Hiperatividade simpática na obesidade

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Efeitos moleculares do exercício físico sobre as vias de sinalização insulínica

O músculo esquelético representa aproximadamente 40% da massa corporal total e exerce papel primordial no metabolismo da glicose (SMITH; MUSCAT, 2005). Este tecido é responsável por aproximadamente 30% do dispêndio de energia, e é um dos principais tecidos responsável pela captação, liberação e estocagem de glicose(NUUTILA et al., 1992). Trabalhos das últimas décadas demonstram claramente que o exercício físico aumenta a captação de glicose pelo (JAMES et al., 1983; ERIKSSON et al., 1998; KENNEDY et al., 1999; LUCIANO et al., 2002). Além disso, recentemente foi demonstrado que a redução de peso corporal associada com o aumento da atividade física em indivíduos com risco aumentado para desenvolver diabetes reduz em 58% a incidência dessa doença (KNOWLER et al., 2002). Assim, atualmente o exercício físico é considerado uma das pedras angulares tanto do tratamento como da prevenção do Diabetes tipo 2. Os mecanismos moleculares envolvidos no aumento da captação de glicose muscular estão sendo intensamente pesquisados. Nesta revisão serão abordados alguns aspectos dessa fascinante área que está se desenvolvendo rapidamente

Obesity as a possible risk factor for progression from monoclonal gammopathy of undetermined significance progression into multiple myeloma: could myeloma be prevented with metformin treatment?

Obesity is increasingly associated with the transformation of monoclonal gammopathy of undetermined significance (MGUS) into multiple myeloma (MM). Obesity, MGUS, and MM share common etiopathogenesis mechanisms including altered insulin axis and the action of inflammatory cytokines. Consistent with this interconnection, metformin could predominantly exert inhibition of these pathophysiological factors and thus be an attractive therapeutic option for MGUS. Despite the possible clinical significance, only a limited number of epidemiological studies have focused on obesity as a risk factor for MGUS and MM. This review describes multiple biological pathways modulated by metformin at the cellular level and their possible impacts on the biology of MGUS and its progression into MM202

Inter-relação entre as vias de transmissão do sinal de insulina e leptina em hipotalamo e figado de ratos

