RESUMO
Dapoxetine is the first oral medication specifically developed for the on-demand treatment of premature ejaculation. The pharmacokinetics and safety of 30 mg (n = 40) and 60 mg (n = 38) dapoxetine in healthy Chinese under fasted and fed states were assessed in 2 studies. Both studies are random, single-center, 2-period, open-label, 2-way crossover designs. Plasma concentration of dapoxetine was determined by high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated using noncompartmental analysis. Dapoxetine was quickly absorbed and reached maximum concentration 1 to 3 hours after oral administration. Elimination was biphasic, and the plasma concentration decreased to 3% to 7% of maximum concentration by 24 hours while half-life was 15 to 18 hours. Meantime, high-fat meals slightly increased its exposure. Both doses of dapoxetine were well tolerated. The adverse events in the high-dose group under fasted and fed states were 37.9% and 19.0%, respectively.
Assuntos
Povo Asiático , Benzilaminas/farmacocinética , Gorduras na Dieta/farmacocinética , Jejum/metabolismo , Interações Alimento-Droga/fisiologia , Naftalenos/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Adolescente , Adulto , Benzilaminas/administração & dosagem , Benzilaminas/efeitos adversos , Estudos Cross-Over , Dieta Hiperlipídica/tendências , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Adulto JovemRESUMO
Background: Children born to diabetic or obese mothers have a higher risk of heart disease at birth and later in life. Using chromatin immunoprecipitation sequencing, we previously demonstrated that late-gestation diabetes, maternal high fat (HF) diet, and the combination causes distinct fuel-mediated epigenetic reprogramming of rat cardiac tissue during fetal cardiogenesis. The objective of the present study was to investigate the overall transcriptional signature of newborn offspring exposed to maternal diabetes and maternal H diet. Methods: Microarray gene expression profiling of hearts from diabetes exposed, HF diet exposed, and combination exposed newborn rats was compared to controls. Functional annotation, pathway and network analysis of differentially expressed genes were performed in combination exposed and control newborn rat hearts. Further downstream metabolic assessments included measurement of total and phosphorylated AKT2 and GSK3ß, as well as quantification of glycolytic capacity by extracellular flux analysis and glycogen staining. Results: Transcriptional analysis identified significant fuel-mediated changes in offspring cardiac gene expression. Specifically, functional pathways analysis identified two key signaling cascades that were functionally prioritized in combination exposed offspring hearts: (1) downregulation of fibroblast growth factor (FGF) activated PI3K/AKT pathway and (2) upregulation of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC1α) mitochondrial biogenesis signaling. Functional metabolic and histochemical assays supported these transcriptome changes, corroborating diabetes- and diet-induced cardiac transcriptome remodeling and cardiac metabolism in offspring. Conclusion: This study provides the first data accounting for the compounding effects of maternal hyperglycemia and hyperlipidemia on the developmental cardiac transcriptome, and elucidates nuanced and novel features of maternal diabetes and diet on regulation of heart health.
Assuntos
Diabetes Gestacional/metabolismo , Dieta Hiperlipídica/efeitos adversos , Redes Reguladoras de Genes/fisiologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Miocárdio/metabolismo , Transcriptoma/fisiologia , Animais , Animais Recém-Nascidos , Diabetes Gestacional/genética , Diabetes Gestacional/patologia , Dieta Hiperlipídica/tendências , Feminino , Perfilação da Expressão Gênica/métodos , Masculino , Miocárdio/patologia , Biogênese de Organelas , Gravidez , RatosRESUMO
BACKGROUND: Previously, it has been shown that obesity is a risk factor for recovery, regeneration, and tissue repair after blunt trauma and can affect the rate of muscle recovery and collagen deposition after trauma. To date, lung tissue regeneration and extracellular matrix regulation in obese mice after injury has not been investigated in detail yet. METHODS: This study uses an established blunt thorax trauma model to analyze morphological changes and alterations on gene and protein level in lean or obese (diet-induced obesity for 16 ± 1 week) male C57BL/6 J mice at various time-points after trauma induction (1 h, 6 h, 24 h, 72 h and 192 h). RESULTS: Morphological analysis after injury showed lung parenchyma damage at early time-points in both lean and obese mice. At later time-points a better regenerative capacity of lean mice was observed, since obese animals still exhibited alveoli collapse, wall thickness as well as remaining filled alveoli structures. Although lean mice showed significantly