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Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.
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Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Ratos , Feminino , Masculino , Animais , Adolescente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fibronectinas , Nociceptividade , Encéfalo/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Modelos Animais de DoençasRESUMO
Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-ß deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-ß PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-ß42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.
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Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.
Assuntos
Transtorno Depressivo Maior , Masculino , Camundongos , Animais , Transtorno Depressivo Maior/metabolismo , Depressão , Fibronectinas/genética , Fibronectinas/metabolismo , Encéfalo/metabolismo , Fatores de Transcrição/metabolismo , Modelos Animais de Doenças , Músculo Esquelético/metabolismoRESUMO
SUMMARY OBJECTIVE: The aim of this study was to investigate the role of irisin in type 2 diabetes mellitus and its association with metabolic alterations and obesity. METHODS: A cross-sectional case-control study was conducted on participants treated at Centro Universitário FMABC between August 2018 and July 2019, by comparing a control group (n=14) with type 2 diabetes mellitus patients (n=16). The control group consisted of participants aged above 21 years with no chronic diseases, diabetes, smoking, or illicit drug use. The type 2 diabetes mellitus group included patients aged above 21 years, who were diagnosed with type 2 diabetes for at least 5 years (glycated hemoglobin>7%). Exclusion criteria were not willing to continue, recent hospitalization, and failure to meet inclusion criteria. Biochemical parameters included blood glucose, glycated hemoglobin, plasma irisin levels, and irisin gene expression in peripheral blood. RESULTS: Type 2 diabetes mellitus patients exhibited significantly higher plasma glucose levels [143 (40) vs. 92 (13) mg/dL, *p<0.05] and glycated hemoglobin levels [7.1% (1.6) vs. 5.6% (0.5), *p<0.05] compared to the control group. Irisin gene expression in type 2 diabetes mellitus patients was lower 0.02288 (0.08050) than the control group 8.506e-006 (1.412e-005) (p=0.06). Correlation analysis revealed a positive association between irisin expression and body mass index in type 2 diabetes mellitus (Rho=0.5221, 95%CI -0.058 to 0.838, p=0.06), while plasma irisin showed a negative correlation with body mass index (Rho=-0.656, 95%CI -0.836 to 0.215, p=0.03). No significant correlations were found between plasma glucose or glycated hemoglobin levels and irisin expression. CONCLUSION: The data suggests that body mass index directly influences plasma irisin levels and the regulation of irisin gene expression, possibly linking irisin to adiposity changes observed in obesity-related type 2 diabetes mellitus.
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Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer's disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenoviral-mediated expression of irisin promotes extracellular brain derived neurotrophic factor (BDNF) accumulation in hippocampal cultures. We further show that irisin stimulates transient activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and prevents amyloid-ß oligomer-induced oxidative stress in primary hippocampal neurons. Finally, analysis of RNA sequencing (RNAseq) datasets shows a trend of reduction of hippocampal FNDC5 mRNA with aging and tau pathology in humans. Results indicate that irisin activates protective pathways in hippocampal neurons and further support the notion that stimulation of irisin signaling in the brain may be beneficial in AD.
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Obesity is an epidemic disease and the expansion of adipose tissue, especially visceral fat, promotes the secretion of factors that lead to comorbidities such as diabetes and cardiovascular diseases. Thus, diet and exercise have been proposed as an intervention to reverse these complications. An adipocytokine, known as irisin, mediates the beneficial effects of exercise. It has been proposed as a therapeutic potential in controlling obesity. In view of the above, this paper attempts to determine the modulation of irisin, visceral adiposity and biochemical markers in response to dietary intervention and aerobic exercise. To do this, 52 diet-induced obese male Wistar rats were divided into the following four groups: high-fat diet and exercise (HFD-Ex); HFD-Sedentary (HFD-Sed); chow-diet and exercise (CD-Exercise); and CD-Sed. The exercise-trained group performed a treadmill protocol for 60 min/day, 3 days/week for 8 weeks. Body mass (BM), body fat (BF), fat mass (FM), and fat-free mass (FFM) were analyzed. Mesenteric (MES), epididymal (EPI), and retroperitoneal (RET) adipose tissue was collected and histological analysis was performed. Biochemical irisin, triglycerides, glucose, insulin and inflammatory markers were determined and, FNDC5 protein expression was analyzed. In this study, the diet was the most important factor in reducing visceral adiposity in the short and long term. Exercise was an important factor in preserving muscle mass and reducing visceral depots after a long term. Moreover, the combination of diet and exercise can enhance these effects. Diet and exercise exclusively were the factors capable of increasing the values of irisin/FNDC5, however it did not bring cumulative effects of both interventions. Prescriptions to enhance the obesity treatments should involve reducing visceral adiposity by reducing the fat content in the diet associated with aerobic exercise.
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Several lines of evidence have consistently indicated that physical exercise has antidepressant effects by improving hippocampal function, although the signaling pathways underpinning these responses are not well established. Therefore, this study investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin signaling in the antidepressant-like effect of physical exercise. We showed that physical exercise (treadmill running - 45 min/day/5 days/week for 4 weeks) produced an antidepressant-like effect as indicated by a reduction on the immobility time in mice subjected to the forced swimming test (FST) without altering locomotor activity in the open field test (OFT). Rapamycin (a selective mTORC1 inhibitor, 0.2 nmol/site, i.c.v.) administration completely abolished the antidepressant-like effect of physical exercise in the FST, suggesting that mTORC1 activation plays a role for its behavioral effect. Accordingly, physical exercise increased the number of phosphorylated mTORC1 (Ser2448)-positive cells in the entire and ventral subgranular zone of the hippocampal dentate gyrus. Physical exercise was also effective in augmenting the hippocampal FNDC5/irisin immunocontent, but rapamycin administration did not alter this effect. Our results reinforce the notion that physical exercise exerts an antidepressant-like effect and identifies the mTORC1-mediated signaling pathway as a target for its behavioral effects. This study provides additional evidence that physical exercise increases hippocampal FNDC5/irisin immunocontent, but this effect seems to be independent on hippocampal mTORC1 activation. Altogether the results contribute to elucidate possible molecular targets implicated in the antidepressant effects of physical exercise and highlight the role of mTORC1 signaling for its behavioral response.
Assuntos
Fibronectinas/metabolismo , Hipocampo/metabolismo , Locomoção/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/fisiologia , Sirolimo/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagemRESUMO
Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.
Assuntos
Comportamento Animal/fisiologia , Fibronectinas/metabolismo , Hipocampo/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Condicionamento Físico Animal/fisiologia , Oxirredutases do Álcool , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Proteínas de Ligação a DNA , Giro Denteado/fisiologia , Depressão/terapia , Feminino , Camundongos , Corrida/fisiologiaRESUMO
In understanding the pathology of neurological diseases, the role played by brain energy metabolism is gaining prominence. Animal models have demonstrated that regular physical exercise improves brain energy metabolism while also providing antidepressant, anxiolytic, antioxidant and neuroprotective functions. This review summarizes the latest evidence on the roles played by peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha (PGC-1α) and mitochondrial uncoupling protein (UCP) in this scenario. The beneficial effects of exercise seem to depend on crosstalk between muscles and nervous tissue through the increased release of muscle irisin during exercise.
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The present study aimed to evaluate the effects of resveratrol on FNDC5 and thermogenesis markers expression in the adipose tissue of mice and humans. Thirty-two male mice were randomly divided into four groups (n = 8) and fed with: Standard Diet; Standard Diet + Resveratrol (400 mg/kg); High-fat Diet; High-fat Diet + Resveratrol for eight weeks. Twenty male and female volunteers, aged 30-55 years, BMI ≥ 30 kg/m² were divided into two groups and treated for four weeks with 500 mg trans-resveratrol or placebo, adipose tissue biopsies were taken. Analysis of body weight, food intake, glycemic and lipid profiles, mRNA expression from tissues and primary culture of adipocytes were performed. The main results show that resveratrol improves the glycaemic and lipid profiles along with an increase in the levels of UCP1, PRDM16, PGC1α, and SIRT1. The increase in FNDC5 expression was observed in the mouse and human subcutaneous adipose tissue. The SIRT1 antagonist in adipocyte primary culture resulted in decreased FNDC5 expression. Our data suggest that improved metabolism produced by oral administration of resveratrol is, at least in part, associated with increased thermogenesis followed by high expression of UCP1, PRDM16, PGC1α and that increased FNDC5 expression in the subcutaneous adipose tissue from mice and human might be modulated by SIRT1.
Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Fibronectinas/genética , Resveratrol/farmacologia , Termogênese/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Dieta Hiperlipídica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/metabolismo , Cultura Primária de Células , Resveratrol/administração & dosagem , Sirtuína 1/antagonistas & inibidores , Termogênese/genéticaRESUMO
The prevalence of childhood obesity has increased worldwide. Although it is considered a polygenic inheritance disease, little is known about its susceptibility when the additive effect is considered. The aim of this study is to investigate whether the genetic risk score (GRS) based on previously associated obesity polymorphisms (SNP) rs9939609 (fat mass and obesity-associated (FTO)), rs6548238 (transmembrane protein 18 (TMEM18)) and rs16835198 (fibronectin type III domain containing 5 (FNDC5)) could serve as a predictor for anthropometric characteristics in a sample of Brazilian children and adolescents. This is a cross-sectional study with 1471 children and adolescents aged 6-17 years. BMI, waist circumference (WC) and percentage of body fat and metabolic parameters were verified. In all, three SNP were genotyped by TaqMan™ allelic discrimination. The metabolic and anthropometric parameters were compared between the genotypes, and the unweighted and weighted GRS (GRS and wGRS, respectively) were created to test the additive effect of these genetic polymorphisms on anthropometric parameters. The prevalence of overweight plus obesity was 41 %. Significant associations were identified for FTO rs9939609, TMEM18 rs6548238 and FNDC5 rs16835198 and for GRS and wGRS with anthropometric phenotypes. The higher score of wGRS was associated with obesity (OR: 2·65, 95 % CI 1·40, 5·04, P=0·003) and with greater WC (OR: 2·91, 95 % CI 1·57, 5·40, P=0·001). Our results suggest that these genetic variants contribute to obesity susceptibility in children and adolescents and reinforce the idea that the additive effect may be useful to elucidate the genetic component of obesity.
Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Fibronectinas/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Obesidade Infantil/genética , Adolescente , Antropometria , Composição Corporal/genética , Índice de Massa Corporal , Brasil/epidemiologia , Criança , Feminino , Genótipo , Humanos , Masculino , Obesidade Infantil/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Circunferência da Cintura/genéticaRESUMO
ABSTRACT Purposes: The aim of this study was to determine the diagnostic significance of fibronectin type III domain containing protein 5 (FNDC5)/Irisin levels in the sera of patients with renal cell cancer. Materials and Methods: In the study, 48 individuals were evaluated. The patient group included 23 subjects diagnosed with renal tumor, and the control group of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected and serum FNDC5/Irisin and carcinoembryonic antigen (CEA) levels were determined using enzyme-linked immunosorbent assay (ELISA). Results: FNDC5/irisin and CEA levels in renal cancer patients were significantly higher compared with the control group (p=0.0001, p=0.009, respectively). Also, FNDC5 levels was more sensitive and specific than CEA levels. The best cut-off points for FNDC5/irisin were >105pg/mL and CEA were >2.67ng/mL for renal cancer. Conclusions: FNDC5/Irisin may be used as a diagnostic biomarker for renal cancer.
Assuntos
Humanos , Masculino , Feminino , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/sangue , Antígeno Carcinoembrionário/sangue , Fibronectinas/sangue , Neoplasias Renais/diagnóstico , Neoplasias Renais/sangue , Valores de Referência , Ensaio de Imunoadsorção Enzimática , Carcinoma de Células Renais/patologia , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Gradação de Tumores , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1â¯ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6â¯h after its administration. Irisin administration (6â¯h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1â¯h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1â¯h) in both structures and remained reduced up to 6â¯h in the prefrontal cortex. Moreover, BDNF administered at 0.25⯵g/mouse, i.c.v. (1 and 6â¯h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6â¯h) and prefrontal cortex (1 and 6â¯h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6â¯h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6â¯h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation.
Assuntos
Antidepressivos/administração & dosagem , Fibronectinas/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Relação Dose-Resposta a Droga , Fibronectinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes/administração & dosagemRESUMO
PURPOSES: The aim of this study was to determine the diagnostic significance of fibronectin type III domain containing protein 5 (FNDC5)/Irisin levels in the sera of patients with renal cell cancer. MATERIALS AND METHODS: In the study, 48 individuals were evaluated. The patient group included 23 subjects diagnosed with renal tumor, and the control group of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected and serum FNDC5/ Irisin and carcinoembryonic antigen (CEA) levels were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: FNDC5/irisin and CEA levels in renal cancer patients were significantly higher compared with the control group (p=0.0001, p=0.009, respectively). Also, FNDC5 levels was more sensitive and specific than CEA levels. The best cut-off points for FNDC5/ irisin were >105pg/mL and CEA were >2.67ng/mL for renal cancer. CONCLUSIONS: FNDC5/Irisin may be used as a diagnostic biomarker for renal cancer.
