Hypothalamic S1p/s1pr1 Axis Controls Energy Homeostasis In Middle-aged Rodents: The Reversal Effects Of Physical Exercise

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.91156169Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP2011/09656-0, 2011/13828-1]Conselho Nacional de desenvolvimento cientifico e tecnologico (CNPq) [304815/2014-4]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed

The effects of physical exercise about the glucose sensing in the hypothalamus of rats : the role of HIF2 alpha

Orientador: Eduardo Rochete RopelleTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências AplicadasResumo: Em mamíferos, a ingestão alimentar e o gasto energético são fortemente regulados por neurônios específicos localizados no hipotálamo. O hipotálamo realiza esse controle através de sinais hormonais e nutricionais advindos da periferia. Um dos principais sinais nutricionais relacionados ao controle da ingestão alimentar é a glicose. Estudos apontam que a perda seletiva de sensibilidade à glicose em neurônios hipotalâmicos está relacionada à hiperfagia e obesidade. Recentemente foi desvendado o papel da proteína HIF2'alfa' como um importante regulador da sensibilidade à glicose em neurônios hipotalâmicos. A perda de função de HIF2'alfa' reduz a capacidade de os neurônios detectarem a presença de glicose, resultando em aumento da ingestão alimentar e peso corporal em camundongos. Nesse contexto, o controle da expressão de HIF2'alfa' nos neurônios pode ser considerado uma estratégia determinante para a manutenção do fenótipo magro. Estudos sugerem que o lactato, subproduto da via glicolítica, pode ser um modulador das HIFs. Paralelamente, evidências mostraram que o exercício físico, considerado um dos maiores contribuintes para o controle do peso corporal e gasto energético, é um potente indutor na produção de lactato. Desse modo, os objetivos deste estudo foram investigar os efeitos do exercício físico sobre a sensibilidade à glicose no hipotálamo de ratos e avaliar a expressão da proteína HIF2'alfa' no hipotálamo. Inicialmente, ratos Wistar foram submetidos ao consumo de dieta com baixo teor calórico (Chow) e/ou dieta rica em gordura (HFD) durante 12 semanas. Posteriormente, utilizamos o exercício físico agudo de natação para induzir a lactacidemia, em seguida, foi feito um tratamento agudo intracerebroventricular (ICV) de glicose ou lactato no hipotálamo. Nossos resultados mostraram que o consumo de dieta HFD causou obesidade e perda de sensibilidade à glicose no hipotálamo em ratos quando comparado ao grupo controle. O exercício físico agudo melhorou a glicemia de jejum e o consumo alimentar de ratos obesos, acompanhado da melhora da sensibilidade à glicose. Também encontramos aumento de HIF2'alfa' no hipotálamo de ratos magros e obesos, bem como nos níveis séricos e centrais de lactato pós-exercício em ratos obesos. Finalmente, a infusão aguda ICV de lactato aumentou o conteúdo proteico de HIF2'alfa' e reduziu o consumo alimentar em ratos magros e obesos. Tomados em conjunto, nossos resultados sugerem que a expressão de HIF2'alfa' hipotalâmica foi mediada, em parte, pelo lactato e que o exercício físico pode ser um alvo terapêutico não farmacológico para indução da lactacidemia, aumento da expressão da HIF2'alfa' e aumento da sensibilidade à glicose no hipotálamoAbstract: In mammals, food intake and energy expenditure are regulated by specific neurons located in the hypothalamus. The hypothalamus controls food intake and energy expenditure through hormonal and nutritional signals coming from the periphery. One of the major nutrients related to the control of food intake is glucose. Studies have shown that the selective loss of sensitivity glucose in hypothalamic neurons is related to overeating and obesity. Recently, Hypoxia Inducible Factor-2 (HIF2'alpha' protein) has emerged as an important regulator in the maintenance of glucose sensitivity and hypothalamic neurons. The loss of function of this molecule reduces the ability of neurons to detect the presence of glucose, resulting in increased food intake and body weight in mice. In this context, the maintenance of neuronal HIF2'alpha' functions can be considered a key strategy for maintaining lean phenotype. At the same time, the exercise is considered a major contributor to the control of body weight and energy expenditure. However, the effects of exercise on glucose sensitivity in the central nervous system (CNS) remain unexploited. Thus, the aim of this study is to investigate the effect of exercise on glucose sensitivity in the hypothalamus of rats and evaluate the expression of neuronal HIF2 'alpha'protein and the effect of lactate treatment about the neuronal HIF2'alpha' protein expression. First, Wistar rats were randomly separated into two groups: One group consumed standard chow diet (Chow), while the other group consumed high-fat diet for twelve weeks. Next, using the acute swimming protocol exercise for induction of lactatemia and after we did a treatment intracerebroventriculary (ICV) of glucose or lactate into the hypothalamus. Here, we showed that HFD consume caused obesity and loss neuronal glucose sensing when compared at control group. Acute physical exercises improved fasting glucose and food consumption and ameliorate the neuronal glucose sensing in obese rats. The HIF2'alpha' in the hypothalamus was raised and also serum and central lactate post-exercise in obese rats. Finally, the injection ICV of lactate increased content protein of HIF2'alpha' in the hypothalamus and reduced food intake in lean and obese rats. Taken together, our results suggest, at least in parts, that the HIF2'alpha' in the hypothalamus is mediate by lactate and the physical exercise can be a therapeutic target stimulating the lactatemia. In conclusion, hypothalamic HIF2'alpha' can be a target against obesity by improvement of neuronal glucose sensingDoutoradoMetabolismo e Biologia MolecularDoutor em Ciências da Nutrição e do Esporte e Metabolismo2013/20052-5FAPES

