RESUMEN
ABSTRACT: Angiotensin (Ang)-(1-7) is a cardioprotective peptide of the renin-angiotensin system. Prepuberty has been considered as a later susceptible window of development, and stressful factors in this life phase can induce chronic diseases in adulthood. We aimed to investigate whether the treatment with Ang-(1-7) during the prepuberty could attenuate the development of hypertension and cardiac injury in adult spontaneously hypertensive rats (SHRs). SHRs were treated with Ang-(1-7) (24 µg/kg/h) from age 4 to 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography up to 17th week. Thereafter, echocardiography was performed, and the rats were euthanized for the collection of tissues and blood. Ang-(1-7) did not change the systolic blood pressure but reduced the septal and posterior wall thickness, and cardiomyocyte hypertrophy and fibrosis in SHR. In addition, Ang-(1-7) reduced the gene expression of atrial natriuretic peptide and brain natriuretic peptide, increased the metalloproteinase 9 expression, and reduced the extracellular signal-regulated kinases 1/2 phosphorylation. Ang-(1-7) also prevented the reduction of Mas receptor but did not change the protein expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1, and AT2. The treatment with Ang-(1-7) decreased the malondialdehyde (MDA) levels and increased superoxide dismutase-1 and catalase activities and protein expression of catalase. Our findings demonstrate that the treatment of SHR with Ang-(1-7) for 3 weeks early in life promotes beneficial effects in the heart later in life, even without altering blood pressure, through mechanisms involving the reduction of oxidative stress and ERK1/2 phosphorylation. In addition, this study supports the prepuberty as an important programming window.
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Angiotensina I , Presión Sanguínea , Cardiomegalia , Hipertensión , Estrés Oxidativo , Fragmentos de Péptidos , Ratas Endogámicas SHR , Animales , Angiotensina I/farmacología , Fragmentos de Péptidos/farmacología , Masculino , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/prevención & control , Cardiomegalia/prevención & control , Cardiomegalia/fisiopatología , Cardiomegalia/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Estrés Oxidativo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Ratas , Fosforilación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Factores de Edad , Metaloproteinasa 9 de la Matriz/metabolismo , Factor Natriurético Atrial/metabolismo , Antihipertensivos/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Early postnatal overfeeding (PO) induces long-term overweight and reduces brown adipose tissue (BAT) thermogenesis. Exercise has been suggested as a possible intervention to increase BAT function. In this study, we investigated chronical effects of moderate-intensity exercise in BAT function in postnatal overfed male Wistar rats METHODS: Litters' delivery was on postnatal-day 0 - PN0. At PN2, litters were adjusted to nine (normal litter - NL) or three pups (small litter - SL) per dam. Animals were weaned on PN21 and in PN30 randomly divided into sedentary (NL-Sed and SL-Sed) or exercised (NL-Exe and SL-Exe), N of 14 litters per group. Exercise protocol started (PN30) with an effort test; training sessions were performed three times weekly at 60% of the VO2max achieved in effort test, until PN80. On PN81, a temperature transponder was implanted beneath the interscapular BAT, whose temperature was assessed in periods of lights-on and -off from PN87 to PN90. Sympathetic nerve activation of BAT was registered at PN90. Animals were euthanized at PN91 and tissues collected RESULTS: PO impaired BAT thermogenesis in lights-on (pPO < 0.0001) and -off (pPO < 0.01). Exercise increased BAT temperature in lights-on (pExe < 0.0001). In NL-Exe, increased BAT activity was associated with higher sympathetic activity (pExe < 0.05), ß3-AR (pExe < 0.001), and UCP1 (pExe < 0.001) content. In SL-Exe, increasing BAT thermogenesis is driven by a combination of tissue morphology remodeling (pExe < 0.0001) with greater effect in increasing UCP1 (pExe < 0.001) and increased ß3-AR (pExe < 0.001) content. CONCLUSION: Moderate exercise chronically increased BAT thermogenesis in both, NL and SL groups. In NL-Exe by increasing Sympathetic activity, and in SL-Exe by a combination of increased ß3-AR and UCP1 content with morphologic remodeling of BAT. Chronically increasing BAT thermogenesis in obese subjects may lead to higher overall energy expenditure, favoring the reduction of obesity and related comorbidities.