Assuntos
Antígeno Carcinoembrionário/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/diagnóstico , Fibronectinas/sangue , Neoplasias Renais/sangue , Neoplasias Renais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
BACKGROUND: Fibronectin type III domain containing 5 (FNDC5) and its protein product Irisin are therapeutic targets for obesity-associated disorders. Irisin plays an important role in energy regulation, inducing browning of white adipocytes, and improving obesity. We aimed to investigate the association between muscle Irisin expression and dietary quality. METHODS: Twenty-eight female mice were divided into four groups and fed the following experimental diets for 60 days: standard diet (SD), high-carbohydrate diet (HCD), high-fat diet (HFD), and high-protein diet (HPD). We evaluated body weight, food intake, serum total cholesterol, triacylglycerol, and glucose. We also performed glucose tolerance and insulin sensitivity tests. Expression of FNDC5 was evaluated by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) of soleus muscle. Western blot was used to assess Irisin protein expression. RESULTS: The major finding of the present study was that HFD and HCD were associated with a downregulation of FNDC5. In addition to these results, we noted a significant reduction in skeletal muscle Irisin level. HPD prevented reductions of both FNDC5 and Irisin levels, as well as increased brown adipose tissue, compared to the control group. CONCLUSIONS: In conclusion, we observed that the HPD type of diet can change both FNDC5 expression and Irisin levels. Thus, the HPD might be the most appropriate diet to achieve high amounts of Irisin, a target molecule for the treatment of obesity and its co-morbidities.
Assuntos
Dieta , Fibronectinas/metabolismo , Músculo Esquelético/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Peso Corporal , Colesterol/sangue , Dieta Hiperlipídica , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Proteínas Alimentares/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Teste de Tolerância a Glucose , Resistência à Insulina , Camundongos , Triglicerídeos/sangueRESUMO
The effects of training on FNDC5/irisin and its association with fitness and metabolic marker improvements induced by training have been poorly investigated in humans. Thus, the present study assessed the effects of combined training (CT) on FNDC5/irisin levels, metabolic markers and fitness adaptations in obese men. Middle-age obese men (age 49.13 ± 5.75, body mass index (BMI) 30.86 ± 1.63) were randomly distributed in the CT group (n = 12) and control group (CG n = 10). The CT consisted of strength followed by aerobic training, 3 times/week, for 24 weeks. Body composition, physical fitness, plasma FNDC5/irisin, biochemical markers and metabolic scores/index were evaluated. CT maintained FNDC5/irisin levels (µg/mL) (pre: 4.15 ± 0.32, post: 4.21 ± 0.32; p = .96) and improved body composition, metabolic and physical fitness markers. In the CG, decreased FNDC5/irisin (µg/mL) (pre: 4.36 ± 0.23, post: 3.57 ± 0.94; p = .01) and reduced strength (supine exercise/kg) (pre: 71 ± 14.7, post: 60.1 ± 14.05; p < .01) were observed, along with a trend to increase HOMA-IR (pre: 2.63 ± 1.11, post: 3.14 ± 1.27; p = .07) and other indicators of metabolic deterioration. An inverse correlation was found between the change (Δ%) in levels of FNDC5/irisin and Δ% glucose, Δ% total cholesterol, Δ% triglycerides and Δ% waist circumference, in addition to a positive relation with Δ% muscle strength. In conclusion, CT maintained FNDC5/irisin levels and provided metabolic and fitness benefits. The correlation between FNDC5/irisin changes and metabolic parameters, as well as the FNDC5/irisin reduction associated with fitness and metabolic worsening in the CG, suggests a relationship between FNDC5/irisin and a healthy metabolic status in humans.
Assuntos
Glicemia/metabolismo , Exercício Físico/fisiologia , Fibronectinas/metabolismo , Lipídeos/sangue , Força Muscular , Obesidade/metabolismo , Circunferência da Cintura , Adulto , Índice de Massa Corporal , Colesterol/sangue , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Obesidade/sangue , Aptidão Física/fisiologia , Treinamento Resistido , Corrida , Triglicerídeos/sangue , CaminhadaRESUMO
In the continuous search of researchers to find an effective method to control obesity, a myokine called Irisin was found. Irisin is secreted mainly by skeletal muscle in response to exercise, either resistance, strength or high intensity, where High Intensity Interval Training (HIIT) is included. This polypeptide hormone acts mainly on subcutaneous adipose cells, turning white fat into brown fat. Brown fat is highly thermogenic, which enhance raising of total energy expenditure and helps maintaining or loosing corporal weight. Plasmatic Irisin levels are related positively with insulin sensitivity and weight loss. It has been also discovered that a greater plasmatic level of Irisin is related to the lengthening of telomeres, to a greater concentration of free tyrosine (T4) and it has been recently found that is related to an antitumoral effect on some types of cancer. All of the functions mediated by Irisin, have given it a protective action against different diseases, especially metabolic ones. The aim of this review was to update the knowledge about Irisin, and to show the effects that exercise has on its plasmatic levels, as well as comprehend how does the release of irisin influences different body systems. Counting with more information will allow the arising of new lines of investigation that will bring up non pharmacological therapeutic strategies for the treatment of non-communicable diseases.
