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INTRODUCTION: Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown. METHODS: Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice. RESULTS: Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression. DISCUSSION: Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance.Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age.
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Ácidos Graxos , Hipotálamo , Envelhecimento , Animais , Coenzima A/metabolismo , Ácidos Graxos/metabolismo , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Wistar , Sindecana-1/metabolismoRESUMO
OBJECTIVE: to describe the implantation of ultrasound screening for Abdominal Aortic Aneurysm (AAA) in our healthcare district in men from 65 to 79 years of age who have had an identifiable risk factor for developing AAA, such as smoking or a history thereof, hypertension, family history of aneurysms, aneurysms in other locations and clinical atherosclerosis, acute myocardial infarction, intermittent claudication, or stroke. Analyse the performance of said screening. SETTING: Primary Care. PARTICIPANTS AND INTERVENTIONS: 656 patients were screened, representing 40% of the target population of 1,658 patients. The remaining part of the target population could not be screened because of the outbreak of the COVID-19 pandemic. 608 ultrasound examinations were performed. MAIN MEASUREMENTS: coverage of the screening programme, prevalence of abdominal aortic aneurysms, prevalence of smoking and other risk factors in patients with/without aneurysms. RESULTS: 19 patients with ectatic aorta (25-29mm) and 11 with abdominal aortic aneurysms (1.81%) were found. 5 were active smokers (45%, compared to 20% in the entire sample) and 6 were former smokers. None of the aneurysm patients were non-smokers. 7 of them were hypertensive. CONCLUSIONS: The prevalence of aneurysms in our sample was 2.6%, which was lower than expected. The wide use of ultrasound and its progressive generalisation in the Primary Care setting should lead to a decrease in the number of undiagnosed AAA.
Assuntos
Aneurisma da Aorta Abdominal , COVID-19 , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/etiologia , Humanos , Masculino , Programas de Rastreamento , Pandemias , Prevalência , Atenção Primária à Saúde , Fatores de Risco , SARS-CoV-2 , UltrassonografiaRESUMO
BACKGROUND: Endoscopic sleeve gastroplasty is a safe and feasible treatment for obesity. This study is focused on our technique modification which suggests a different suturing pattern in order to distribute suture tension more evenly. METHODS: A retrospective study of 148 patients (121 women) who underwent this procedure and were monitored for 12 months was conducted. The average age was 41.53 ± 10 years. The average BMI was 35.11 ± 5.5 kg/m2 with the average initial weight being 98.7 ± 17 kg. A subgroup of the first 72 patients (60 women) were monitored for 18 months. A new running "Z" stitch pattern was used to provide gastric cavity reduction by means of 4 parallel suture rows. The stitch pattern was intended to provide a homogenous distribution of the disruptive force on the suture among all stitch points. RESULTS: %TWL was 17.53 ± 7.57 in 12 months and 18.5 ± 9% in 18 months indicating durability of the procedure. Patients with a BMI < 35 benefited most from an endoscopic gastroplasty. Leptin did not predict a response to endoscopic gastroplasty and decreased in all patients. In just one case there was a mild bleeding (0.67%) at the insertion point of the helix, which was resolved by sclerotherapy. CONCLUSIONS: Endoscopic gastroplasty offers a real choice for obese patients. This single-center experience with a modified suturing pattern provides a successful technique for weight loss.
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Endoscopia/métodos , Gastroplastia/métodos , Obesidade/cirurgia , Técnicas de Sutura , Adulto , Índice de Massa Corporal , Feminino , Humanos , Leptina/sangue , Masculino , Estudos Retrospectivos , Redução de PesoRESUMO
AIMS: Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful. MATERIALS AND METHODS: In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics. KEY FINDINGS: Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release. SIGNIFICANCE: The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature.