Effects of physical exercise on leptina signaling in the hypothalamus of rats : the role of neuronal S1PR1

Orientador: Eduardo Rochete RopelleDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências AplicadasResumo: A ingestão alimentar e o gasto energético são minuciosamente regulados por neurônios específicos localizados no hipotálamo. Durante as duas últimas décadas, a localização dos receptores da leptina em núcleos hipotalâmicos, bem como a descrição da via de transmissão intracelular disparado por este hormônio em neurônios hipotalâmicos, foi determinante para o entendimento do controle da ingestão alimentar e do gasto energético. Cada vez mais os distúrbios alimentares associados a doenças como obesidade são relacionados à disfunções na transmissão do sinal da leptina no hipotálamo. O processo inflamatório subclínica frequentemente observado em modelos experimentais de obesidade estão diretamente associados à distintos mecanismos de resistência à leptina no hipotálamo e resultam em aumento da ingestão alimentar e ganho de peso corporal. Por outro lado, estudos demonstram que o exercício físico é capaz de aumentar a sensibilidade da leptina no hipotálamo de animas obesos através de citocinas anti-imflamatórias, contudo, esses mecanismos permanecem apenas parcialmente conhecidos. Recentemente, a proteína S1PR1 (sphingosine-1-phosphate receptor-1) foi descrita como uma molécula com alta capacidade de exercer potentes efeitos sinérgicos sobre a via de sinalização da leptina, sustentando a ativação da via Jak2/STAT3 em algumas linhagens celulares. Assim, o presente estudo tem por objetivo investigar o os efeitos do exercício físico sobre a atividade da SIPR1 e a sensibilidade à leptina em hipotálamo de roedores obesos. Acreditamos que a realização do presente estudo contribuirá para caracterizar a participação da S1PR1 na sinalização da leptina no hipotálamo, bem como determinar os efeitos do exercício físico sobre a atividade da S1PR1 neuronalAbstract: The food intake and energy expenditure are closely regulated by specific neurons in the hypothalamus. During the last two decades, the location of the leptin receptor in hypothalamic nuclei as well as the description of the route of transmission Intracellular triggered by this hormone in hypothalamic neurons, were crucial to the understanding of the control of food intake and energy expenditure.Increasingly, eating disorders, diseases associated with obesity are related to signal transmission malfunction of leptin in the hypothalamus. The subclinical inflammatory process frequently observed in experimental models of obesity are directly associated with distinct mechanisms of leptin resistance in the hypothalamus and result in increased food intake and body weight gain. Furthermore, studies have shown that physical exercise can increase the sensitivity of leptin in the hypothalamus of obese animals, through of antiinflammatory cytokines, however, these mechanisms remain only partially understood. Recently, the protein S1PR1 (sphingosine-1-phosphate receptor-1) was described as a molecule with high ability to exert potent synergistic effects on the signaling pathway of leptin, supporting the activation of Jak2/STAT3 in some cell lines. Thus, this project aims to investigate the effects of exercise on the activity of SIPR1 and leptin sensitivity in hypothalamus of obese rodents. We believe that the completion of this project will contribute to characterize the involvement of S1PR1 in leptin signaling in the hypothalamus, and to determine the effects of exercise on the activity of neuronal S1PR1MestradoMetabolismo e Biologia MolecularMestre em Ciências da Nutrição e do Esporte e Metabolism