En la búsqueda continua de los investigadores por combatir de manera más efectiva la obesidad, se descubre una mioquina llamada Irisina. La Irisina es secretada principalmente por el músculo esquelético en respuesta al ejercicio, ya sea aeróbico, de fuerza o de alta intensidad, donde se incluyen, ejercicios de intervalo de alta intensidad (HIIT). Esta hormona polipeptídica actúa principalmente sobre células adiposas subcutáneas, transformando grasa blanca en grasa parda. La grasa parda es altamente termogénica, lo que favorece el aumento del gasto energético total y ayuda a mantener o incluso a perder peso corporal. La concentración de Irisina plasmática se relaciona positivamente con la sensibilidad a la insulina y la pérdida de peso. Además, se ha descubierto que una mayor concentración de Irisina plasmática se relaciona con el alargamiento de los telómeros, y también, con una mayor concentración de T4 libre y con un recién descubierto efecto antitumoral en algunos tipos de cáncer. Todas las funciones mediadas por la Irisina, le atribuyen una acción protectora contra distintas enfermedades, especialmente metabólicas. El objetivo de esta revisión fue actualizar el conocimiento sobre la Irisina, evidenciando los efectos que tiene la realización de ejercicio sobre los niveles plasmáticos de ésta, así como también comprender como su liberación influye en distintos sistemas corporales. El contar con mayor información dará paso a nuevas líneas de investigación y permitirá contar con estrategias terapéuticas no farmacológicas que contribuyan en el tratamiento de enfermedades crónicas no transmisibles.
Assuntos
Humanos , Peptídeos , Exercício Físico , Hormônios , Obesidade , Doença Crônica , FibronectinasRESUMO
Objective Our objective in this study was to determine the relationship between irisin hormone, which has a similar effect with thyroid hormones on adipose tissue and the metabolism, and the thyroid functions and the obesity secondary to thyroid disease. Subjects and methods Seventy-four patients were included in the study, of the patients, 37 were newly diagnosed with Hashimoto’s thyroiditis related hypothyroidism but not started on a treatment yet, and the remaining 37 were healthy volunteers without a known disease. Serum thyroid stimulating hormone (TSH), free thyroxin (fT4), anti-thyroglobulin and anti-thyroid peroxidase were measured and thyroid ultrasonography was performed in both groups. Serum irisin levels were measured using the commercially available ELISA kit. The hypothyroidism group had higher levels of irisin compared to the control group (2.77 ng/mL vs. 2.15 ng/mL respectively; p = 0.017). Results The hypothyroidism group had higher median levels of irisin in the obese patients than those in the control group (3.10 ng/mL vs. 2.10 ng/mL respectively; p = 0.013). Irisin level was negatively correlated with age in the whole population and patients with hypothyroidism (r = -0.255, p = 0.028; r = -0.346, p = 0.036 respectively). Irisin level was positively correlated with TSH (r = 0.247, p = 0.034) but negatively correlated with the fT4 (r = -0.316, p = 0.006) in the whole population. Obesity, fT4 and irisin levels were identified to be independent predictors in the diagnosis of hypothyroidism in the multivariable logistic regression analysis. Conclusion To the best of our knowledge, this study is the first in literature to identify that obesity, irisin level and fT4 level are independent risk factors for hypothyroidism.
Assuntos
Humanos , Adulto , Pessoa de Meia-Idade , Fibronectinas/sangue , Doença de Hashimoto/fisiopatologia , Doença de Hashimoto/sangue , Hipotireoidismo/fisiopatologia , Hipotireoidismo/sangue , Obesidade/fisiopatologia , Autoanticorpos/sangue , Glândula Tireoide/fisiopatologia , Pressão Sanguínea/fisiologia , Ensaio de Imunoadsorção Enzimática , Estudos de Casos e Controles , Modelos Logísticos , Tecido Adiposo/metabolismo , Fatores de Risco , Doença de Hashimoto/complicações , Hipotireoidismo/complicaçõesRESUMO
INTRODUCTION: Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM. OBJECTIVE: To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features. METHODS: We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program. RESULTS: Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL-cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men. CONCLUSIONS: These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM.