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Subclinical inflammation is linked to comorbidities and risk factors, consolidating the diagnosis of chronic non-communicable diseases, such as insulin resistance, atherosclerosis, hepatic steatosis, and some types of cancer. In this context, the role of macrophages is highlighted as a marker of inflammation as well as for the high power of plasticity of these cells. Macrophages can be activated in a wide range between classical or proinflammatory, named M1, and alternative or anti-inflammatory, also known as M2 polarization. All nuances between M1 and M2 macrophages orchestrate the immune response by secreting different sets of chemokines, while M1 cells promote Th1 response, the M2 macrophages recruit Th2 and Tregs lymphocytes. In turn, physical exercise has been a faithful tool in combating the proinflammatory phenotype of macrophages. This review proposes to investigate the cellular and molecular mechanisms in which physical exercise can help control inflammation and infiltration of macrophages within the non-communicable diseases scope. During obesity progress, proinflammatory macrophages predominate in adipose tissue inflammation, which reduces insulin sensitivity until the development of type 2 diabetes, progression of atherosclerosis, and diagnosis of non-alcoholic fatty liver disease. In this case, physical activity restores the balance between the proinflammatory/anti-inflammatory macrophage ratio, reducing the level of meta-inflammation. In the case of cancer, the tumor microenvironment is compatible with a high level of hypoxia, which contributes to the advancement of the disease. However, exercise increases the level of oxygen supply, favoring macrophage polarization in favor of disease regression.
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Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.
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Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal models. However, since PPIs can induce microbiota modulation despite the absence of a high-fat diet or weight gain, it is an interesting model to correlate microbiota modulation with the establishment of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of pantoprazole treatment on TLR4 signaling and liver histology in C57BL/6J mice for 60 days, trying to correlate microbiota modulation with some aspects of liver injury. We performed glucose (GTT) and insulin (ITT) tolerance tests, serum lipopolysaccharide (LPS) dosage, liver histology, liver and intestine extraction for Western blot and qPCR. Fecal microbiota were investigated via metagenomics. Chronic treatment with pantoprazole induced microbiota modulation and impaired ileum barrier integrity, without an association with insulin resistance. Furthermore, increased circulating LPS and increased Toll-like receptor 4 (TLR4) and TGFß downstream signaling may have an important role in the development of the observed liver microvesicular steatosis and fibrosis. Finally, this model of PPI-induced changes in microbiota might be useful to investigate liver microvesicular steatosis and fibrosis.
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Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Ratones , Humanos , Animales , Receptor Toll-Like 4/uso terapéutico , Pantoprazol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Inhibidores de la Bomba de Protones/uso terapéutico , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , FibrosisRESUMEN
BACKGROUND: Patient-derived xenograft (PDX) involve the direct surgical transfer of fresh human tumor samples to immunodeficient mice. This systematic review aimed to identify publications of head and neck cancer PDX (HNC-PDX) models, describing the main methodological characteristics and outcomes. METHODS: An electronic search was undertaken in four databases, including publications having used HNC-PDX. Data were analyzed descriptively. RESULTS: 63 articles were yielded. The nude mouse was one most commonly animal model used (38.8 %), and squamous cell carcinoma accounted for the majority of HNC-PDX (80.6 %). Tumors were mostly implanted in the flank (86.3 %), and the latency period ranged from 30 to 401 days. The successful rate ranged from 17 % to 100 %. Different drugs and pathways were identified. CONCLUSION: HNC-PDX appears to significantly recapitulate the morphology of the original HNC and represents a valuable method in translational research for the assessment of the in vivo effect of novel therapies for HNC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Animales , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In obesity, insulin resistance (IR) and diabetes, there are proteins and hormones that may lead to the discovery of promising biomarkers and treatments for these metabolic disorders. For example, these molecules may impair the insulin signaling pathway or provide protection against IR. Thus, identifying proteins that are upregulated in IR states is relevant to the diagnosis and treatment of the associated disorders. It is becoming clear that hepatocyte growth factor (HGF) is an important component of the pathophysiology of IR, with increased levels in most common IR conditions, including obesity. HGF has a role in the metabolic flux of glucose in different insulin sensitive cell types; plays a key role in ß-cell homeostasis; and is capable of modulating the inflammatory response. In this review, we discuss how, and to what extent HGF contributes to IR and diabetes pathophysiology, as well as its role in cancer which is more prevalent in obesity and diabetes. Based on the current literature and knowledge, it is clear that HGF plays a central role in these metabolic disorders. Thus, HGF levels could be employed as a biomarker for disease status/progression, and HGF/c-Met signaling pathway modulators could effectively regulate IR and treat diabetes.
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Here we review how immune activation and insulin resistance contribute to the metabolic alterations observed in HIV-infected patients, and how these alterations increase the risk of developing CVD. The introduction and evolution of antiretroviral drugs over the past 25 years has completely changed the clinical prognosis of HIV-infected patients. The deaths of these individuals are now related to atherosclerotic CVDs, rather than from the viral infection itself. However, HIV infection, cART, and intestinal microbiota are associated with immune activation and insulin resistance, which can lead to the development of a variety of diseases and disorders, especially with regards to CVDs. The increase in LPS and proinflammatory cytokines circulating levels and intracellular mechanisms activate serine kinases, resulting in insulin receptor substrate-1 (IRS-1) serine phosphorylation and consequently a down regulation in insulin signaling. While lifestyle modifications and pharmaceutical interventions can be employed to treat these altered metabolic functions, the mechanisms involved in the development of these chronic complications remain largely unresolved. The elucidation and understanding of these mechanisms will give rise to new classes of drugs that will further improve the quality of life of HIV-infected patients, over the age of 50.
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Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
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Diabetes Mellitus Tipo 2/prevención & control , Disbiosis/prevención & control , Microbioma Gastrointestinal , Resistencia a la Insulina , Mucosa Intestinal/fisiopatología , Obesidad/dietoterapia , Probióticos/uso terapéutico , Tejido Adiposo Blanco/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Regulación del Apetito , Bifidobacterium bifidum/clasificación , Bifidobacterium bifidum/crecimiento & desarrollo , Bifidobacterium bifidum/inmunología , Bifidobacterium bifidum/aislamiento & purificación , Permeabilidad de la Membrana Celular , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/microbiología , Dieta Alta en Grasa/efectos adversos , Disbiosis/etiología , Disbiosis/inmunología , Disbiosis/microbiología , Heces/microbiología , Microbioma Gastrointestinal/inmunología , Técnica de Clampeo de la Glucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lactobacillus acidophilus/clasificación , Lactobacillus acidophilus/crecimiento & desarrollo , Lactobacillus acidophilus/inmunología , Lactobacillus acidophilus/aislamiento & purificación , Lacticaseibacillus rhamnosus/clasificación , Lacticaseibacillus rhamnosus/crecimiento & desarrollo , Lacticaseibacillus rhamnosus/inmunología , Lacticaseibacillus rhamnosus/aislamiento & purificación , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Tipificación Molecular , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Distribución AleatoriaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article. A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper. All authors have been notified of this decision. The University of Campinas (UNICAMP) in São Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response.
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Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of ß-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of ß-endorphin levels, is the earliest hypothalamic defect leading to obesity.
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Hipotálamo/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Proopiomelanocortina/metabolismo , betaendorfina/metabolismo , Adolescente , Adulto , Animales , Dieta , Grasas de la Dieta/metabolismo , Ingestión de Energía , Humanos , Hipotálamo/inmunología , Inflamación/inmunología , Masculino , Ratones , Ratones Obesos , Obesidad/inmunología , Proopiomelanocortina/inmunología , Ratas , Ratas Wistar , Adulto JovenRESUMEN
Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.
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Metabolismo Energético , Hipotálamo/metabolismo , Lisofosfolípidos/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/análogos & derivados , Animales , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Ratas , Ratas Wistar , Receptores de Lisoesfingolípidos/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Esfingosina/metabolismo , Receptores de Esfingosina-1-FosfatoRESUMEN
OBJECTIVE: It has become clear that exercise may be a useful therapy in the insulin resistance treatment, as it has anti-inflammatory effects and improves insulin sensitivity. However, it remains uncertain whether exercise affects the adipocytes or infiltrated macrophages. Thus, the aim was to investigate the effects of acute exercise on the inflammatory status and insulin signaling of the white adipose tissue (WAT) fractions (stromal-vascular fraction [SVF] and adipocytes). DESIGN AND METHODS: The effect of acute swimming exercise was investigated on insulin sensitivity, insulin signaling, inflammatory pathways in the WAT fractions of high-fat fed Wistar rats. Additionally, macrophage infiltration and polarization were analyzed in the WAT. RESULTS: Acute exercise can improve insulin signaling in WAT fractions, along with a phenotypic switch from M1- to M2-macrophages in obese rats, as indicated by a marked increase in macrophage galactose-type C-type lectin 1-positive cells in WAT was observed. Additionally, exercise promoted a reduction in circulating levels of lipopolysaccharide, and toll-like receptor 4 activity along with TNF-alpha, IL-1-beta and MCP-1 mRNA levels in WAT fractions. CONCLUSIONS: These data suggest that acute exercise improves insulin signaling in the WAT, at least in part by inducing macrophage polarization toward the M2-state.
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Tejido Adiposo Blanco/citología , Dieta Alta en Grasa/efectos adversos , Macrófagos/metabolismo , Obesidad/metabolismo , Condicionamiento Físico Animal , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Quimiocina CCL2/sangre , Insulina/sangre , Resistencia a la Insulina , Interleucina-1/sangre , Interleucina-10/sangre , Lipopolisacáridos/sangre , Masculino , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Hypothalamic 5'-adenosine monophosphate-activated protein kinase (AMPK) senses intracellular metabolic stress, i.e., an increase in the cellular AMP:ATP ratio, and integrates diverse hormonal and nutritional signals to restore energy balance. Recent evidence suggests that different nutrients can modulate AMPK activity in the hypothalamus, thereby controlling weight gain through a leptin-independent mechanism. Understanding the mechanisms by which nutrients control hypothalamic AMPK activity is crucial to the development of effective nutritional interventions for the treatment of food intake-related disorders, such as anorexia and obesity. This article highlights the current evidence for the intricate relationship between nutrients and hypothalamic AMPK activity.
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Proteínas Quinasas Activadas por AMP/metabolismo , Ingestión de Alimentos/fisiología , Hipotálamo/metabolismo , Animales , Metabolismo Energético/fisiología , Homeostasis/fisiología , Humanos , Hipotálamo/enzimologíaRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article. A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper. All authors have been notified of this decision. The University of Campinas (UNICAMP) in São Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response.
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Colitis/etiología , Colon/inmunología , Neoplasias del Colon/etiología , Mediadores de Inflamación/metabolismo , Obesidad/complicaciones , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Apoptosis , Azoximetano , Western Blotting , Proliferación Celular , Colitis/genética , Colitis/inmunología , Colitis/metabolismo , Colitis/patología , Colitis/prevención & control , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Sulfato de Dextran , Modelos Animales de Enfermedad , Activación Enzimática , Células HT29 , Humanos , Hiperinsulinismo/tratamiento farmacológico , Hiperinsulinismo/etiología , Hiperinsulinismo/metabolismo , Hipoglucemiantes/farmacología , Quinasa I-kappa B/metabolismo , Inmunohistoquímica , Mediadores de Inflamación/antagonistas & inhibidores , Infliximab , Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Obesidad/genética , Obesidad/inmunología , Obesidad/metabolismo , Fosfatidilinositol 3-Quinasa , Pioglitazona , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Tiazolidinedionas/farmacología , Factores de Tiempo , Carga Tumoral , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKß)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKß, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKß phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.
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Antraquinonas/uso terapéutico , Antiinflamatorios/uso terapéutico , Dieta Alta en Grasa , Intolerancia a la Glucosa/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Obesidad/tratamiento farmacológico , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Antraquinonas/farmacología , Antiinflamatorios/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Insulina/metabolismo , Masculino , Ratones , Ratones Obesos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/metabolismoRESUMEN
PURPOSE: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines. EXPERIMENTAL DESIGN: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments. RESULTS: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G(2)-M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments. CONCLUSION: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment.
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Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/farmacología , Activación Enzimática/efectos de los fármacos , Hipoglucemiantes/farmacología , Metformina/farmacología , Neoplasias/metabolismo , Animales , Antimetabolitos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Desoxiglucosa/farmacología , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Ratones SCID , Paclitaxel/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKbeta/NF-kappaB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKbeta/NF-kappaB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKbeta and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.
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Antiinflamatorios/metabolismo , Retículo Endoplásmico/patología , Proteínas I-kappa B/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Antiinflamatorios/farmacología , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Metabolismo Energético , Hiperfagia , Hipotálamo/fisiopatología , Insulina/fisiología , Interleucina-10/farmacología , Interleucina-6/farmacología , Leptina/fisiología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Obesidad/metabolismo , Ratas , Ratas WistarRESUMEN
About 25% of cancer cases globally are due to excess weight and a sedentary lifestyle. These results are alarming, as the world knows a pandemic of obesity and, in consequence, insulin resistance. Obesity may increase risk for various cancers by several mechanisms, including increasing sex and metabolic hormones, and inflammation. Here, we present a review of epidemiological and molecular evidences linking obesity and cancer--particularly colorectal, post-menopausal breast, endometrial, pancreatic, high grade prostate, hepatocellular, gallbladder, kidney and esophageal adenocarcinoma. The expected striking increase in the incidence of cancer in the near future related to obesity turns the knowledge of this field of great impact as it is needed to the development of strategies to prevent and treat this disease.
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Neoplasias/etiología , Obesidad/complicaciones , Tejido Adiposo/fisiopatología , Adiposidad/fisiología , Hormonas Esteroides Gonadales/fisiología , Humanos , Inflamación/fisiopatología , Resistencia a la Insulina/fisiología , Neoplasias/epidemiología , Obesidad/epidemiología , Obesidad/metabolismoRESUMEN
Insulin signalling in the hypothalamus plays a role in maintaining body weight. The forkhead transcription factor Foxo1 is an important mediator of insulin signalling in the hypothalamus. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase/Akt signalling pathway, but the role of hypothalamic Foxo1 in insulin resistance and obesity remains unclear. Here, we identify that a high-fat diet impaired insulin-induced hypothalamic Foxo1 phosphorylation and degradation, increasing the nuclear Foxo1 activity and hyperphagic response in rats. Thus, we investigated the effects of the intracerebroventricular (i.c.v.) microinfusion of Foxo1-antisense oligonucleotide (Foxo1-ASO) and evaluated the food consumption and weight gain in normal and diet-induced obese (DIO) rats. Three days of Foxo1-ASO microinfusion reduced the hypothalamic Foxo1 expression by about 85%. i.c.v. infusion of Foxo1-ASO reduced the cumulative food intake (21%), body weight change (28%), epididymal fat pad weight (22%) and fasting serum insulin levels (19%) and increased the insulin sensitivity (34%) in DIO but not in control animals. Collectively, these data showed that the Foxo1-ASO treatment blocked the orexigenic effects of Foxo1 and prevented the hyperphagic response in obese rats. Thus, pharmacological manipulation of Foxo1 may be used to prevent or treat obesity.
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Ingestión de Alimentos/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Expresión Génica/efectos de los fármacos , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Obesidad/tratamiento farmacológico , Oligonucleótidos Antisentido/farmacología , Tejido Adiposo Blanco/anatomía & histología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Dieta , Ingestión de Energía/efectos de los fármacos , Epidídimo/anatomía & histología , Epidídimo/efectos de los fármacos , Factores de Transcripción Forkhead/genética , Hipotálamo/efectos de los fármacos , Insulina/administración & dosificación , Insulina/sangre , Insulina/farmacología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Obesidad/sangre , Obesidad/patología , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Receptor de Insulina/metabolismo , Factores de Transcripción p300-CBP/metabolismoRESUMEN
About 25 percent of cancer cases globally are due to excess weight and a sedentary lifestyle. These results are alarming, as the world knows a pandemy of obesity and, in consequence, insulin resistance. Obesity may increase risk for various cancers by several mechanisms, including increasing sex and metabolic hormones, and inflammation. Here, we present a review of epidemiological and molecular evidences linking obesity and cancer - particularly colorectal, post-menopausal breast, endometrial, pancreatic, high grade prostate, hepatocellular, gallbladder, kidney and esophageal adenocarcinoma. The expected striking increase in the incidence of cancer in the near future related to obesity turns the knowledge of this field of great impact as it is needed to the development of strategies to prevent and treat this disease.
Aproximadamente 25 por cento dos casos de câncer são decorrentes do excesso de peso e do modo de vida sedentário. Esses resultados são alarmantes, pois o mundo vive uma pandemia de obesidade e, consequentemente, de resistência à insulina. A obesidade pode aumentar o risco de vários tipos de câncer por diversos mecanismos, incluindo aumento dos hormônios sexuais e metabólicos, e de inflamação. Neste trabalho, apresentamos uma revisão das evidências epidemiológicas e moleculares que relacionam a obesidade ao câncer - em particular aos cânceres colorretal, mamário na pós-menopausa, endometrial, pancreático, prostático avançado, hepatocelular, de bexiga, renal e esofágico. O aumento esperado da incidência de câncer relacionado à obesidade em um futuro próximo torna o conhecimento dessa área de grande importância, uma vez que este é fundamental para o desenvolvimento de estratégias preventivas e terapêuticas para a doença.