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Hipotálamo , Leptina , Proteoma , Proteômica , Ratos Wistar , Receptores para Leptina , Transdução de Sinais , Animais , Masculino , Leptina/metabolismo , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/deficiência , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteômica/métodos , Proteoma/metabolismo , Obesidade/metabolismo , Metabolismo Energético/efeitos dos fármacosRESUMO
The zinc alkaline battery is one of the most popular sources of portable electrical energy, with more than 300,000 tons being consumed per year. Accordingly, it is critical to recycle its components. In this work, we propose the use of zinc oxide (ZnO) microparticles recovered from worn-out batteries as fillers of epoxy resins. These nanocomposites can be used as protective coatings or pigments and as structural composites with high thermal stability. The addition of ceramic nanofillers, such as ZnO or/and TiO2, could enhance the thermal and mechanical properties, and the hardness and hydrophobicity, of the epoxy resins, depending on several factors. Accordingly, different nanocomposites reinforced with recycled ZnO and commercial ZnO and TiO2 nanoparticles have been manufactured with different nanofiller contents. In addition to the different ceramic oxides, the morphology and size of fillers are different. Recycled ZnO are"desert roses" such as microparticles, commercial ZnO are rectangular parallelepipeds nanoparticles, and commercial TiO2 are smaller spherical nanoparticles. The addition of ceramic fillers produces a small increase of the glass transition temperature (<2%), together with an enhancement of the barrier effect of the epoxy resin, reducing the water diffusion coefficient (<21%), although the maximum water uptake remains constant. The nanocomposite water absorption is fully reversible by subsequent thermal treatment, recovering its initial thermomechanical behavior. The water angle contact (WCA) also increases (~12%) with the presence of ceramic particles, although the highest hydrophobicity (35%) is obtained when the epoxy resin reinforced with recycled flowerlike ZnO microparticles is etched with acid stearic and acetic acid, inducing the corrosion of the ZnO on the surface and therefore the increment of the surface roughness. The presence of desert rose ZnO particles enhances the de lotus effect.
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S-resistin is a non-secretable resistin spliced variant described in white adipose tissue from Wistar rats. Since resistin has been implicated in adipogenesis regulation, here we have investigated the possible role of this new isoform in this process. For that, we have studied the adipocyte development in 3T3-L1 pre-adipocyte cell line stably expressing s-resistin and resistin. Both isoforms are able to restrain 3T3-L1 pre-adipocyte differentiation though affecting differently the expression pattern of pro-adipogenic transcription factors such CCAAT/enhancer binding proteins alpha and beta (C/EBPalpha and C/EBPbeta) and peroxisome proliferator-activated receptor gamma (PPARgamma), as well of proteins implicated in lipid metabolism such perilipin, fatty acid synthase (FAS), adipocyte lipid binding protein (ALBP/aP2) and carnitine palmitoyltransferase1 (CPT1). Likewise, both resistin isoforms impair insulin-stimulated glucose transport by decreasing glucose transport 4 (GLUT4) expression but to a different degree. In addition, s-resistin expressing 3T3-L1 cells display other remarkable differences. Thus, in these cells, endogenous resistin expression falls down while tumor necrosis factor alpha (TNFalpha) and interleukine 6 (IL-6) productions are increased along differentiation. These findings indicate that s-resistin isoform also impairs adipocyte differentiation affecting the expression pattern of key pro-adipogenic transcription factors and insulin sensitivity. Additionally, s-resistin may play a role in inflammatory processes.
Assuntos
Adipócitos/metabolismo , Diferenciação Celular/fisiologia , Resistina/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipogenia/genética , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Diferenciação Celular/genética , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Perfilação da Expressão Gênica , Glucose/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Interleucina-6/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos , PPAR gama/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Ratos , Ratos Wistar , Resistina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , TransfecçãoRESUMO
Increased adiposity, through adipocyte hypertrophy, and/or hyperplasia, characterizes aging and obesity. Both are leptin-resistant states, associated with disturbed lipid metabolism, reduced insulin sensitivity and inflammation. Nevertheless, fat tissue dysfunction appears earlier in obesity than in normal aging. In contrast, lipodystrophy is accompanied by diabetes, and improving the fat cell capacity to expand rescues the diabetic phenotype. Fat tissue dysfunction is extensively studied in the diet-induced obesity, but remains relatively neglected in the aging-associated obesity. In the Wistar rat, as occurs in humans, early or middle aging is accompanied by an increase in adiposity. Using this experimental model, we describe the molecular mechanisms contributing to the white adipose tissue (WAT) hypertrophy. WAT from middle-old age rats is characterized by decreased basal lipogenesis and lipolysis, increased esterification, as demonstrated by the higher TAG and cholesterol content in visceral WAT, and the maintenance of total ceramide levels within normal values. In addition, we describe alterations in the adipose tissue plasma membrane lipid composition, as increased total ether-phosphatidylcholine, sphingomyelin, and free cholesterol levels that favor an enlarged fat cell size with aging. All these metabolic changes may be regarded as a survival advantage that prevents the aged rats from becoming overtly diabetic.