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Tejido Adiposo Pardo/metabolismo , Obesidad/fisiopatología , Condicionamiento Físico Animal/fisiología , Animales , Brasil , Modelos Animales de Enfermedad , Ratones , Obesidad/diagnóstico , Condicionamiento Físico Animal/métodos , Ratas Wistar/crecimiento & desarrollo , Ratas Wistar/metabolismoRESUMEN
Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with early-life adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re-set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease.
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Glucocorticoides/fisiología , Enfermedades Metabólicas/etiología , Mitocondrias/fisiología , Embarazo/fisiología , Animales , Epigénesis Genética , Femenino , Desarrollo Fetal/fisiología , Feto/fisiología , HumanosRESUMEN
KEY POINTS: Cancer growth, cell proliferation and cachexia index can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins in adolescence. Walker 256 tumour-bearing rats who started exercise training during adolescence did not revert the basal low glycaemia and insulinaemia observed before tumour cell inoculation. The moderate exercise training improved glucose tolerance and peripheral insulin sensitivity only in rats exercised early in adolescence. The chronic effects of our exercise protocol are be beneficial to prevent cancer cachexia and hold clear potential as a nonpharmacological therapy of insulin sensitization. ABSTRACT: We tested the hypothesis that moderate exercise training, performed early, starting during adolescence or later in life during adulthood, can inhibit tumour cell growth as a result of changes in biometric and metabolic markers. Male rats that were 30 and 70 days old performed a treadmill running protocol over 8 weeks for 3 days week-1 , 44 min day-1 and at 55-65% VÌO2max . After the end of training, a batch of rats was inoculated with Walker 256 carcinoma cells. At 15 days after carcinoma cell inoculation, the tumour was weighed and certain metabolic parameters were evaluated. The data demonstrated that physical performance was better in rats that started exercise training during adolescence according to the final workload and VÌO2max . Early or later moderate exercise training decreased the cachexia index, cell proliferation and tumour growth; however, the effects were more pronounced in rats that exercised during adolescence. Low glycaemia, insulinaemia and tissue insulin sensitivity was not reverted in Walker 256 tumour-bearing rats who trained during adolescence. Cancer growth can be attenuated by the beneficial programming effect of moderate exercise training, especially if it begins during adolescence. In addition, improvement in glucose-insulin homeostasis might be involved in this process.
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Carcinoma 256 de Walker/terapia , Condicionamiento Físico Animal/métodos , Animales , Caquexia/metabolismo , Caquexia/prevención & control , Carcinoma 256 de Walker/patología , Carcinoma 256 de Walker/prevención & control , Células Cultivadas , Glucosa/metabolismo , Resistencia a la Insulina , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND/AIMS: Particulate matter (PM) is an important risk factor for immunological system imbalance due to its small size, which can reach more distal regions of the respiratory tract, independently of its chemical composition. Some studies have suggested that PM exposure is associated with an increased incidence of diabetes, especially in industrialized urban regions. However, studies regarding the effects of PM exposure during perinatal life on glucose metabolism are limited. We tested whether exposure to PM from an urban area with poor air quality during pregnancy and lactation could cause short- and long-term dysfunction in rat offspring. METHODS: Samples of < 10 µm PM were collected in an urban area of Cotonou, Benin (West Africa), and reconstituted in corn oil. Pregnant Wistar rats received 50 µg PM/day by gavage until the end of lactation. After birth, we analyzed the dams' biochemical parameters as well as those of their male offspring at 21 and 90 days of age. RESULTS: The results showed that PM exposure did not lead to several consequences in dams; however, the male offspring of both ages presented an increase of approximately 15% in body weight. Although the blood glucose levels remained unchanged, the insulin levels were increased 2.5- and 2-fold in PM exposure groups of both ages, respectively. HOMA-IR and HOMA-ß were also increased at both ages. We also demonstrated that the number, islet area and insulin immunodensity of pancreatic islets were significantly increased at both ages from PM exposure. CONCLUSION: Our data show that chronic PM exposure by the oral route during perinatal life in rats leads to glucose dyshomeostasis in male offspring both in early and later life. Thus, we suggest that an ambience with poor air quality, mainly where traffic is dense, can contribute to an increase in metabolic disease incidence.