Orientador: Mario Jose Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Insulina e leptina atuam de forma semelhante e aditiva para controlar a homeostase energética. Entretanto, a base molecular desse sinergismo permanece desconhecida. A insulina sinaliza através de um receptor tirosina quinase que fosforila e ativa seus substratos (IRSs - substratos do receptor de insulina), enquanto a leptina e sua proteína tirosina quinase associada JAK2 (Janus Kinase 2) medeiam a fosforilação e ativação do fator de transcrição STAT3 (Signal Transducer and Activator of Transcription). Para investigar se a insulina e a leptina ativam as mesmas vias de sinalização e para determinar se esses hormônios interagem em hipotálamo, ratos Wistar machos foram estudados após implante de cânula no terceiro ventrículo através de imunoprecipitação, immunoblotting e gel shift. A administração aguda intracerebroventricular (icv) de insulina resultou em aumento da fosforilação do receptor de insulina (IR), substrato 1 do receptor de insulina (JRS-l), substrato 2 do receptor de insulina (IRS-2) e MAPK (Mitogen Activated Protein Kinase), além da associação entre os IRSs e a PI 3-quinase e a fosforilação em serina da Akt. A administração icv de leptina resultou na fosforilação em tirosina da JAK2, OBR, STAT3, IRS-1, IRS-2 e MAPK, bem como da associação entre os IRSs e a PI 3-quinase mas não foi observada a fosforilação da Akt. O estímulo simultâneo com os dois hormônios não aumentou a fosforilação do IRS-1, IRS-2, Akt e MAPK quando comparado com a administração isolada de insulina. Em contrapartida, a insulina induziu a fosforilação da JAK2 e do receptor de leptina (OBR) que, em presença de leptina, aumentou a interação entre o STAT3 e o OBR com conseqüente aumento da ativação do STAT3. A leptina ativou as vias de sinalização classicamente induzidas pela insulina no hipotálamo, e essas vias se intercruzaram, mas foram utilizadas de forma distinta que quando utilizadas pela insulina. Por outro lado a insulina modulou positivamente a via de sinalização da leptina. Esses resultados proporcionam uma base molecular para os efeitos coordenados da insulina e leptina no controle do apetite e peso corporal. Para demonstrar interdependência entre as vias de sinalização da insulina e leptina em hipotálamo de ratos, a transmissão do sinal de insulina em direção às vias da PI 3-quinase e MAPK foi comparada em hipotálamo de ratos zucker obesos (modelo animal de resistência insulina causado pela mutação do receptor de leptina) e controle. A infusão icv de insulina reduziu a ingestão alimentar de ratos controle, o que não foi observado nos animais obesos. Constatamos redução da fosforilação do IR, IRS-1, IRS-2, da associação entre a subunidade p85 da PI 3-quinase com as proteínas IRSs, bem como da fosforilação em serina da Akt no hipotálamo de ratos obesos comparado com os ratos magros. Em contraste, a insulina estimulou a fosforilação em tirosina da MAPK de forma similar em ratos magros e obesos. Assim, documentamos resistência à sinalização da insulina em tecidos hipotalâmicos de ratos Zucker obesos. Esses resultados fortalecem a hipótese de que a insulina tem suas ações anti-obesidade através da via da PI 3-quinase e que a diminuição do sinal por esta via no hipotálamo pode contribuir para o desenvolvimento de obesidade em estados de resistência à insulina. Originalmente, pensava-se que o hipotálamo era o único tecido a expressar a forma longa do receptor de leptina. Entretanto, evidências recentes sugerem que órgãos periféricos, entre eles o figado, também expressam a forma longa do receptor. Assim, na segunda parte deste estudo investigamos os efeitos rápidos e diretos da leptina em figado e determinamos se a leptina interage com a insulina nesse órgão. Em figado de ratos a injeção aguda de leptina ou insulina estimulou a fosforilação da JAK2, STAT3 e STAT5b. A leptina foi menos efetiva que a insulina em estimular as proteínas IRS e a associação destas com a PI 3-quinase. O tratamento simultâneo com os dois hormônios não modificou a fosforilação máxima do STAT3, IRS-l, IRS-2 e Akt, mas causou aumento significativo da fosforilação da JAK2 e do STAT5b quando comparado com a administração isolada de insulina ou leptina. Assim, detectamos uma inter-relação positiva nas vias de sinalização desses hormônios nas proteínas JAK2 e STAT5b em figado de ratos. Concluindo, estes estudos caracterizaram as vias de transmissão do sinal de leptina em hipotálamo e figado, evidenciando mecanismos para a integração da sinalização de insulina e leptina bem como a modulação destas vias em modelo animal de resistência à insulina e leptina nesses tecidosAbstract: Insulin and leptin have overlapping effects in the control of energy homeostasis and glucose metabolism, but the molecular basis of this synergism is unknown. Insulin signals through a receptor tyrosine kinase that phosphorylates and activates the docking proteins IRSs (insulin receptor substrates), whereas the leptin receptor and its associated protein tyrosine kinase JAK2 (Janus kinase 2) mediate phosphorylation and activation of the transcription factor STAT3 (signal transducer and activator oftranscription). To investigate whether insulin and leptin share common intracellular signal transduction pathways and to determine whether these hormonal signaling systems modulate each other's action in rat hypothalamus male Wistar rats were studied after chronic implantation of an intracerebroventricular (i.c.v.) catheter into the third ventricle. Immunoprecipitation, immunoblotting and EMSA assays were used to examine the activation of insulin and leptin signaling molecules in the rat hypothalamus. Acute i.c.v. administration of insulin resulted in a time-dependent increase in tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrate 1 (IRS-1), insulin receptor substrate 2 (IRS-2) and MAPK (mitogen activated proein kinase), PI 3 kinase docking and serine phosphorylation of Akt. The i.c.v. administration of leptin resulted in tyrosine phosphorylation of JAK2, IRS-1, IRS-2 and MAPK and PI 3 kinase docking but no phosphorylation of Akt was observed. Simultaneous stimulation with both hormones did not increment tyrosine phosphorylation of IRS-1, IRS-2, Akt and MAPK when compared with isolated administration of insulin. In addition insulin induced JAK2 tyrosine phosphorylation and leptin receptor phosphorylation, which in the presence of leptin, augmented the interaction between STAT3 and this receptor. Insulin also increased the leptin-induced phosphorylation of STAT3 and its activation. Leptin rapidly activates classically insulin signaling pathways directly at the level of hypothalamus, and these pathways overlap with, but are distinct from, those engaged by insulin. On the other side, insulin modulates the leptin signal transduction pathway, and may provide a molecular basis for the coordinated effects of insulin and leptin in feeding behavior and weight control. To demonstrate the interdependence between insulin and leptin signaling in rat hypothalamus in vivo insulin signaling through the phosphatidylinositol 3-kinase (pI 3-kinase), mitogen-activated protein (MAP) kinase were compared in the hypothalamictissues of lean (Fa/?) and obese Zucker (falfa) rats (animal model of insulin resistance, which has a defect in the leptin receptor). Icv insulin infusion reduced food intake in Iean rats but no effect was observed in obese Zucker rats. Pretreatment with PI 3-kinase inhibitors prevents insulin-induced anorexia in lean rats. Insulin-stimulated tyrosine phosphorylation of insulin receptor (IR), IR substrates (IRS-1, IRS-2), the associations of p85 subunit of PI 3-kinase to the IRS proteins and serine phosphorylation of Akt in the hypothalamus of obese rats were significantly decreased compared with the lean rats. In contrast, insulin stimulated tyrosine phosphorylation of MAP kinase was similar in lean and obese rats. This segment of the study provides direct measurements of insulin signaIing in hypothalamic tissues, and document selective resistance to insulin signaling in the hypothalamus of obese Zucker rats at the molecular leveI. These findings have provided support for the hypothesis that insulin may have anti-obesity actions mediated by the PI 3-kinase pathway and that the impaired PI 3-kinase signal pathway in the hypothalamus may Iead to the development of obesity in insulin resistance and diabetic patients. Originally, it was thought that the hypothalamus was the only tissue expressing OBRb. However, recent evidence at the level of messenger RNA expression and cellular function suggest that peripheral organs including liver also express OBRb. Therefore the second part of the study was designed to investigate the rapid and potentially direct effects of leptin on signal transduction in liver and to determine whether insulin and leptin share common intracellular signal transduction pathways. Chronic leptin treatment markedly enhances the action of insulin on hepatic glucose production out of proportion to the body weight loss and increased insulin sensitivity. In the present experiments the cross-talk between insulin and leptin was evaluated in rat liver. Leptin, upon stimulation of JAK2 tyrosine phosphorylation, induced JAK2 coimmunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin at stimulating IRSs phosphorylation and their associations with PI 3-kinase. Simultaneous treatment with both hormones promoted no change in maximal phosphorylation of STAT3, IRS-l, IRS-2 and Akt, but led to marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. Thus, there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver. We have characterized the leptin signaling pathway in hypothalamus and liver and demonstrate various mechanisms for the integration between insulin and leptin in these tissues. We have also showed that the cross-talk between these hormones is tissue dependent and that the effects of this interaction affects the energetic homeostasis and glucose metabolism in the various stepsDoutoradoClinica MedicaDoutor em Clínica Médic