Cardiorespiratory fitness and the association with galectin-1 in middle-aged individuals.

Galectin-1 plays a functional role in human metabolism and the levels are altered in obesity and type 2 diabetes (T2D). This study investigates the association of cardiorespiratory fitness (CRF) with galectin-1 and the interconnection with body fatness. Cross-sectional data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot was analyzed, including a sample of 774 middle-aged individuals. A submaximal cycle ergometer test was used to estimate CRF as an indirect measure of the physical activity (PA) level. Serum-galectin-1 concentration was determined from venous blood collected after an overnight fast. Body mass index (BMI) was used as an indirect measure of body fatness. CRF was significantly associated with galectin-1, when controlled for age and sex (regression coefficient (regr coeff) = -0.29, p<0.001). The strength of the association was attenuated when BMI was added to the regression model (regr coeff = -0.09, p = 0.07), while the association between BMI and galectin-1 remained strong (regr coeff = 0.40, p<0.001). CRF was associated with BMI (regr coeff = -0.50, p<0.001). The indirect association between CRF and galectin-1 through BMI (-0.50 x 0.40) contributed to 69% of total association (mediation analysis). In group comparisons, individuals with low CRF-high BMI had the highest mean galectin-1 level (25 ng/ml), while individuals with high CRF-low BMI had the lowest level (21 ng/ml). Intermediate levels of galectin-1 were found in the low CRF-low BMI and high CRF-high BMI groups (both 22 ng/ml). The galectin-1 level in the low CRF-high BMI group was significantly different from the other three groups (P<0.001). In conclusion, galectin-1 is associated with CRF as an indirect measure of the PA level through interconnection with body fatness. The size of the association is of clinical relevance

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data

Measurement of the inelastic pppp cross-section at a centre-of-mass energy of 13 TeV

The cross-section for inelastic proton-proton collisions at a centre-of-mass energy of 13 TeV is measured with the LHCb detector. The fiducial cross-section for inelastic interactions producing at least one prompt long-lived charged particle with momentum p > 2 GeV/c in the pseudorapidity range 2 < η < 5 is determined to be σ$_{acc}$ = 62.2 ± 0.2 ± 2.5 mb. The first uncertainty is the intrinsic systematic uncertainty of the measurement, the second is due to the uncertainty on the integrated luminosity. The statistical uncertainty is negligible. Extrapolation to full phase space yields the total inelastic proton-proton cross-section σ$_{inel}$ = 75.4 ± 3.0 ± 4.5 mb, where the first uncertainty is experimental and the second due to the extrapolation. An updated value of the inelastic cross-section at a centre-of-mass energy of 7 TeV is also reported