Assuntos
Adipócitos/patologia , Tecido Adiposo Branco , Envelhecimento , Leptina/metabolismo , Metabolismo dos Lipídeos , Obesidade , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Hipertrofia , Masculino , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia , Ratos , Ratos WistarRESUMO
OBJECTIVE: Aging is a significant risk factor for the development of obesity and hepatic steatosis associated with insulin and leptin resistance. Food restriction (FR) is commonly used for reducing body weight (BW), adiposity, and liver steatosis. Thus, this study aimed to determine whether FR in middle-aged rats can recover the central leptin antisteatotic effects observed in the liver in young animals. METHODS: Two groups of 4-month-old Wistar rats were fed ad libitum (AL) or were on FR for 3 months. At 7 months of age, both groups were centrally treated with rat leptin (0.2 µg/d, 7 days) or saline. RESULTS: Central leptin reduced food intake and BW, but not the hepatic triglyceride content, in 7-month-old rats fed AL. However, in 7-month-old FR rats, leptin did not affect BW but markedly reduced serum leptin, serum and hepatic triglyceride levels, and the expression of hepatic lipogenic genes. In addition, central leptin decreased serum and hepatic endogenous norepinephrine levels of FR rats, exerting a homeostatic effect beyond its antisteatotic actions. CONCLUSIONS: These findings suggest that in middle-aged rats, moderate FR is required for both preserving the antisteatotic actions of central leptin and avoiding excessive weight loss.
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Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/terapia , Leptina/sangue , Animais , Masculino , Ratos , Ratos WistarRESUMO
S-resistin, a non-secretable resistin isoform, acts as an intracrine factor that regulates adipocyte maduration, inflammatory and insulin response in 3T3-L1 cells. However, its intracellular function in vivo is still unknown. In this study, we analyze the central role of s-resistin, decreasing its hypothalamic expression using an intracerebroventricular injection of lentiviral RNAi. The data present herein support an improvement in the hypothalamic leptin and insulin signaling pathway upon s-resistin downregulation. Furthermore, hypothalamic levels of pro-inflammatory markers decrease, meanwhile those of the anti-inflammatory cytokine IL-10 increases. Interestingly, peripheral NEFA decreases alike circulating leptin and resistin levels. These data demonstrate that hypothalamic s-resistin controls fuel mobilization and adipokines secretion. Importantly, central s-resistin downregulation improves systemic insulin sensitivity, as demonstrated after an IPGTT. Interestingly, our data also indicate that s-resistin downregulation could improve hypothalamic inflammation in aged Wistar rats. Altogether, our findings suggest that hypothalamic s-resistin seems to be a key regulator of the brain-fat axis which links inflammation with metabolic homeostasis.
Assuntos
Adipócitos/metabolismo , Hipotálamo/metabolismo , Inflamação/prevenção & controle , Resistência à Insulina , Insulina/metabolismo , Resistina/antagonistas & inibidores , Adipócitos/imunologia , Adipócitos/patologia , Animais , Citocinas/metabolismo , Células HEK293 , Células HeLa , Homeostase , Humanos , Hipotálamo/imunologia , Hipotálamo/patologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Resistina/genética , Resistina/metabolismoRESUMO
The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor ß/δ (PPARß/δ, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal ß-oxidation. Finally, the pharmacological inhibition of PPARß/δ decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARß/δ, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight.
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Coração/efeitos dos fármacos , Leptina/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Miocárdio/metabolismo , PPAR delta/metabolismo , PPAR beta/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Glucose/metabolismo , Infusões Intraventriculares , Masculino , Coativadores de Receptor Nuclear/metabolismo , Oxirredução , PPAR delta/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Palmitatos/metabolismo , Distribuição Aleatória , Ratos Wistar , Sulfonas , Tiofenos , Triglicerídeos/metabolismoRESUMO
Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.