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Glucosa/metabolismo , Material Particulado/toxicidad , Animales , Área Bajo la Curva , Glucemia/análisis , Femenino , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Curva ROC , Ratas , Ratas WistarRESUMEN
PURPOSE: Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life. METHODS: Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection. RESULTS: MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in ß-cell function (p < 0.05). MG mothers also showed dyslipidemia (p < 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (p < 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in ß-cell function (p < 0.05). Besides, MG offspring showed dyslipidemia (p < 0.05) increasing cardiovascular diseases risk. CONCLUSIONS: Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.
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Diabetes Mellitus Tipo 2/inducido químicamente , Dislipidemias/inducido químicamente , Contaminantes Ambientales/toxicidad , Lactancia/efectos de los fármacos , Exposición Materna/efectos adversos , Obesidad/inducido químicamente , Piruvaldehído/toxicidad , Adiposidad/efectos de los fármacos , Administración Oral , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dislipidemias/sangre , Dislipidemias/metabolismo , Dislipidemias/patología , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/análisis , Femenino , Insulina/análisis , Insulina/sangre , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Lactancia/metabolismo , Masculino , Leche/química , Obesidad/sangre , Obesidad/metabolismo , Obesidad/patología , Embarazo , Piruvaldehído/administración & dosificación , Piruvaldehído/análisis , Distribución Aleatoria , Ratas Sprague-Dawley , Toxicocinética , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Trichilia catigua A. Juss., known as "catuaba" in Brazil, has been popularly used as a tonic for fatigue, impotence and memory deficits. Previously, our group demonstrated that the ethyl-acetate fraction (EAF) of T. catigua has antioxidant and anti-inflammatory effects. The present study evaluated the anti-diabetic activity of EAF in type 1 diabetic rats. METHODS: Male Wistar rats were divided into four groups (N: non-diabetic group, D: type 1 diabetic group, NC: non-diabetic + EAF group and DC: type 1 diabetic + EAF group). The latter two groups were treated with 200 mg/kg EAF. Type 1 diabetes was induced by intravenous streptozotocin (STZ) injection (35 mg/kg). Starting two days after STZ injection, EAF was administered daily by gavage for 8 weeks. RESULTS: EAF attenuated body mass loss and reduced food and water intake. EAF improved hyperglycaemia and other biochemical parameters, such as alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Furthermore, the number of pancreatic ß-cells and the size of the islets had increased by ß-cell proliferation in the DC group. EAF promoted reduction in kidney tissue damage in STZ-induced diabetic rats by reduction of renal fibrosis. CONCLUSION: The present study showed that EAF improves glucose homeostasis and endocrine pancreas morphology and inhibits the development of diabetic nephropathy in STZ-induced diabetic rats.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Meliaceae/química , Extractos Vegetales/uso terapéutico , Acetatos/química , Animales , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/patología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/patología , Hipoglucemiantes/química , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/patología , Masculino , Extractos Vegetales/química , Ratas WistarRESUMEN
BACKGROUND/AIMS: The sulphonylurea glibenclamide (Gli) is widely used in the treatment of type 2 diabetes. In addition to its antidiabetic effects, low incidences of certain types of cancer have been observed in Gli-treated diabetic patients. However, the mechanisms underlying this observation remain unclear. The aim of the present work was to evaluate whether obese adult rats that were chronically treated with an antidiabetic drug, glibenclamide, exhibit resistance to rodent breast carcinoma growth. METHODS: Neonatal rats were treated with monosodium L-glutamate (MSG) to induce prediabetes. Control and MSG groups were treated with Gli (2 mg/kg body weight/day) from weaning to 100 days old. After Gli treatment, the control and MSG rats were grafted with Walker-256 tumour cells. After 14 days, grafted rats were euthanized, and tumour weight as well as glucose homeostasis were evaluated. RESULTS: Treatment with Gli normalized tissue insulin sensitivity and glucose tolerance, suppressed fasting hyperinsulinaemia, reduced fat tissue accretion in MSG rats, and attenuated tumour growth by 27% in control and MSG rats. CONCLUSIONS: Gli treatment also resulted in a large reduction in the number of PCNA-positive tumour cells. Although treatment did improve the metabolism of pre-diabetic MSG-rats, tumour growth inhibition may be a more direct effect of glibenclamide.
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Proliferación Celular/efectos de los fármacos , Gliburida/farmacología , Estado Prediabético/prevención & control , Animales , Caquexia/etiología , Línea Celular Tumoral , Glucosa/metabolismo , Gliburida/uso terapéutico , Hiperinsulinismo/prevención & control , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inmunohistoquímica , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/patología , Estado Prediabético/etiología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Wistar , Glutamato de Sodio/toxicidadRESUMEN
INTRODUCTION: A sedentary lifestyle and high-fat feeding are risk factors for cardiometabolic disorders. This study determined whether moderate exercise training prevents the cardiometabolic changes induced by a high-fat diet (HFD). MATERIALS AND METHODS: Sixty-day-old rats were subjected to moderate exercise three times a week for 30 days. After that, trained rats received a HFD (EXE-HFD) or a commercial normal diet (EXE-NFD) for 30 more days. Sedentary animals also received the diets (SED-HFD and SED-NFD). Food intake and body weight were measured weekly. After 120 days of life, analyses were performed. Data were analysed with two-way ANOVA and the Tukey post-test. RESULTS: Body weight gain induced by HFD was attenuated in trained animals. HFD reduced food intake by approximately 30% and increased body fat stores by approximately 75%. Exercise attenuated 80% of the increase in fat pads and increased 24% of soleus muscle mass in NFD animals. HFD induced a hyper-response to glucose injection, and exercise attenuated this response by 50%. Blood pressure was increased by HFD, and the beneficial effect of exercise in reducing blood pressure was inhibited by HFD. HFD increased vagal activity by 65% in SED-HFD compared with SED-NFD rats, and exercise blocked this increase. HFD reduced sympathetic activity and inhibited the beneficial effect of exercise on ameliorating sympathetic activity. CONCLUSION: Four weeks of moderate exercise at low frequency was able to prevent the metabolic changes induced by a HFD but not the deleterious effects of diet on the cardiovascular system.
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Dieta Alta en Grasa/efectos adversos , Enfermedades Metabólicas/prevención & control , Condicionamiento Físico Animal , Animales , Glucemia/metabolismo , Presión Sanguínea , Composición Corporal , Peso Corporal , Grasas de la Dieta/administración & dosificación , Ingestión de Energía , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Masculino , Síndrome Metabólico/prevención & control , Músculo Esquelético/fisiología , Obesidad/prevención & control , Ratas , Ratas Wistar , Conducta Sedentaria , Aumento de PesoRESUMEN
Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1-14]. For this, two experimental models were used: (i) LEAP2[1-14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1-14] or MK677. Perinatal GHSR modulation by LEAP2[1-14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.
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Hígado , Receptores de Ghrelina , Animales , Hígado/metabolismo , Receptores de Ghrelina/metabolismo , Receptores de Ghrelina/genética , Femenino , Ratas , Embarazo , Masculino , Transducción de Señal , Ghrelina/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Ratas Wistar , Metabolismo Energético , Maduración Sexual/fisiología , Glucosa/metabolismo , Proteínas SanguíneasRESUMEN
BACKGROUND: Though maternal diabetes effects are well described in the literature, the effects of maternal diabetes in postnatal phases are often overlooked. Diabetic individuals have higher levels of circulating glycotoxins, and there is a positive correlation between maternal-derived glycotoxins and circulating glycotoxins in their progeny. Previous studies evaluated the metabolic effects of high glycotoxin exposure during lactation in adult animals. However, here we focus on the cardiovascular system of juvenile rats. METHODS: For this, we used two experimental models: 1. High Methylglyoxal (MG) environment: pregnant Wistar rats were injected with PBS (VEH group) or Methylglyoxal (MG group; 60 mg/kg/day; orally, postnatal day (PND) 3 to PND14). 2. GLO-1 inhibition: pregnant Wistar rats were injected with dimethyl sulfoxide (VEH group) or a GLO-1 inhibitor (BBGC group; 5 mg/kg/day; subcutaneously, PND1-PND5). The offspring were evaluated at PND45. RESULTS: MG offspring presented cardiac dysfunction and subtly worsened vasomotor responses in the presence of perivascular adipose tissue, without morphological alterations. In addition, an endogenous increase in maternal glycotoxins impacts offspring vasomotricity due to impaired redox status. CONCLUSIONS: Our data suggest that early glycotoxin exposure led to cardiac and vascular impairments, which may increase the risk for developing cardiovascular diseases later in life.
