RESUMEN

OBJECTIVE: To investigate the effect of voluntary physical activity (VPA) on inflammatory profile and the progression of experimental periodontal disease (PD) in mice. METHODS: Male C57BL/6 mice were randomly distributed into Control; VPA; PD and PD/VPA groups. We registered VPA (total volume of revolutions) and average speed (revolutions/minute) in a free running wheel for 30 days. On the 15th day, animals from the PD and PD/VPA groups received ligatures on the upper second molars bilaterally. On the 30th day animals were euthanized, and PD progression was assessed by measuring alveolar bone loss (ABL - the linear distance between the cemento-enamel junction and the alveolar bone crest on the teeth buccal surface). Gene expression of RANKL (kappa nuclear factor B receptor) OPG (osteoprotegerin), IL-1ß (interleukin 1 beta), IL-6 (interleukin 6) and TNF-α (tumor necrosis factor alpha) were evaluated by real-time PCR (quantitative Polymerase Chain Reaction - relative gene expression). RESULTS: The total volume of physical activity and the activity speed decreased along the seven days after ligature-placement (p < 0.05), returning to a similar pattern in relation to VPA group. Ligature placement produced significant bone resorption, and increased RANKL, IL-1ß, IL-6 and TNF-α expression. VPA reduced ABL (p < 0,05) and the expression of TNF-α and IL-1ß, whereas increased OPG expression. CONCLUSION: Animals induced to PD with access to the VPA wheel presented both lower gingival inflammation and less alveolar bone resorption in comparison to animals without access to the wheel.

Asunto(s)

Pérdida de Hueso Alveolar , Periodontitis , Pérdida de Hueso Alveolar/patología , Animales , Interleucina-6 , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoprotegerina/metabolismo , Periodontitis/metabolismo , Ligando RANK/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

In experimental obesity, the hypothalamus is affected by an inflammatory response activated by dietary saturated fats. This inflammation is triggered as early as one day after exposure to a high-fat diet, and during its progression, there is recruitment of inflammatory cells from the systemic circulation. The objective of the present study was identifying chemokines potentially involved in the development of hypothalamic diet-induced inflammation. In order to identify chemokines potentially involved in this process, we performed a real-time PCR array that determined Ackr2 as one of the transcripts undergoing differential regulation in obese-prone as compared to obese-resistant mice fed a high-fat diet for three days. ACKR2 is a decoy receptor that acts as an inhibitor of the signals generated by several CC inflammatory chemokines. Our results show that Ackr2 expression is rapidly induced after exposure to dietary fats both in obese-prone and obese-resistant mice. In immunofluorescence studies, ACKR2 was detected in hypothalamic neurons expressing POMC and NPY and also in microglia and astrocytes. The lentiviral overexpression of ACKR2 in the hypothalamus reduced diet-induced hypothalamic inflammation; however, there was no change in spontaneous caloric intake and body mass. Nevertheless, the overexpression of ACKR2 resulted in improvement of glucose tolerance, which was accompanied by reduced insulin secretion and increased whole body insulin sensitivity. Thus, ACKR2 is a decoy chemokine receptor expressed in most hypothalamic cells that is modulated by dietary intervention and acts to reduce diet-induced inflammation, leading to improved glucose tolerance due to improved insulin action.

Asunto(s)

Perfilación de la Expresión Génica , Glucosa/metabolismo , Hipotálamo/metabolismo , Inflamación/genética , Obesidad/genética , Receptores de Quimiocina/genética , Animales , Astrocitos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Prueba de Tolerancia a la Glucosa , Hipotálamo/citología , Inflamación/etiología , Inflamación/metabolismo , Resistencia a la Insulina/genética , Masculino , Ratones , Neuronas/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Receptores de Quimiocina/metabolismo