increased collagen and fibronectin gene levels, analysis of collagen deposition showed no difference based on colorimetric quantification of collagen and visual assessment of Sirius red staining. When investigating the organization of the ECM on gene level, a decreased response of obese mice after trauma regarding extracellular matrix composition and organization was detectable. Differences in the lung tissue between the diets regarding early responding MMPs (MMP8/9) and late responding MMPs (MMP2) could be observed on gene and protein level. Obese mice show differences in regulation of extracellular matrix components compared to normal weight mice, which results in a decreased total MMP activity in obese animals during the whole regeneration phase. Starting at 6 h post traumatic injury, lean mice show a 50% increase in total MMP activity compared to control animals, while MMP activity in obese mice drops to 50%. CONCLUSIONS: In conclusion, abnormal regulation of the levels of extracellular matrix genes in the lung may contribute to an aberrant regeneration after trauma induction with a delay of repair and pathological changes of the lung tissue in obese mice.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Matriz Extracelular/patologia , Pulmão/patologia , Obesidade/patologia , Traumatismos Torácicos/patologia , Ferimentos não Penetrantes/patologia , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/tendências , Matriz Extracelular/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/metabolismo , Traumatismos Torácicos/complicações , Traumatismos Torácicos/metabolismo , Tórax , Ferimentos não Penetrantes/complicações , Ferimentos não Penetrantes/metabolismoRESUMO
AIMS: Obesity suppresses brain-derived neurotrophic factor (BDNF) expression and increases the expression of pro-inflammatory cytokines. Herein, we assessed whether exercise training (ET), melatonin administration (MT), or their combination can affect the expressions of BDNF and cytokines in the cerebellum of high-fat diet (HFD)-fed rats. METHODS: Wistar rats (4 weeks old) were divided into five groups: normal diet (ND)-fed control (ND-SED), HFD-fed control (HFD-SED), HFD-fed ET (HFD-ET), HFD-fed MT (HFD-MT), and HFD-fed MT plus ET (HFD-ETMT) group. The rats were fed ND or HFD for 17 weeks. Rats were subjected to ET (running on a treadmill) and/or MT (melatonin 5 mg/kg body weight, i.p.) for 9 weeks, 8 weeks after beginning the diet intervention. Changes in BDNF and cytokine expression levels were determined using immunoblotting and cytokine arrays, respectively, 36 hours following the last bout of ET. RESULTS: Neither HFD-ET nor HFD-MT rats exhibited enhanced BDNF expression in the cerebellum, but HFD-ETMT rats had higher level of BDNF expression compared with the others. The expression of TrkB, a BDNF receptor, was higher in HFD-ETMT rats than in HFD-ET and HFD-MT rats. HFD enhanced the expression of interleukin (IL)-1, IL-2, and interferon-γ but reduced the expression of IL-4, IL-6, and IL13. ET and ET plus MT counteracted these HFD-induced changes in cytokine expressions. CONCLUSION: Exercise in combination with melatonin confers the potential benefits of increasing BDNF and improving HFD-induced dysregulations of cytokines in the cerebellum.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Cerebelo/metabolismo , Citocinas/biossíntese , Dieta Hiperlipídica/efeitos adversos , Melatonina/farmacologia , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Cerebelo/efeitos dos fármacos , Citocinas/genética , Dieta Hiperlipídica/tendências , Expressão Gênica , Masculino , Ratos , Ratos WistarRESUMO
Maternal high-fat diet (HFD) consumption can promote a systemic inflammatory condition that may impair the offspring brain development, damaging memory and learning, when it reaches the hippocampus. This study aims to evaluate maternal HFD effects, during pregnancy and lactation, upon dams/mice offspring nutritional status, protein and gene expression of inflammatory pathway (JNK, pJNK and TNF-α), serotonin system molecules (Tryptophan Hydroxylase 2 (TPH2), key-enzyme of serotonin synthesis, serotonin transporter (SERT); 5-HT1A serotonergic receptor (5-HT1A)) and brain derived neurotrophic factor (BDNF) on recently weaned mice offspring hippocampus. Female Swiss mice were fed a control diet (CD, 11,5% fat) or a HFD (45.0% fat) from pre-mating to lactation. After weaning, the offspring received CD up to 28 post-natal days (PND28). Body weight and visceral adiposity (retroperitoneal and gonadal adipose tissue) of dams and offspring were measured. After euthanasia, the offspring hippocampus was dissected for evaluations of BDNF, inflammatory pathway and serotonergic system molecules protein and gene expression, through the techniques of Western Blotting, RTqPCR and ELISA. Our findings show that, during pregnancy, HFD-dams and HFD-offspring exhibited an increase in body weight gain and visceral adipose tissue compared to control animals. The hippocampus of HFD-offspring showed increased protein expression of TPH2, BDNF, pJNK and increased mRNA levels of TNF-α. However, the TPH2 increase in HFD-offspring did not alter hippocampal serotonin levels quantified through ELISA. Maternal HFD promoted an obesity phenotype in its offspring with increased body weight and visceral adiposity, increased protein and gene expression of the pro-inflammatory proteins pJNK and TNF-α. These changes were accompanied by increased TPH2 and BDNF protein expression. Thus, our findings show that maternal HFD during gestation and lactation increased pJNK and TNF-α expression in their offspring hippocampus indicating a pro-inflammatory state, with increased BDNF expression and alterations in its serotonergic system reflected by increased TPH2 expression.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Triptofano Hidroxilase/biossíntese , Adiposidade/fisiologia , Fatores Etários , Animais , Peso Corporal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Dieta Hiperlipídica/tendências , Feminino , Regulação Enzimológica da Expressão Gênica , Masculino , Camundongos , Gravidez , Transdução de Sinais/fisiologia , Triptofano Hidroxilase/genéticaRESUMO
Maternal undernutrition may cause injuries in several organs of the offspring, as well as lead to diseases in adulthood. Obesity and/or the consumption of a high-fat diet may also induce metabolic and cardiorespiratory diseases. We hypothesized that the consumption of a post-weaning high-fat diet would potentiate the deleterious effects of maternal protein undernutrition. This study evaluated the effects of the association of a low-protein diet during gestation and lactation with a post-weaning high-fat diet on the biochemical and ventilatory parameters of rats. Male Wistar rats from mothers who received a low-protein (9% of protein) or normoprotein diet during pregnancy and lactation received a high-fat (32% of total kilocalories from lipids) or a normal fat diet after weaning. Mass gain and somatic growth of the offspring were monitored. Also examined were biochemical chemical parameters and respiratory frequency, tidal volume (volume of air displaced in each normal respiratory cycle when extra effort is not applied), and pulmonary ventilation. Offspring from undernourished mothers presented lower birth weight (P = .0225), which remained until the end of lactation (P < .01). The rats that consumed high-fat diet and had been submitted to maternal undernutrition presented higher tidal volume when compared to the ones that consumed control diet at the 21st day of life (P Ë .05). At 30 and 90 days, no further ventilatory changes were observed. Our data show that the consumption of a high-fat diet post-weaning did not seem to potentiate the changes induced by maternal undernutrition.
Assuntos
Índice de Massa Corporal , Tamanho Corporal/fisiologia , Dieta Hiperlipídica/tendências , Dieta com Restrição de Proteínas/tendências , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Animais , Dieta com Restrição de Proteínas/efeitos adversos , Feminino , Metabolismo dos Lipídeos/fisiologia , Masculino , Desnutrição/metabolismo , Gravidez , Proteínas/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: The influence of pre- or postprandial administration on pharmacokinetics of cyclosporine is supposed to be less in gel-based formulations than in microemulsions. This study was designed to investigate the influence of a high-fat meal on the pharmacokinetic profile of the two cyclosporine containing formulations Ciclosporin Pro (gel-based emulsion) and Sandimmun®Optoral (microemulsion) in renal transplant recipients. METHODS: A randomized, open-label, repeated-measurement, comparative phase IV trial was conducted with two sequence groups for nutrition condition (fastingâfed, fedâfasting) and two treatment phases (Sandimmun® Optoral â Ciclosporin Pro), each covering both nutrition conditions. Primary pharmacokinetic variable of interest was the reduction of bioavailability due to high-fat food compared to fasting conditions measured by the difference D of ln-transformed bioavailability variables (AUCSS, τ, Css, max, und Css, min). RESULTS: A nutrition effect was found for both study medications with respect to the parameters AUCSS, τ and CSS, max, but not to CSS, min. The reduction of bioavailability caused by high-fat food was not significantly different for Sandimmun®Optoral and Ciclosporin Pro. CONCLUSIONS: An effect of high-fat breakfast prior to the morning dose on AUCSS, τ and CSS, max was found for Sandimmun® Optoral and for Ciclosporin Pro. Trough level monitoring did not capture ingestion-related variability. Conversion to Ciclosporin Pro seems to be safe with regard to intra-individual pharmacokinetic variability. TRIAL REGISTRATION: EudraCT No. 2009-011354-18 (29th April 2019).
Assuntos
Ciclosporina/metabolismo , Dieta Hiperlipídica , Composição de Medicamentos/métodos , Jejum/metabolismo , Imunossupressores/metabolismo , Transplante de Rim , Adulto , Idoso , Disponibilidade Biológica , Dieta Hiperlipídica/tendências , Indústria Farmacêutica/tendências , Feminino , Humanos , Transplante de Rim/tendências , Masculino , Pessoa de Meia-Idade , Método Simples-CegoRESUMO
BACKGROUND: Epidemiological studies have identified strong relationships between maternal obesity and offspring respiratory dysfunction; however, the causal direction is not known. We tested whether maternal obesity alters respiratory function of offspring in early life. METHODS: Female C57Bl/6 J mice were fed a high or low fat diet prior to and during two rounds of mating and resulting pregnancies with offspring lung function assessed at 2 weeks of age. The lung function of dams was measured at 33 weeks of age. RESULTS: A high fat diet caused significant weight gain prior to conception with dams exhibiting elevated fasting glucose, and glucose intolerance. The number of surviving litters was significantly less for dams fed a high fat diet, and surviving offspring weighed more, were longer and had larger lung volumes than those born to dams fed a low fat diet. The larger lung volumes significantly correlated in a linear fashion with body length. Pups born from the second pregnancy had reduced tissue elastance compared to pups born from the first pregnancy, regardless of the dam's diet. As there was reduced offspring survival born to dams fed a high fat diet, the statistical power of lung function measures of offspring was limited. There were signs of increased inflammation in the bronchoalveolar lavage fluid of dams (but not offspring) fed a high fat diet, with more tumour necrosis factor-α, interleukin(IL)-5, IL-33 and leptin detected. Dams that were fed a high fat diet and became pregnant twice had reduced fasting glucose immediately prior to the second mating, and lower levels of IL-33 and leptin in bronchoalveolar lavage fluid. CONCLUSIONS: While maternal high fat diet compromised litter survival, it also promoted somatic and lung growth (increased lung volume) in the offspring. Further studies are required to examine downstream effects of this enhanced lung volume on respiratory function in disease settings.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Pulmão/crescimento & desenvolvimento , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Animais , Peso Corporal/fisiologia , Dieta Hiperlipídica/tendências , Feminino , Medidas de Volume Pulmonar/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Distribuição Aleatória , Taxa de Sobrevida/tendênciasRESUMO
The objective of this study was to evaluate the effect of the butanol fraction from Allium tuberosum (BFAT) in high fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy. Wistar rats were fed with HFD for 4 weeks and thereafter administered with 35 mg/kg STZ intraperitoneally. Diabetic rats were treated with BFAT (100 or 400 mg/kg) and metformin (150 mg/kg) for 40 days. After treatment, the blood, urine and kidney tissues were obtained for biochemical and histological analysis. BFAT markedly decreased blood glucose, serum creatinine, blood urea nitrogen and urinary albumin levels in diabetic rats. Furthermore, BFAT upregulated renal antioxidant enzymes status (glutathione, superoxide dismutase and catalase) and decreased lipid peroxidation product in diabetic rats as well as reduced the levels of renal pro-inflammatory cytokines in diabetic rats. In addition, BFAT significantly decreased serum and renal levels of triglyceride and cholesterol in the treated diabetic rats. These results revealed that A. tuberosum possesses attenuative effects against diabetic nephropathy.
Assuntos
Allium , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Hiperglicemia/tratamento farmacológico , Mediadores da Inflamação/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/tendências , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/fisiologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Wistar , Estreptozocina/toxicidadeRESUMO
BACKGROUND: White adipose tissue (WAT) have a relevant metabolic and inflammatory function, in overweight or obesity conditions. In this regard, the WAT under over feeding nutrition present a significant increment in oxidative stress, pro-inflammatory status and depletion of n-3 long chain polyunsaturated fatty acid. Hydroxytyrosol (HT) is a polyphenol with important cytoprotective effects, and this molecule can modulate the gene expression, transcription factors and enzymatic activity. OBJECTIVE: Therefore, the purpose of this study was evaluate the anti-inflammatory, anti-oxidant and anti-lipogenic effects of HT supplementation mice and the molecular adaptations involved, on dysfunctional WAT from high-fat diet (HFD)-fed mice. METHODS AND RESULTS: Male C57BL/6 J mice received (i) control diet (10% fat); (ii) control diet + HT (daily doses of 5 mg kg body weight), (iii) HFD (60% fat); or (iv) HFD + HT for 12 weeks. HFD-fed mice exhibited: (i) WAT hypertrophy; (ii) oxidative stress and depletion of antioxidant defenses, (iii) increased lipogenesis and pro-inflammatory status, (iv) depletion of n-3 LCPUFA and (v) up-regulation of NF-κB and SREBP 1c with down-regulation Nrf2, and PPAR-γ. HT supplementation attenuated the metabolic impairment produced by HFD in WAT, attenuating increment of NF-κB and SREBP 1c, and increasing the activity of Nrf2 and PPAR-γ. CONCLUSION: Supplementation with HT improve the WAT dysfunction induced by HDF in mice through the modulation of transcription factors NF-κB, Nrf2, SREBP-1c and PPAR-γ as well as their target genes, involved in inflammation, antioxidant defenses and lipogenesis.
Assuntos
Tecido Adiposo Branco/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Álcool Feniletílico/análogos & derivados , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/tendências , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
Adiposis is reputed as a twin disease of type 2 diabetes and greatly harmful to human health. In order to understand the molecular mechanisms of adiposis, the changes of physiological, pathological, epigenetic and correlative gene expression were investigated during the adiposis development of C57BL/6J mice induced by long time (9 months) high-fat and high-sucrose diet (HFSD) sustainably. The results showed that mRNA transcription level of the Leptin, Glut4 and Glut2 genes have been obviously changed, which exhibit a negative correlation with methylation on their promoter DNA. The results also revealed that HFSD induced higher level of DNA methyltransferase 1 (DNMT1) in fat tissue might play important role in regulating the changes of methylation pattern on Glut4 and Leptin genes, and which might be one of the molecular mechanisms for the adiposis development.
Assuntos
Tecido Adiposo/metabolismo , Adiposidade/fisiologia , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Fígado/metabolismo , Tecido Adiposo/patologia , Animais , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Dieta Hiperlipídica/tendências , Transportador de Glucose Tipo 4/metabolismo , Leptina/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
Mice with a deletion of the p50 subunit of the proinflammatory nuclear factor kappa B pathway (NF-κB p50) have reduced weight compared to wild-type control mice. However, the physiological underpinning of this phenotype remains unknown. This study addressed this issue. Compared to littermate controls, lean male p50 null mice (p50-/- ) had an increased metabolic rate (~20%) that was associated with increased skeletal muscle (SkM, ~35%), but not liver, oxidative metabolism. These metabolic alterations were accompanied by decreases in adiposity, and tissue and plasma triglyceride levels (all ~30%). Notably, there was a marked decrease in skeletal muscle, but not liver, DGAT2 gene expression (~70%), but a surprising reduction in muscle PPARα and CPT1 (both ~20%) gene expression. Exposure to a high-fat diet accentuated the diminished adiposity of p50-/- mice despite elevated caloric intake, whereas plasma triglycerides and free fatty acids (both ~30%), and liver (~40%) and SkM (~50%) triglyceride accumulation were again reduced compared to WT. Although SkM cytokine expression (IL-6 and TNFα, each ~100%) were increased in p50-/- mice, neither cytokine acutely increased SkM oxidative metabolism. We conclude that the reduced susceptibility to diet-induced obesity and dyslipidemia in p50-/- mice results from an increase in metabolic rate, which is associated with elevated skeletal muscle oxidative metabolism and decreased DGAT2 expression.
Assuntos
Metabolismo Basal/fisiologia , Mediadores da Inflamação/metabolismo , Músculo Esquelético/metabolismo , Subunidade p50 de NF-kappa B/deficiência , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/tendências , Metabolismo Energético/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/prevenção & controleRESUMO
Recent studies have shown that obesity and its related metabolic dysfunction exacerbate outcomes of ischemic brain injuries in some brain areas, such as the hippocampus and cerebral cortex when they are subjected to transient ischemia. However, the impact of obesity in the striatum after brief transient ischemia has not yet been addressed. The objective of this study was to investigate effects of obesity on neuronal damage and inflammation in the striatum after transient ischemia and to examine the role of mTOR which is involved in the pathogenesis of metabolic and neurological diseases. Gerbils were fed with normal diet (ND) or high-fat diet (HFD) for 12 weeks and subjected to 5â¯min of transient ischemia. HFD-fed gerbils showed significant increase in body weight, blood glucose level, serum triglycerides, total cholesterol and low-density lipoprotein cholesterol without affecting food intake. Neuronal death/loss in the HFD-fed gerbils occurred in the dorsolateral striatum 2 days after transient ischemia, and neuronal loss was increased 5 days after transient ischemia, although no neuronal loss was observed in ND-fed gerbils at any time after transient ischemia. The HFD-fed gerbils showed hypertrophied microglia and further increased expressions of tumor necrosis factor-alpha, interukin-1beta, mammalian target of rapamycin (mTOR) and phosphorylated-mTOR during pre- and post-ischemic phases compared with the ND-fed gerbils. Additionally, we found that treatment with mTOR inhibitor rapamycin in the HFD-fed gerbils significantly attenuated transient ischemia-induced neuronal death in the dorsolateral striatum. These findings reveal that chronic HFD-induced obesity results in severe neuroinflammation and significant increase of mTOR activation, which could contribute to neuronal death in the stratum following 5â¯min of transient ischemia. Especially, abnormal mTOR activation would play a key role in mediating obesity-induced severe ischemic brain injury.
Assuntos
Corpo Estriado/metabolismo , Citocinas/biossíntese , Dieta Hiperlipídica/efeitos adversos , Ataque Isquêmico Transitório/metabolismo , Obesidade/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Morte Celular/fisiologia , Corpo Estriado/patologia , Dieta Hiperlipídica/tendências , Gerbillinae , Mediadores da Inflamação/metabolismo , Ataque Isquêmico Transitório/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Obesidade/patologiaRESUMO
Background Obesity has been implicated in impaired salivary secretion. This study aimed at evaluating the influence of diet-induced obesity on salivary secretion and how re-feeding with normal diet would affect changes in salivary secretion associated with diet-induced obesity. Methods Weaning rats weighing 55-65 g were randomly divided into three groups (control, diet-induced obese, re-fed obese) of seven rats each. The diet-induced obese group was fed a high-fat diet for 15 weeks, whereas the re-fed obese group received normal diet for another 15 weeks following the 15 weeks of high-fat diet. After treatment, blood and stimulated saliva samples were collected for the analyses of total protein, electrolytes, amylase, Immunoglobulin A (IgA), leptin and ghrelin. Tissue total protein, nitric oxide level, expressions of Na+/K+-ATPase, muscarinic (M3) receptor and aquaporin 5 in the submandibular glands were determined. Data were presented as mean±SEM and compared using independent student t-test and ANOVA with Tukey's post-hoc test. Results Results indicated increases in the levels of salivary calcium, phosphate, bicarbonate and leptin, whereas the levels of salivary amylase and ghrelin showed reduction in the obese group compared with the control. Most of these changes were reversed in the re-fed obese group. There were no significant differences in salivary lag time, flow rate, levels of tissue total protein, nitric oxide and the relative expressions of M3 receptor, Na++/K+-ATPase and aquaporin 5 in the submandibular glands between the obese and control groups. Conclusions Diet-induced obesity lead to some changes in salivary factors which were reversed by returning to normal diet.
Assuntos
Dieta Saudável/tendências , Dieta Hiperlipídica/efeitos adversos , Dieta Hiperlipídica/tendências , Obesidade/metabolismo , Saliva/metabolismo , Amilases/metabolismo , Animais , Biomarcadores/metabolismo , Grelina/metabolismo , Imunoglobulina A/metabolismo , Leptina/metabolismo , Masculino , Obesidade/patologia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
A key factor in the development of obesity is the overconsumption of fatty foods, which, in addition to facilitating weight gain, alters neuronal structures within brain reward circuitry. Our previous work demonstrates that sustained consumption of a high-fat diet (HFD) attenuates spine density in the prefrontal cortex (PFC). Whether HFD promotes structural adaptation among inhibitory cells of the PFC is presently unknown. One structure of interest is the perineuronal net (PNN), a specialized extracellular matrix surrounding, primarily, parvalbumin-containing GABAergic interneurons. PNNs contribute to synaptic stabilization, protect against oxidative stress, regulate the ionic microenvironment within cells, and modulate regional excitatory output. To examine diet-induced changes in PNNs, we maintained rats on one of three dietary conditions for 21 days: ad libitum chow, ad libitum 60% high fat (HF-AL), or limited-access calorically matched high fat (HF-CM), which produced no significant change in weight gain or adiposity with respect to chow controls. The PNN "number" and intensity were then quantified in the prelimbic (PL-PFC), infralimbic (IL-PFC), and ventral orbitofrontal cortex (OFC) using Wisteria floribunda agglutinin (WFA). Our results demonstrated that fat exposure, independent of weight gain, induced a robust decrease in the PNN intensity in the PL-PFC and OFC and a decrease in the PNN number in the OFC.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Dieta Hiperlipídica/tendências , Interneurônios/patologia , Masculino , Rede Nervosa/patologia , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Córtex Pré-Frontal/patologia , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: This study aimed to investigate the effect and possible underlying mechanisms of high-fat diet-induced obesity on spermatogenesis in male rats. METHODS: A total of 45 male rats were randomly divided into control (n = 15, normal diet) and obesity groups (n = 30, high-fat diet) and were fed for 16 weeks. Body weight and organ indexes were determined after sacrifice. Indicators of reproductive function, including sperm count, sperm motility, apoptosis of spermatogenic cells, and oxidative stress levels, were measured. Serum metabolic parameters and reproductive hormones were also assayed. RESULTS: Compared with the control group, epididymal sperm motility in the obese rats was significantly decreased (P < 0.01). Morphological analysis of the obesity group showed vacuolar changes in seminiferous tubules, spermatogenic cell dysfunction, and increased apoptosis of spermatogenic cells in testicular tissue (P < 0.05). The calculated free testosterone (cFT) concentration in serum was decreased (P < 0.05), whereas the serum sex hormone-binding globulin (SHBG) level was significantly increased (P < 0.01). The superoxide dismutase (SOD) concentration decreased and the malondialdehyde (MDA) concentration increased in testis tissues; however, neither changes were statistically significant (P > 0.05). RESULTS: Nutritional obesity can damage spermatogenesis in male rats due to long-term effects on spermatogenesis.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Infertilidade Masculina/patologia , Obesidade/patologia , Espermatogênese/fisiologia , Animais , Dieta Hiperlipídica/tendências , Infertilidade Masculina/etiologia , Masculino , Obesidade/complicações , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Doença de Alzheimer/patologia , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/tendências , Hipocampo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de ÓrgãosRESUMO
AIMS/INTRODUCTION: Peripheral neuropathy is a common complication of diabetes and also occurs in 30% of human obese individuals with impaired glucose tolerance. Even though peripheral neuropathy affects both sexes, most pre-clinical studies have been carried out using male rodents. The aim of the present study was to create diet-induced obesity and type 2 diabetes in female rats and mice in order to examine the development of peripheral neuropathy. MATERIALS AND METHODS: At 12 weeks-of-age, rats and mice were separated into three groups. Two groups or rats and mice were fed a 60-kcal% high-fat diet for 12 weeks (rats) or 8 weeks (mice). To induce type 2 diabetes, one group of high-fat diet-fed rats and mice were treated with a low dose of streptozotocin. Analyses of multiple neural end-points were carried out 12 weeks later. RESULTS: Glucose utilization was impaired in diet-induced obese female rats and mice, as was a number of neurological end-points including nerve conduction velocity, intraepidermal and subepithelial corneal nerve fiber densities, and thermal and mechanical sensitivity. When female diet-induced obese rats or mice were made hyperglycemic, glucose utilization and sensory nerve density of the skin and cornea, as well as thermal and mechanical sensitivity, were more significantly impaired compared with diet-induced obese female rodents. CONCLUSIONS: These studies show that diet-induced obese and type 2 diabetic female rodents develop peripheral neuropathy that is similar to that occurring in male rodents. However, for female rats, more aggressive treatment is required to induce dietary obesity.
Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/patologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Dieta Hiperlipídica/tendências , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/etiologia , Ratos , Ratos Sprague-Dawley , Estreptozocina , Resultado do TratamentoRESUMO
The excessive consumption of carbohydrates is related to non-alcoholic fatty liver disease (NAFLD) in infants and adults. The effect of combining maternal malnutrition and a high carbohydrate intake on the development of NAFLD in adulthood remains unknown. We therefore hypothesized that consumption of 5% sucrose by the offspring of dams fed a low-protein diet during pregnancy promotes liver fat accumulation and oxidative damage differently in females and males. To test this, 12-month-old female and male offspring of mothers fed a Control (C) or low-protein diet (Restricted, R) were provided with either tap water or 5% sucrose for a period of 10 weeks. Livers were excised to measure the fat content and 3-nitrotyrosine (3-NTyr) immunostaining; serum samples were also obtained to measure the concentration of malondialdehyde (MDA). Data were analyzed using a non-repeated measures three-way analysis of variance to determine significant differences (P<0.05) regarding to the interaction among maternal diet, sucrose consumption and sex. Results showed that the liver fat content of females from R mothers was higher than that of their male counterpart. Hepatic 3-NTyr immunostaining and serum MDA concentrations were not affected by the interaction involving maternal diet, sucrose consumption and sex. Otherwise, liver fat content was correlated with the hepatic 3-NTyr immunostaining and serum MDA concentrations only in females. Thus, sucrose intake in adulthood increases fat content in the female but not in the male rat offspring of dams fed with a low-protein diet during pregnancy. This research emphasizes the importance of a balanced diet during pregnancy and the influence of the diet on the adult offspring.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Dieta com Restrição de Proteínas/efeitos adversos , Sacarose Alimentar/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Caracteres Sexuais , Fatores Etários , Animais , Dieta Hiperlipídica/tendências , Dieta com Restrição de Proteínas/tendências , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos WistarRESUMO
The aim of this study was to investigate the long-term neurochemical alterations in the hippocampus of mice fed a high-fat diet (HFD) while plasma leptin and corticosterone levels were monitored. Although metabolic disturbances induced by the excess intake of fat are assumed to cause depression, the relationship underlying dysfunctional adipose tissue, stress hormone release, and excitatory metabolism has not been fully understood yet. Four-week-old male C57BL/6 mice were separated into a HFD-fed group (nâ¯=â¯8) and low-fat diet-fed group (nâ¯=â¯8). Proton magnetic resonance spectroscopy was used to measure the long-term changes in neurochemicals in the hippocampus at 0, 5, and 10 weeks and blood samples were taken at the same time to assess plasma hormones levels. At the end of the experiment, magnetic resonance imaging was performed to quantify abdominal fat accumulation. At 10 weeks, corticosterone and leptin levels were significantly increased in the HFD group compared with the low-fat diet group. In addition, aspartate, glutamate, total choline, and N-acetylaspartic acid levels were significantly increased, but glutamine/glutamate ratios were substantially decreased at 10 weeks in the HFD group. These results were compatible with HFD-induced acute stress responses and changes in N-methyl-d-aspartate receptor-induced plasticity. These findings demonstrated that the long-term ingestion of a HFD induced hyperglutamatergic metabolism and altered glutamine-glutamate cycling. Therfore, it is suggested that hypothalamic-pituitary-adrenal dysfunction and hyperglutamatergic activation in the hippocampus resulting from the HFD.