Outcomes of COVID-19 Patients under Cytotoxic Cancer Chemotherapy in Brazil

Background: Cancer patients present a distinct vulnerability to COVID-19. It is unclear if chemotherapy could accentuate the overall risk in these patients. Methods: We performed a retrospective analysis linking COVID-19 data and oncological information systems to compare lethality in patients undergoing cytotoxic chemotherapy before COVID-19. We considered patients who received chemotherapy in the last 30 days as in “active treatment”, and patients who did not receive drugs in this period as “non-active treatment” for propensity-score pair matching. We also tested the influence of baseline variables in our results in a multivariate model. Results: 66.1% (162/246) of patients in matched active chemotherapy died vs. 70.2% (172/246) in the matched non-active chemotherapy group. The risk of death was positively associated with palliative intent of treatment and hematologic neoplasms. Being in active chemotherapy was not associated with increased mortality compared to non-active treatment. We also noted in exploratory propensity-score matchings that the use of alkylating agents (odds ratio [OR] 0.38, 95% confidence interval [CI], 0.21–0.70) and topoisomerase II inhibitors (OR 0.28, 95% CI 0.14–0.56) were protective factors. Conclusions: This study does not demonstrate an increase in mortality for cancer patients under active cytotoxic chemotherapy with COVID-19

Effect Of Obesity On Insulin Signaling Through Jak2 In Rat Aorta.

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.43346-5

Analysis Of The Physical Activity Effects And Measurement Of Pro-inflammatory Cytokines In Irradiated Lungs In Rats.

To study if the pre-radiotherapy physical activity has radio-protective elements, by measuring the radio-induced activation of pro-inflammatory cytokines as interleukin-6 (il-6), transforming growth factor -β (tgf -β), tumor necrosis factor -α (tnf-α) and protein beta kinase β (ikkβ), through western blotting analysis. A randomized study with 28 Wistar hannover rats, males, with a mean age of 90 days and weighing about 200 grams. The animals were divided into three groups: (GI, GII and GIII). GIII group were submitted to swimming for eight weeks (zero load, three times a week, about 30 minutes). Then, the groups (except the control group) were submitted to irradiation by cobalt therapy, single dose of 3.5 gray in the whole body. All animals were sacrificed by overdose of pentobarbital, according to the time for analysis of cytokines, and then a fragment of the lower lobe of the right lung went to western blotting analysis. The cytokines IKK β, TNF-α and IL-6 induced by radiation in the lung were lower in the exercised animals. However, exercise did not alter the radiation-induced increase in tgf-β. The results show a lower response in relation to inflammatory cytokines in the group that practiced the exercise pre-radiotherapy, showing that exercise can protect tissues from tissue damage due to irradiation.27223-3

Modulation Of Ir/ptp1b Interaction And Downstream Signaling In Insulin Sensitive Tissues Of Msg-rats.

PTP1B has been shown to be a negative regulator of the insulin signal transduction in insulin resistant states. Herein we investigated IR/PTP1B interaction and downstream signaling in insulin sensitive tissues of 10 and 28-week-old MSG-insulin resistant rats which represent different stages of insulin resistance. Our results demonstrated that the increase in PTP1B expression and/or association with IR in MSG animals may contribute to the impaired insulin signaling mainly in liver and muscle. Although, adipose tissue of 10-week-old MSG rats showed higher PTP1B expression and IR/PTP1B interaction, they were not sufficient to impair all insulin signaling since IRS-2 phosphorylation and association with PI3-kinase and Akt serine phosphorylation were increased, which may contribute for the increased adiposity of these animals. In 28-week-old-MSG rats there was an increase in IR/PTP1B interaction and reduced insulin signaling in liver, muscle and adipocytes, and a more pronounced insulin resistance.731369-8