detrusor overactivity in a mouse model of obesity associated overactive bladder. MATERIALS AND METHODS: C57BL/6 male mice fed for 10 weeks with standard chow or a high fat diet were treated with 1 mg/kg BAY 60-2770 per day for 2 weeks via gavage. Cystometric evaluations were done and responses to contractile agents in isolated bladders were determined. RESULTS: Obese mice showed an irregular micturition pattern characterized by significant increases in voiding and nonvoiding contractions, which were normalized by BAY 60-2770. Carbachol, KCl and CaCl2 produced concentration dependent contractions in isolated bladder strips, which were markedly greater in obese than in lean mice. BAY 60-2770 normalized bladder contractions in the obese group. A 78% increase in reactive oxygen species generation in the bladder tissue of obese mice was observed, which was unaffected by BAY 60-2770. Treatment with BAY 60-2770 generated a tenfold increase in cyclic guanosine monophosphate in the bladders of obese mice without affecting the nucleotide level in the lean group. Protein expression of the soluble guanylyl cyclase α1 and ß1 subunits was decreased 40% in the bladder tissue of obese mice but restored by BAY 60-2770. CONCLUSIONS: Two-week BAY 60-2770 therapy increased cyclic guanosine monophosphate and rescued expression of the soluble guanylyl cyclase α1 and ß1 subunits in bladder tissue, resulting in great amelioration of bladder dysfunction.