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Adiposidade/fisiologia , Envelhecimento/metabolismo , Hipotálamo/metabolismo , Resistência à Insulina , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Injeções Intraventriculares , Insulina/administração & dosagem , Insulina/metabolismo , Insulina/farmacologia , Masculino , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
Catastrophic collapse of a mine tailings dam released several million cubic meters of toxic mud and acidic water into the Guadiamar River valley, southern Spain, in 1998. Remediation efforts removed most of the sludge from the floodplain, but contamination persists. Clean-up activities also produced clouds of aerosolized materials that further contaminated the surrounding landscape. Whole-body concentrations of 21 elements in the Moorish wall gecko, Tarentola mauritanica, a common inhabitant of both rural and urban areas, were compared among seven locations. Locations spanned an expected contamination gradient and included a rural and an urban non-mine-affected location, two mine-affected towns, and three locations on the contaminated floodplain. Multivariate analyses of whole-body concentrations identified pollutants that increased across the expected contamination gradient, a trend particularly evident for As, Pb, and Cd. Additionally, higher contaminant concentrations occurred in prey items eaten by geckos from mine-affected areas. Comparison of element concentrations in tails and whole bodies suggests that tail clips are a viable nondestructive index of contaminant accumulation. Our results indicate that areas polluted by the mine continue to experience contamination of the terrestrial food chain. Where abundant, geckos represent useful taxa to study the bioavailability of some hazardous pollutants.
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Desastres , Monitoramento Ambiental/métodos , Lagartos/metabolismo , Metais/metabolismo , Mineração , Animais , Demografia , Dieta , Metais/análise , Rios/química , Poluentes do Solo/análise , Espanha , Cauda , Poluentes Químicos da Água/análiseRESUMO
In rodents, soluble leptin receptor (SLR) may be generated by alternative splicing of ObR mRNA and/or as a cleavage product of ObR membrane-anchored receptors. In this study, we investigated the contribution of both processes on the generation of SLR in 3-, 8-, and 24-month-old Wistar rats fed ad libitum (AL) or under food restriction (FR). To this end, we determined serum SLR levels and analyzed ObRa and ObRe mRNA expression under these physiological conditions. Additionally, we studied the cellular distribution of ObRa and the generation of SLR by N-ethyl-maleimide-induced shedding from ObRa membrane receptors in isolated adipocytes. Serum SLR levels were significantly increased in 8- and 24-month-old rats under FR, whereas similar amounts were found in rats of different ages fed AL. ObRa and ObRe mRNA expression in epididymal adipose tissue increased with aging. In contrast, after FR, ObRe mRNA expression decreased, whereas ObRa mRNA expression further increased compared with 8- and 24-month-old rats fed AL. Additionally, FR promoted a change in the distribution of ObRa between internal and plasma membranes in isolated adipocytes, increasing its presence at the cell surface. Finally, the generation of SLR by N-ethyl-maleimide-induced shedding from ObRa was also increased under FR. These data suggest that shedding of ObRa membrane-anchored receptors, rather than ObRe expression, might preferentially contribute to the generation of the increased levels of SLR in serum under conditions of FR.
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Tecido Adiposo/metabolismo , Envelhecimento/metabolismo , Restrição Calórica , Receptores de Superfície Celular/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Epididimo , Etilmaleimida/farmacologia , Masculino , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Receptores para Leptina , Solubilidade , Frações Subcelulares/metabolismo , Reagentes de Sulfidrila/farmacologia , Distribuição TecidualRESUMO
Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.
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Adipócitos/fisiologia , Insulina/farmacologia , Leptina/farmacologia , Adipócitos/efeitos dos fármacos , Envelhecimento , Animais , Dieta Redutora , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Ratos , Ratos Wistar , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina , Fatores de Transcrição/genéticaRESUMO
S-resistin is a non-secretable resistin spliced variant, which is expressed mainly in the white adipose tissue from Wistar rats. Previous results confirmed that 3T3-L1 cells expressing s-resistin (3T3-L1-s-res) showed an inflammatory response and exhibited a decrease in glucose transport, both basal and insulin-stimulated. Here we present evidences demonstrating for the first time that s-resistin, like resistin, blocks insulin signalling pathway by inhibiting insulin receptor, insulin receptor substrate 1, protein kinase B/Akt and the mammalian target of rapamycin phosphorylation, and increasing the suppressor of cytokine signalling 3 levels being the later probably due to augmented of leptin expression. Thus, our data suggest that s-resistin could act by a still unknown intracrine pathway as an intracellular sensor, regulating the adipocyte insulin sensitivity.