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Efectos Tardíos de la Exposición Prenatal , Piruvaldehído , Ratas Wistar , Animales , Femenino , Piruvaldehído/toxicidad , Embarazo , Ratas , Sistema Cardiovascular/efectos de los fármacos , Masculino , Enfermedades Cardiovasculares/inducido químicamenteRESUMEN
Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.
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Arritmias Cardíacas , Daño por Reperfusión Miocárdica , Ratas Wistar , Animales , Ratas , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Masculino , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/fisiopatología , Diástole/fisiología , Cloruro de Sodio Dietético/efectos adversos , Frecuencia Cardíaca/fisiologíaRESUMEN
BACKGROUND/AIMS: Metabolic syndrome has been identified as one of the most significant threats to human health in the 21(st) century. Exercise training has been shown to counteract obesity and metabolic syndrome. The present study aimed to investigate the effects of moderate exercise training on pancreatic beta-cell function and autonomic nervous system (ANS) activity in rats fed a high-fat diet (HFD). METHODS: Weaning rats were divided into four groups: rats fed a standard chow or HFD (sedentary, Control-SED and HFD-SED; or exercised, Control-EXE and HFD-EXE, respectively). Exercised rats ran (from 21- to 91-days-old) for 60 minutes (3 times/week) over a 10-week period. Glucose and insulin tolerance tests were performed. Pancreatic islets were isolated to study glucose-induced insulin secretion (GIIS). Parasympathetic and sympathetic nerve electrical signals were measured, and liver samples were processed and histologically analyzed. RESULTS: Exercise prevented obesity, insulin resistance, and liver steatosis as well as improved total cholesterol, ALT, and AST levels. Islets from HFD rats showed insulin hypersecretion which was ameliorated by exercise. Exercise decreased vagal nerve activity in the HFD-EXE group and increased the activity of the sympathetic nervous system in both exercised groups. CONCLUSION: Exercise prevents obesity and liver steatosis and restores pancreatic beta-cell function and ANS activity in HFD-obese rats.
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Sistema Nervioso Autónomo/metabolismo , Dieta Alta en Grasa , Células Secretoras de Insulina/metabolismo , Condicionamiento Físico Animal , Animales , Células Cultivadas , Masculino , Obesidad/fisiopatología , Obesidad/terapia , Ratas , Ratas WistarRESUMEN
AIM: Lactation is an important programming window for metabolic disease and neuronal alterations later in life. We aimed to study the effect of maternal glycation during lactation on offspring neurodevelopment and behaviour, assessing possible sex differences and underpinning molecular players. METHODS: Female Wistar rats were treated with Glyoxalase-1 inhibitor S-p-Bromobenzylguthione cyclopentyl diester (BBGC 5 mg/kg). A control and vehicle group treated with dimethyl sulfoxide were also considered. Male and female offspring were tested at infancy for neurodevelopment hallmarks. After weaning, triglycerides and total antioxidant capacity were measured in breast milk. At adolescence, offspring were tested for locomotor ability, anxious-like behaviour, and recognition memory. Metabolic parameters were assessed, and the hippocampus and prefrontal cortex were collected for molecular analysis. KEY FINDINGS: Maternal glycation reduced triglycerides and total antioxidant capacity levels in breast milk. At infancy, both male and female offspring presented an anticipation on the achievement of neurodevelopmental milestones. At adolescence, male offspring exposed to maternal glycation presented hyperlocomotion, whereas offspring of both sexes presented a risk-taking phenotype, accompanied by increase GABAA receptor levels in the hippocampus. Females also demonstrated GABAA and PSD-95 changes in prefrontal cortex. Furthermore, lower levels of GLO1 and consequently higher accumulation of AGES were also observed in both male and female offspring hippocampus. SIGNIFICANCE: Early exposure to maternal glycation induces changes in milk composition leading to neurodevelopment changes at infancy, and sex-specific behavioural and neurometabolic changes at adolescence, further evidencing that lactation period is a critical metabolic programming window and in sculpting behaviour.
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Antioxidantes , Efectos Tardíos de la Exposición Prenatal , Ratas , Animales , Femenino , Masculino , Humanos , Ratas Wistar , Antioxidantes/farmacología , Reacción de Maillard , Leche/metabolismo , Lactancia , Triglicéridos , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABAA in females and higher GABAA levels in males), while, in the prefrontal cortex, similar higher GABAA receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner.
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Ansiedad , Roedores , Femenino , Masculino , Animales , Trastornos de Ansiedad , Corteza Prefrontal , Ácido gamma-AminobutíricoRESUMEN
Obesogenic environments such as Westernized diets, overnutrition, and exposure to glycation during gestation and lactation can alter peripheral neuroendocrine factors in offspring, predisposing for metabolic diseases in adulthood. Thus, we hypothesized that exposure to obesogenic environments during the perinatal period reprograms offspring energy balance mechanisms. Four rat obesogenic models were studied: maternal diet-induced obesity (DIO); early-life obesity induced by postnatal overfeeding; maternal glycation; and postnatal overfeeding combined with maternal glycation. Metabolic parameters, energy expenditure, and storage pathways in visceral adipose tissue (VAT) and the liver were analyzed. Maternal DIO increased VAT lipogenic [NPY receptor-1 (NPY1R), NPY receptor-2 (NPY2R), and ghrelin receptor], but also lipolytic/catabolic mechanisms [dopamine-1 receptor (D1R) and p-AMP-activated protein kinase (AMPK)] in male offspring, while reducing NPY1R in females. Postnatally overfed male animals only exhibited higher NPY2R levels in VAT, while females also presented NPY1R and NPY2R downregulation. Maternal glycation reduces VAT expandability by decreasing NPY2R in overfed animals. Regarding the liver, D1R was decreased in all obesogenic models, while overfeeding induced fat accumulation in both sexes and glycation the inflammatory infiltration. The VAT response to maternal DIO and overfeeding showed a sexual dysmorphism, and exposure to glycotoxins led to a thin-outside-fat-inside phenotype in overfeeding conditions and impaired energy balance, increasing the metabolic risk in adulthood.
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Fenómenos Fisiologicos Nutricionales Maternos , Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Masculino , Embarazo , Ratas , Tejido Adiposo/metabolismo , Dieta Alta en Grasa , Metabolismo Energético , Hígado/metabolismo , Obesidad/metabolismo , Obesidad Materna/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismoRESUMEN
The aim of this study was to evaluate whether high-fat (HF) diet intake during puberty can program obesity as well as generate glucose imbalance and hepatic metabolic dysfunctions in adult life. Male Wistar rats were randomly assigned into two groups: rats fed standard chow (NF) and rats fed a HF from postnatal 30-day-old (PND30) until PND60. Then, both groups were fed a standard chow from PND60 until PND120. Euthanasia and samples collections occurred at PND120. HF animals were overweight (+11%) and had increased adiposity, hyperphagia (+12%), hyperglycaemia (+13%), hyperinsulinemia (+69%), and hypertriglyceridemia (+34%). Plasma glucose levels during intravenous glucose tolerance test (ivGTT) and intraperitoneal insulin tolerance test (ipITT) were also higher in the HF group, whereas Kitt was significantly lower (-34%), suggesting reduced insulin sensitivity. In the same sense, HF animals present pancreatic islets hypertrophy and high ß-cell mass. HF animals also had a significant increase in blood glucose levels during pyruvate tolerance test, indicating increased gluconeogenesis. Hepatic morphology analyses showed an increase in lipid inclusion in the HF group. Moreover, PEPCK and FAS protein expression were higher in the livers of the HF animals (+79% and + 37%, respectively). In conclusion, HF during puberty causes obese phenotype leading to glucose dyshomeostasis and nonalcoholic fatty liver disease, which can be related to the overexpression of proteins PEPCK and FAS.
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Glucemia , Dieta Alta en Grasa , Ratas , Masculino , Animales , Dieta Alta en Grasa/efectos adversos , Glucemia/análisis , Ratas Wistar , Maduración Sexual , Obesidad/complicaciones , Obesidad/metabolismo , Glucosa/metabolismoRESUMEN
Herein, we assessed milk hormones, the biochemical composition of milk, and its association with neonatal body weight gain and metabolic homeostasis in weaned rats whose mothers were undernourished in the last third of pregnancy. From the 14th day of pregnancy until delivery, undernourished mothers had their food restricted by 50% (FR50), whereas control mothers were fed ad libitum. The litter size was adjusted to eight pups, and rats were weaned at 22 days old. Milk and blood from mothers, as well as blood and tissues from pups, were collected for further analyses. At birth, FR50 pups were smaller than control pups, and they exhibited hyperphagia and rapid catch-up growth during the suckling period. On day 12, the milk from FR50 mothers had higher energy content, glucose, total cholesterol, triglycerides, and acylated ghrelin but lower leptin and corticosterone levels. Interestingly, FR50 mothers were hypoglycemic and hyperleptinemic at the end of the nursing period. Weaned FR50 pups had an obese phenotype and exhibited insulin resistance, which was associated with hyperglycemia and hypertriglyceridemia; they also had high blood levels of total cholesterol, leptin, and acylated ghrelin. In addition, the protein expression of growth hormone secretagogue receptor (GHSR) in the hypothalamus was increased by almost 4-fold in FR50 pups. In summary, maternal calorie restriction during the last third of pregnancy disrupts energy and metabolic hormones in milk, induces pup hyperleptinemia and hyperghrelinemia, and upregulates their hypothalamic GHSR, thus suggesting that the hypothalamic neuroendocrine circuitry may be working to address the early onset of obesity.
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Leptina , Desnutrición , Animales , Peso Corporal/fisiología , Colesterol , Femenino , Ghrelina , Desnutrición/complicaciones , Leche , Obesidad , Embarazo , Ratas , Ratas WistarRESUMEN
Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (p = 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (p = 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (p = 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (p = 0.062 and p = 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (p = 0.044) and increased interstitial fibrosis (p = 0.028) compared with controls. Reduced protein carbonyls (PC) (p = 0.030) and catalase activity (p = 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (p = 0.002) and the activity of superoxide dismutase and catalase (p = 0.044 and p = 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (p = 0.039 and p = 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.
RESUMEN
Postnatal early overfeeding (PO) is a risk factor for cardiometabolic disorders. However, remains unknown the cardiac effects in the second generation from postnatal overfed dams. Our aim was to investigate the effects of maternal PO on cardiac parameters in second generation (F2) offspring. For this, pregnant Wistar rats (F0) were divided into two groups: normal litter (NL, 9 pups) and small litter (SL, 3 pups). At P70, female offspring (F1) of both groups were mated with non-PO male rats. At P21 male and female F2 offspring (NLO and SLO) were weaned, and at P45 they were euthanized to evaluate the cardiac function and sample collection. Male and female SLO showed increased body weight, food intake and adiposity. Blood estradiol levels were increased in the male SLO and decreased in the female SLO. Blood testosterone levels increased in SLO females, but not change in SLO male rats. Although SLO offspring presented cardiac hypertrophy, only males had ex vivo functional impairments, such as reduction of the intraventricular systolic pressure and dP/dt. Male and female SLO had increased interstitial fibrosis; however, only the male SLO had increased perivascular fibrosis. In addition, only male rats from SLO group had decreased AKT and Type 2 Ang-2 receptor, increased catalase and type alpha estrogenic receptor protein levels. Maternal PO leads to obese phenotype and alters sex-steroid levels in both male and female offspring. Although both sexes showed cardiac hypertrophy, only male offspring showed cardiac dysfunction, which may be related with Ang2 and AKT signaling impairments.