RESUMEN

Obesity is a public health issue that affects more than 600 million adults worldwide. The disease is characterized by fat accumulation, mainly in the abdominal area. The human body is mainly composed of two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT); however, the browning process generates a different type of brown fat-like adipocyte in WAT, which similar to BAT has thermogenic capacity by activating UCP-1. The hypothalamic arcuate nucleus plays an important role in WAT browning via POMC neurons, which are influenced by synergistic insulin and leptin signaling. On the other hand, stimulation of AgRP neurons suppresses WAT browning. The hypothalamic inflammatory process that occurs in obesity impairs insulin and leptin signaling in this tissue and, consequently, can decrease WAT browning. In addition, practicing physical exercise may be a great strategy for triggering the browning process since it reduces hypothalamic inflammation and increases POMC neurons gene expression. Moreover, physical exercise stimulates irisin gene expression, which has an important impact on thermogenesis, which in turn culminates in increased gene expression of proteins such as UCP-1 and Cidea, which are related to WAT browning. Furthermore, thermogenetic activation of WAT leads to increased energy expenditure, favoring obesity treatment. Therefore, this mini-review aimed to highlight the most recent studies that link the control of hypothalamic activity with the browning metabolism of adipose tissue in response to physical exercise.

RESUMEN

AIM: To evaluate the effects of physical training on inflammatory and behavioural parameters of Wistar rats with periodontal disease (PD). MATERIALS AND METHODS: Twenty four animals were distributed in a 2 × 2 factorial design (with and without exercise, with and without PD). Trained animals swimmed one hour daily during 8 weeks. PD was induced by ligature 14 days before the end of experiment, and in the last week, all animals were submitted to the Marble Burying Test. Histomorphometric analyses of the mandibles and expression of cytokines were conducted by Western blotting. We also evaluated the morphometry of hippocampal astrocytes using anti-glial fibrillary acidic protein antibody. RESULTS: Physical training attenuated bone loss and epithelial attachment loss levels of rats with PD. Trained animals with PD presented lower TNF-α expression in periodontal tissues while IL-10 was increased. TNF-α/IL-10 ratio was lower in trained animals with PD compared to those with induced periodontitis. PD increased anxiety-like behaviour, and physical training attenuated this parameter. Exercise increased the ramifications of hippocampal astrocytes in rats without PD. CONCLUSIONS: Exercise decreased anxiety behaviour, inflammatory proteins expression and bone loss in rats with PD.

Asunto(s)

Pérdida de Hueso Alveolar/prevención & control , Ansiedad/prevención & control , Periodontitis/terapia , Condicionamiento Físico Animal , Animales , Western Blotting , Citocinas/análisis , Encía/química , Masculino , Periodontitis/psicología , Ratas , Ratas Wistar

RESUMEN

BACKGROUND: The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity. METHODS: Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic surgery to place an indwelling cannula into the right lateral ventricle. intracerebroventricular (icv)-cannulated mice were treated twice a day for 6 days with 2.0 µL saline or GPR40 and GPR120 agonists: GW9508, TUG1197, or TUG905 (2.0 µL, 1.0 mM). Food intake and body mass were measured during the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis. RESULTS: We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus. Reducing GPR120 hypothalamic expression using a lentivirus-based approach resulted in the loss of the anti-inflammatory effect of GW9508 and increased energy efficiency. Intracerebroventricular treatment with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively, resulted in milder effects than those produced by GW9508. CONCLUSIONS: GPR120 and GPR40 act in concert in the hypothalamus to reduce energy efficiency and regulate the inflammation associated with obesity. The combined activation of both receptors in the hypothalamus results in better metabolic outcomes than the isolated activation of either receptor alone.

Asunto(s)

Metabolismo Energético/fisiología , Ácidos Grasos Insaturados/biosíntesis , Homeostasis/fisiología , Hipotálamo/metabolismo , Receptores Acoplados a Proteínas G/biosíntesis , Animales , Línea Celular , Ácidos Grasos Insaturados/genética , Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Masculino , Ratones , Microglía/metabolismo , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/genética

RESUMEN

BACKGROUND: Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. Studies have shown that polyunsaturated fats can reduce hypothalamic inflammation. Here, we evaluated the presence and function of RvD2, a resolvin produced from docosahexaenoic acid, in the hypothalamus of mice. METHODS: Male Swiss mice were fed either chow or a high-fat diet. RvD2 receptor and synthetic enzymes were evaluated by real-time PCR and immunofluorescence. RvD2 was determined by mass spectrometry. Dietary and pharmacological approaches were used to modulate the RvD2 system in the hypothalamus, and metabolic phenotype consequences were determined. RESULTS: All enzymes involved in the synthesis of RvD2 were detected in the hypothalamus and were modulated in response to the consumption of dietary saturated fats, leading to a reduction of hypothalamic RvD2. GPR18, the receptor for RvD2, which was detected in POMC and NPY neurons, was also modulated by dietary fats. The substitution of saturated by polyunsaturated fats in the diet resulted in increased hypothalamic RvD2, which was accompanied by reduced body mass and improved glucose tolerance. The intracerebroventricular treatment with docosahexaenoic acid resulted in increased expression of the RvD2 synthetic enzymes, increased expression of anti-inflammatory cytokines and improved metabolic phenotype. Finally, intracerebroventricular treatment with RvD2 resulted in reduced adiposity, improved glucose tolerance and increased hypothalamic expression of anti-inflammatory cytokines. CONCLUSIONS: Thus, RvD2 is produced in the hypothalamus, and its receptor and synthetic enzymes are modulated by dietary fats. The improved metabolic outcomes of RvD2 make this substance an attractive approach to treat obesity.

Asunto(s)

Ácidos Docosahexaenoicos/uso terapéutico , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Hipotálamo/metabolismo , Obesidad/complicaciones , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Proteínas de Unión al Calcio/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/química , Ácidos Docosahexaenoicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Hipotálamo/patología , Masculino , Ratones , Proteínas de Microfilamentos/metabolismo , Neuronas/metabolismo , Neuropéptido Y/metabolismo , Obesidad/inducido químicamente , Consumo de Oxígeno/fisiología , Proopiomelanocortina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo

RESUMEN

Apoptosis of hypothalamic neurons is believed to play an important role in the development and perpetuation of obesity. Similar to the hippocampus, the hypothalamus presents constitutive and stimulated neurogenesis, suggesting that obesity-associated hypothalamic dysfunction can be repaired. Here, we explored the hypothesis that n-3 polyunsaturated fatty acids (PUFAs) induce hypothalamic neurogenesis. Both in the diet and injected directly into the hypothalamus, PUFAs were capable of increasing hypothalamic neurogenesis to levels similar or superior to the effect of brain-derived neurotrophic factor (BDNF). Most of the neurogenic activity induced by PUFAs resulted in increased numbers of proopiomelanocortin but not NPY neurons and was accompanied by increased expression of BDNF and G-protein-coupled receptor 40 (GPR40). The inhibition of GPR40 was capable of reducing the neurogenic effect of a PUFA, while the inhibition of BDNF resulted in the reduction of global hypothalamic cell. Thus, PUFAs emerge as a potential dietary approach to correct obesity-associated hypothalamic neuronal loss.

Asunto(s)

Glucemia/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Hipotálamo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Animales , Glucemia/metabolismo , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Prueba de Tolerancia a la Glucosa , Hipotálamo/citología , Hipotálamo/metabolismo , Ratones , Neuronas/metabolismo , Neuropéptido Y , Proopiomelanocortina/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

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.

Asunto(s)

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/metabolismo

RESUMEN

The anomalous activation of toll-like receptor 4 (TLR4) by dietary fats is one of the most important mechanisms linking obesity to insulin resistance. TLR4 is expressed in most tissues of the body, but its activity in the cells of the immune system is expected to underlie its most important roles of inducing inflammation and insulin resistance. Here we explore the hypothesis that TLR4 expression in bone marrow-derived cells mediates most of the actions of this receptor as an inducer of insulin resistance. Wild type and TLR4-mutant mice were used in bone marrow transplant experiments producing chimeras that harbored the functional receptor in all cells of the body except bone marrow-derived cells or only in bone marrow-derived cells. Transplanted mice were fed chow or a high-fat diet, and glucose homeostasis was evaluated by glucose and insulin tolerance tests. Insulin signal transduction and the expression of markers of inflammation were evaluated in the liver and white adipose tissue. In addition, we performed liver histology and evaluated the expression of gluconeogenic enzymes. The expression of TLR4 in bone marrow-derived cells only, but not in non-bone marrow-derived tissues only, was a determining factor in the induction of diet-induced insulin resistance, which was accompanied by an increased expression of inflammatory markers in both white adipose tissue and liver as well as increased liver steatosis and increased expression of gluconeogenic enzymes. TLR4 expressed in bone marrow-derived cells is an important mediator of obesity-associated insulin resistance in mice.

Asunto(s)

Grasas de la Dieta/efectos adversos , Regulación de la Expresión Génica/fisiología , Resistencia a la Insulina/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Receptor Toll-Like 4/metabolismo , Tejido Adiposo/metabolismo , Animales , Trasplante de Médula Ósea , Grasas de la Dieta/administración & dosificación , Inflamación/genética , Inflamación/metabolismo , Resistencia a la Insulina/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Obesidad/etiología , Obesidad/metabolismo , Proteínas Proto-Oncogénicas c-akt , Receptor Toll-Like 4/genética

RESUMEN

Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.

Asunto(s)

Quimiocina CX3CL1/metabolismo , Hipotálamo/metabolismo , Inflamación/metabolismo , Obesidad/metabolismo , Animales , Quimiocina CX3CL1/genética , Dieta Alta en Grasa/efectos adversos , Citometría de Flujo , Hipotálamo/inmunología , Immunoblotting , Inflamación/etiología , Inflamación/inmunología , Masculino , Ratones , Obesidad/etiología , Obesidad/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Receptor Toll-Like 4/metabolismo

RESUMEN

In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.

Asunto(s)

Hipotálamo/metabolismo , Obesidad/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Animales , Autofagia , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Microglía/metabolismo , Neuronas/metabolismo , Fenotipo , Factor de Transcripción TFIIH , Factores de Transcripción/metabolismo , Aumento de Peso , Pérdida de Peso

RESUMEN

The purpose of this study was to investigate, in older women, the acute effect of static stretching (SS) on both muscle activation and force output. Twenty-three older women (64.6 +/- 7.1 yr) participated in the study. The maximal voluntary contraction (MVC), rate of force development (RFD) (50, 100, 150, and 200 ms relative to onset of muscular contraction), and peak RFD (PRFD) (the steepest slope of the curve during the first 200 ms) were tested under 2 randomly separate conditions: SS and control (C). Electromyographic (EMG) activity of the vastus medialis (VM), vastus lateralis (VL), and biceps femoris (BF) muscles also was assessed. The MVC was significantly lower (p < 0.05) in the 3 trials of SS when compared with the C condition (control: 925.0 +/- 50.9 N; trial 1: 854.3 +/- 55.3 N; trial 2: 863.1 +/- 52.2 N; and trial 3: 877.5 +/- 49.9 N). PRFD showed a significant decrease only for the first 2 trials of SS when compared with the C condition (control: 2672.3 +/- 259.1 N/s; trial 1: 2296.6 +/- 300.7 N/s; and trial 2: 2197.9 +/- 246.3 N/s). However, no difference was found for RFD (50, 100, 150, and 200 ms relative to onset of muscular contraction). The EMG activity for VM, VL, and BF was not significantly different between the C and SS conditions. In conclusion, the older women's capacity to produce muscular force decreased after their performance of SS exercises. The mechanisms responsible for this effect do not appear to be related to muscle activation. Thus, if flexibility is to be trained, it is recommended that SS does not occur just before the performance of activities that require high levels of muscular force.

Asunto(s)

Contracción Isométrica/fisiología , Ejercicios de Estiramiento Muscular , Músculo Esquelético/fisiología , Anciano , Nalgas , Femenino , Humanos , Persona de Mediana Edad