Assuntos
Insulina/fisiologia , Resistina/fisiologia , Células 3T3-L1 , Adipogenia , Animais , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Resistência à Insulina , Camundongos , Fosforilação , Isoformas de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
The present study examined the contribution of three main cognitive factors (i.e., anxiety sensitivity, catastrophic misinterpretations of bodily symptoms, and panic self-efficacy) in predicting panic disorder (PD) severity in a sample of patients with a principal diagnosis of panic disorder. It was hypothesized that anxiety sensitivity (AS), catastrophic misinterpretation of bodily sensations, and panic self-efficacy are uniquely related to panic disorder severity. One hundred and sixty-eight participants completed measures of AS, catastrophic misinterpretations of panic-like sensations, and panic self-efficacy prior to receiving treatment. Results of multiple linear regression analyses indicated that AS, catastrophic misinterpretations and panic self-efficacy independently predicted panic disorder severity. Results of path analyses indicated that AS was direct and indirectly (mediated by catastrophic misinterpretations) related with panic severity. Results provide evidence for a tripartite cognitive account of panic disorder.
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Cognição , Transtorno de Pânico/diagnóstico , Autoeficácia , Adolescente , Adulto , Idoso , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/complicações , Transtorno de Pânico/psicologia , Análise de Regressão , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Espanha , Adulto JovemRESUMO
Aging is associated with alterations of lipid metabolism and increased prevalence of non alcoholic hepatic steatosis. Nevertheless, the mechanisms by which fat is accumulated in the liver during aging remain incompletely understood. In the present study, we investigated potential alterations that might contribute to the development of hepatic steatosis with aging. To this end, we analyzed the expression and the subcellular localization of key transcriptional factors involved in lipid metabolism such as ChREBP, Foxo1, Foxa2 and SREBP-1c in the liver of 3- and 24-month old Wistar rats. In addition, we studied the intracellular redistribution of ChREBP in response to fasting/refeeding transition. Old rats were characterized by hepatic steatosis, low serum ketone body levels and postprandial hyperinsulinemia. These observations were paralleled by the cytoplasmic localization and decreased expression of Foxa2, while ChREBP expression was markedly up-regulated and mainly localized in the nucleus. Consequently, the expression of lipogenic and ß-oxidation genes was up-regulated or down-regulated, respectively. Besides, the intracellular redistribution of ChREBP in response to fasting/refeeding transition was also impaired in old animals. Additionally, a negative correlation between serum ketone body levels and the nuclear localization of ChREBP was observed only in adult but not in old rats. Taken together, these data suggest that an age-related dysfunctional adaptation of ChREBP, in response to changes in the nutritional state, might contribute to the development of liver steatosis with aging.
Assuntos
Envelhecimento/metabolismo , Ingestão de Alimentos/fisiologia , Jejum/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fígado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Núcleos Cerebelares/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Metabolismo dos Lipídeos/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Regulação para CimaRESUMO
CONTEXT: Insulin resistance and type 2 Diabetes have been associated to a low grade of inflammation and their prevalence increase with ageing. OBJECTIVE: To analyse the development of inflammation in adipose tissue, liver, muscle and hypothalamus during ageing and the effects of caloric restriction. MATERIALS AND METHODS: We have analysed the expression of inflammatory cytokines (TNFα, IL1-ß, IL-12B and IL-6), proteins involved in macrophage recruitment (MCP-1, CCR2), TLR4 and macrophage markers (CD11c, CD11b and arginase1). Immunohistochemistry of macrophages has also been performed. RESULTS: All studied tissues present signs of inflammation during ageing, but with different pattern and intensity. Caloric restriction decreases the expression of most of inflammatory markers. DISCUSSION AND CONCLUSIONS: These data indicate a role of adiposity in the development of inflammation and insulin resistance during ageing. Dietetic intervention could be a useful tool to ameliorate the development of inflammation and insulin resistance associated with ageing.
Assuntos
Envelhecimento/fisiologia , Restrição Calórica , Inflamação/metabolismo , Ratos Wistar , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Biomarcadores/metabolismo , Citocinas/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estresse Oxidativo , RNA/metabolismo , Distribuição Aleatória , RatosRESUMO
Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 µg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [(3)H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity.