RESUMO
Aging is a complex biological process, resulting in gradual and progressive decline in structure and function in many organ systems. Our objective is to determine if structural changes produced by aging vary with sex in a stressful situation such as dehydration. The expression of Slc12a3 mRNA in the renal cortex, α-smooth muscle actin (α-SMA), and fibronectin was evaluated in male and female rats, aged 3 and 18 months, submitted and not submitted to water deprivation (WD) for 48 h, respectively. When comparing ages, 18-month-old males showed a lower expression of Slc12a3 mRNA than 3-month-old males, and control and WD 18-month-old male and female rats exhibited a higher expression of α-SMA than the respective 3-month-old rats. Fibronectin was higher in both control and WD 18-month-old males than the respective 3-month-old males. In females, only the control 18-month-old rats showed higher fibronectin than the control 3-month-old rats. When we compared sex, control and WD 3-month-old female rats had a lower expression of Slc12a3 mRNA than the respective males. The WD 18-month-old male rats presented a higher expression of fibronectin and α-SMA than the WD 18-month-old female rats. When we compared hydric conditions, the WD 18-month-old males displayed a lower relative expression of Slc12a3 mRNA and higher α-SMA expression than the control 18-month-old males. Aging, sex, and dehydration lead to alterations in kidney structure.
Assuntos
Desidratação , Fibronectinas , Rim , Animais , Feminino , Masculino , Ratos , Envelhecimento/genética , Desidratação/genética , Fibronectinas/genética , Rim/patologia , RNA Mensageiro/genética , Privação de ÁguaRESUMO
Low-grade inflammation of the hypothalamus is associated with the disturbance of energy balance. The endocannabinoid system has been implicated in the development and maintenance of obesity as well as in the control of immune responses. The type 2 cannabinoid receptor (CB2) signaling has been associated with anti-inflammatory effects. Therefore, in high fat diet (HFD)-induced obese mice, we modulated CB2 signaling and investigated its effects on energy homeostasis and hypothalamic microgliosis/astrogliosis. We observed no effect on caloric intake and body weight gain in control diet-fed animals that received prolonged icv infusion of the CB2 receptor agonist HU308. Interestingly, we observed a decrease in glucose tolerance in HFD-fed animals treated with HU308. Prolonged icv infusion of HU308 increases astrogliosis in the ventromedial nucleus (VMH) of obese animals and reduced HFD-induced microgliosis in the hypothalamic arcuate (ARC) but not in the paraventricular (PVN) or VMH nuclei. These data indicate that central CB2 signaling modulates glucose homeostasis and glial reactivity in obesogenic conditions, irrespective of changes in body weight.
Assuntos
Dieta Hiperlipídica , Gliose , Animais , Peso Corporal , Encéfalo , Dieta Hiperlipídica/efeitos adversos , Glucose , Hipotálamo , Camundongos , Obesidade/etiologiaRESUMO
OBJECTIVE: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes (Clock, Bmal1) and genes involved in lipid metabolism (Pgc1a, Pparg, Ucp2) through nutrient-sensing pathways (Sirt1, Ampk, Nampt) in peripheral tissues. METHODS: Rats were grouped according to food access: Control group (CG, food ad libitum), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. RESULTS: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a, Pparg, and Ucp2 but not Ampk and Nampt. CONCLUSION: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.
Assuntos
Hipotálamo , Fígado , Animais , Ritmo Circadiano , Metabolismo dos Lipídeos , Fígado/metabolismo , Nutrientes , RatosRESUMO
BACKGROUND/AIMS: Furosemide is a loop diuretic widely used in clinical practice for the treatment of oedema and hypertension. The aim of this study was to determine physiological and molecular changes in the hypothalamic-neurohypophysial system as a consequence of furosemide-induced sodium depletion. METHODS: Male rats were sodium depleted by acute furosemide injection (10 and 30 mg/kg) followed by access to low sodium diet and distilled water for 24 h. The renal and behavioural consequences were evaluated, while blood and brains were collected to evaluate the neuroendocrine and gene expression responses. RESULTS: Furosemide treatment acutely increases urinary sodium and water excretion. After 24 h, water and food intake were reduced, while plasma angiotensin II and corticosterone were increased. After hypertonic saline presentation, sodium-depleted rats showed higher preference for salt. Interrogation using RNA sequencing revealed the expression of 94 genes significantly altered in the hypothalamic paraventricular nucleus (PVN) of sodium-depleted rats (31 upregulated and 63 downregulated). Out of 9 genes chosen, 5 were validated by quantitative PCR in the PVN (upregulated: Ephx2, Ndnf and Vwf; downregulated: Caprin2 and Opn3). The same genes were also assessed in the supraoptic nucleus (SON, upregulated: Tnnt1, Mis18a, Nr1d1 and Dbp; downregulated: Caprin2 and Opn3). As a result of these plastic transcriptome changes, vasopressin expression was decreased in PVN and SON, whilst vasopressin and oxytocin levels were reduced in plasma. CONCLUSIONS: We thus have identified novel genes that might regulate vasopressin gene expression in the hypothalamus controlling the magnocellular neurons secretory response to body sodium depletion and consequently hypotonic stress.
Assuntos
Diuréticos/farmacologia , Furosemida/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sódio/metabolismo , Transcriptoma/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Animais , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo , Transcriptoma/fisiologia , Vasopressinas/metabolismo , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Exposure to stressful environmental events during the perinatal period can increase vulnerability to psychopathologies that cause neuroendocrine changes associated with deficits in emotional behavior that can appear early in life. Post-traumatic stress disorder (PTSD) is a frequent, chronic, and disabling disorder that negatively impacts the emotional, social, and cognitive behaviors of affected individuals. Thus, we induced PTSD in pregnant rats by applying inescapable footshocks and then investigated the behavioral parameters similar to anxiety in offspring at prepubertal age, in addition to the plasma levels of maternal and offspring corticosterone and expression of glucocorticoid receptors (GR) in the offspring's hippocampus. With the dams, maternal behavior, open field, and object recognition tests were performed. With the male and female offspring, we performed the following: quantification of ultrasonic vocalizations, elevated plus-maze test, evaluation of exploratory activity in the open field, and hole board test, as well as plasma corticosterone measurements and Western blotting for GR. Our results showed that gestational PTSD affected maternal behavior, led to anxiety-like symptoms, increased corticosterone levels, and increased GR expression in the offspring's hippocampus. Therefore, our data can contribute to the understanding of the onset of early (childhood and juvenile/pre-pubertal phases) anxiety owing to exposure to a traumatic event during the gestation period.
Assuntos
Ansiedade , Comportamento Animal/fisiologia , Corticosterona/metabolismo , Comportamento Materno/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Receptores de Glucocorticoides/metabolismo , Transtornos de Estresse Pós-Traumáticos/complicações , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos WistarRESUMO
ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.
Assuntos
Animais , Ratos , Hipotálamo , Fígado/metabolismo , Nutrientes , Ritmo Circadiano , Metabolismo dos LipídeosRESUMO
Aging affects the body composition and balance of energy metabolism. Here, we collected in a single work several physiological parameters to show how aging and sex differences can influence energy homeostasis. Body mass index (BMI), Lee index, glucose tolerance, glycemia, and lipidogram in fasting were measured in male and female Wistar rats at the ages of 2, 6, 9, 12, and 18 months. We also measured the lipid profile, free fatty acids, glycerol, glycemia, leptin, adiponectin, insulin, corticosterone (CORT), prolactin (PRL), thyroid stimulated hormone, and triiodothyronine (T3) in 3- and 18-month-old rats of both sexes, fed ad libitum. Animals were classified as obese beginning at 2 months in males and 6 months in females. Aged male rats showed hyperglycemia and glucose intolerance compared to young males and old females. In the ad libitum condition, the 18-month males presented higher serum levels of triglycerides, total cholesterol, and free fatty acids than females. The 18-month-old females had higher PRL and CORT concentration than males, but insulin and T3 were higher in 18-month-old males than females. Our work demonstrated that aging processes on energy metabolism in rats is sex specific, with a better lipid profile and glucose tolerance in aged females.
Assuntos
Envelhecimento/fisiologia , Composição Corporal , Metabolismo Energético , Hormônios Peptídicos/metabolismo , Caracteres Sexuais , Envelhecimento/metabolismo , Animais , Feminino , Glucose/metabolismo , Homeostase , Metabolismo dos Lipídeos , Masculino , Ratos , Ratos WistarRESUMO
Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.
Assuntos
Fatores Etários , Comportamento Animal/fisiologia , Desidratação/fisiopatologia , Fatores Sexuais , Privação de Água/fisiologia , Animais , Arginina Vasopressina/metabolismo , Ingestão de Líquidos/efeitos dos fármacos , Feminino , Masculino , Ratos Wistar , Cloreto de Sódio/farmacologia , Órgão Subfornical/metabolismoRESUMO
BACKGROUND: Changes in the nutritional supply during the perinatal period can lead to metabolic disturbances and obesity in adulthood. OBJECTIVE: The divergent litter size model was used to investigate the hypothalamic sensitivity to leptin and ghrelin as well as the mechanisms involved in the disruption of food intake and energy expenditure. METHODS: On postnatal day 3 (P3), male Wistar rats were divided into 3 groups: small litter (SL - 3 pups), normal litter (NL - 10 pups), and large litter (LL - 16 pups). Animals at P60 were intraperitoneally treated with leptin (500 µg/Kg), ghrelin (40 µg/Kg), or vehicle (0.9% NaCl) at 5 pm and the following parameters were assessed: food intake and body weight; immunostaining of p-STAT-3 in the hypothalamus; Western Blotting analysis of p-AMPKα and UCP2 in the mediobasal hypothalamus (MBH), and UCP1 in the interscapular brown adipose tissue (BAT); or heat production, VO2, VCO2, and locomotor activity. RESULTS: SL rats had earlier leptin and ghrelin surges, while LL rats had no variations. At P60, after leptin treatment, LL rats showed hypophagia and increased p-STAT-3 expression in the arcuate nucleus, but SL rats had no response. After ghrelin treatment, LL rats did not have the orexigenic response or AMPKα phosphorylation in the MBH, while SL animals, unexpectedly, decreased body weight gain, without changes in food intake, and increased metabolic parameters and UCP1 expression in the BAT. CONCLUSIONS: Changes in the nutritional supply at early stages of life modify leptin and ghrelin responsiveness in adulthood, programming metabolic and central mechanisms, which contribute to overweight and obesity in adulthood.
Assuntos
Grelina/metabolismo , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Desnutrição/metabolismo , Envelhecimento , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal , Ingestão de Alimentos , Metabolismo Energético/fisiologia , Feminino , Tamanho da Ninhada de Vivíparos , Masculino , Obesidade/etiologia , Gravidez , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismoRESUMO
Adrenalectomy (ADX) induces hypophagia and glucocorticoids counter-regulate the peripheral metabolic effects of insulin. This study evaluated the effects of ADX on ICV (lateral ventricle) injection of insulin-induced changes on food intake, mRNA expression of hypothalamic neuropeptides (insulin receptor (InsR), proopiomelanocortin, cocaine and amphetamine-regulated transcript (Cart), agouti-related protein, neuropeptide Y (Npy) in the arcuate nucleus of the hypothalamus (ARC), corticotrophin-releasing factor in the paraventricular nucleus of the hypothalamus) and hypothalamic protein content of insulin signaling-related molecules (insulin receptor substrate (IRS) 1, protein kinase B (AKT), extracellular-signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), protein tyrosine phosphatase-1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP)) Compared with sham animals, ADX increased the hypothalamic content of pJNK/JNK, PTP1B and TCPTP, as well as decreased mRNA expression of InsR, and corticosterone (B) treatment reversed these effects. Insulin central injection enhanced hypothalamic content of pAKT/AKT and Cart mRNA expression, decreased Npy mRNA expression and food intake only in sham rats, without effects in ADX and ADX + B rats. Insulin did not alter the hypothalamic phosphorylation of IRS1 and ERK1/2 in the three experimental groups. These data demonstrate that ADX reduces the expression of InsR and increases insulin counter-regulators in the hypothalamus, as well as ADX abolishes hypophagia, activation of hypothalamic AKT pathway and changes in Cart and Npy mRNA expression in the ARC induced by insulin. Thus, the higher levels of insulin counter-regulatory proteins and lower expression of InsR in the hypothalamus are likely to underlie impaired insulin-induced hypophagia and responses in the hypothalamus after ADX.
Assuntos
Adrenalectomia/métodos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Insulina/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Corticosterona/farmacologia , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipotálamo/metabolismo , Injeções Intraventriculares , Insulina/administração & dosagem , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Ratos Wistar , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMO
Vasopressin (AVP) and oxytocin (OT) are essential for the control of extracellular fluid osmolality and volume. Secretion of these hormones is modulated by several mechanisms, including NMDA and AMPA L-glutamate receptors in magnocellular cells of paraventricular (PVN) and supraoptic (SON) hypothalamic nuclei. Thus, to better understand the participation of L-glutamate on the neuroendocrine control of AVP and OT, this work evaluated the effects of intracerebroventricular (icv) NMDA and AMPA receptor antagonists on plasma AVP and OT levels induced by extracellular volume expansion (EVE). Cannulated rats received icv NMDA (AP5) and AMPA (NBQX) antagonists in 10 and 30nmol/5µl/rat doses and were subjected to either isotonic (0.15 M NaCl, 2ml/100g) or hypertonic (0.30 M NaCl, 2ml/100g) EVE. Blood samples were collected for plasma AVP and OT determination. Isotonic EVE did not change plasma AVP and OT levels, but hypertonic EVE increased both AVP and OT plasma levels. AP5 reduced plasma AVP, but it did not change the OT level induced by hypertonic EVE. On the other hand, NBQX reduced plasma OT, but did not alter the AVP plasma level. Our data shows that L-glutamate controls the secretion of neurohypophyseal hormones through the NMDA receptor for AVP release, and through the AMPA receptor for OT release, both in response to hypertonic EVE. This article is protected by copyright. All rights reserved.
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It is known that circulating angiotensin II (ANG-II) acts on the circumventricular organs (CVOs), which partially lack a normal blood-brain barrier, to stimulate pressor responses, vasopressin (AVP), and oxytocin (OT) secretion, as well as sodium and water intake. Although ANG-II type 1 receptors (AT1R) are expressed in neurons and astrocytes, the involvement of CVOs glial cells in the neuroendocrine, cardiovascular and behavioral responses induced by central ANG II remains to be further elucidated. To address this question, we performed a set of experiments combining in vitro studies in primary hypothalamic astrocyte cells (HACc) and in vivo intracerebroventricular (icv) microinjections into the lateral ventricle of awake rats. Our results showed that ANG-II decreased glutamate uptake in HACc. In addition, in vivo studies showed that fluorocitrate (FCt), a reversible glial inhibitor, increased OT secretion and mean arterial pressure (MAP) and decreased breathing at rest. Furthermore, previous FCt decreased AVP secretion and sodium intake induced by central ANG-II. Together, our findings support that CVOs glial cells are important in mediating neuroendocrine and cardiorespiratory functions, as well as central ANG-II-induced AVP release and salt-intake behavior in awake rats. In the light of our in vitro studies, we propose that these mechanisms are, at least in part, by ANG-II-induced astrocyte mediate reduction in glutamate extracellular clearance.
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Neonatal nutritional changes induce long-lasting effects on energy homeostasis. Adiponectin influences food intake and body weight. The aim of this study was to investigate the effects of neonatal nutritional programming on the central stimulation of adiponectin. Male Wistar rats were divided on postnatal (PN) day 3 in litters of 3 (small litter, SL), 10 (normal litter, NL), or 16 pups/dam (large litter, LL). We assessed body weight gain for 60 days, adiponectin concentration, and white adipose tissue weight. We examined the response of SL, NL, and LL rats on body weight gain, food intake, oxygen consumption (VÌo2), respiratory exchange ratio (RER), calorimetry, locomotor activity, phosphorylated-AMP-activated protein kinase (AMPK) expression in the hypothalamus, and uncoupling protein (UCP)-1 in the brown adipose tissue after central stimulus with adiponectin. After weaning, SL rats maintained higher body weight gain despite similar food intake compared with NL rats. LL rats showed lower body weight at weaning, with a catch up afterward and higher food intake. Both LL and SL groups had decreased plasma concentrations of adiponectin at PN60. SL rats had increased white adipose tissue. Central injection of adiponectin decreased body weight and food intake and increased VÌo2, RER, calorimetry, p-AMPK and UCP- 1 expression in NL rats, but it had no effect on SL and LL rats, compared with the respective vehicle groups. In conclusion, neonatal under- and overfeeding induced an increase in body weight gain in juvenile and early adult life. Unresponsiveness to central effects of adiponectin contributes to the imbalance of the energy homeostasis in adult life induced by neonatal nutritional programming.
Assuntos
Adiponectina/metabolismo , Animais Recém-Nascidos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Fenômenos Fisiológicos da Nutrição/fisiologia , Adiponectina/genética , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Animais , Ingestão de Alimentos/fisiologia , Metabolismo Energético/genética , Feminino , Homeostase/genética , Masculino , Desnutrição/fisiopatologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Atividade Motora , Hipernutrição/fisiopatologia , Consumo de Oxigênio/fisiologia , Gravidez , Ratos , Ratos Wistar , Aumento de PesoRESUMO
Overtraining (OT) may be defined as an imbalance between excessive training and adequate recovery period. Recently, a downhill running-based overtraining (OTR/down) protocol induced the nonfunctional overreaching state, which is defined as a performance decrement that may be associated with psychological and hormonal disruptions and promoted intramuscular and systemic inflammation. To discriminate the eccentric contraction effects on interleukin 1beta (IL-1ß), IL-6, IL-10, IL-15, and SOCS-3, we compared the release of these cytokines in OTR/down with other two OT protocols with the same external load (i.e., the product between training intensity and volume), but performed in uphill (OTR/up) and without inclination (OTR). Also, we evaluated the effects of these OT models on the muscle morphology and fiber type composition, serum levels of fatigue markers and corticosterone, as well as androgen receptor (AR) and glucocorticoid receptor (GR) expressions. For extensor digitorum longus (EDL), OTR/down and OTR groups increased the cytokines and exhibited micro-injuries with polymorphonuclear infiltration. While OTR/down group increased the cytokines in soleus muscle, OTR/up group only increased IL-6. All OT groups presented micro-injuries with polymorphonuclear infiltration. In serum, while OTR/down and OTR/up protocols increased IL-1ß, IL-6, and tumor necrosis factor alpha, OTR group increased IL-1ß, IL-6, IL-15, and corticosterone. The type II fibers in EDL and soleus, total and phosphorylated AR levels in soleus, and total GR levels in EDL and soleus were differentially modulated by the OT protocols. In summary, the proinflammatory cytokines were more sensitive for OTR/down than for OTR/up and OTR. Also, the specific treadmill inclination of each OT model influenced most of the other evaluated parameters.
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Acute administration of lipopolysaccharide (LPS) from Gram-negative bacteria induces hypophagia. However, the repeated administration of LPS leads to desensitization of hypophagia, which is associated with increased hypothalamic p-AMPK expression. Because ghrelin and endocannabinoids modulate AMPK activity in the hypothalamus, we hypothesized that these neuromodulators play a role in the reversal of tolerance to hypophagia in rats under long-term exposure to LPS. Male Wistar rats were treated with single (1 LPS, 100µg/kg body weight, ip) or repeated injections of LPS over 6days (6 LPS). Food intake was reduced in the 1 LPS, but not in the 6 LPS group. 6 LPS rats showed an increased serum concentration of acylated ghrelin and reduced ghrelin receptor mRNA expression in the hypothalamus. Ghrelin injection (40µg/kg body weight, ip) increased food intake, body weight gain, p-AMPK hypothalamic expression, neuropeptide Y (NPY) and Agouti related peptide (AgRP) mRNA expression in control animals (Saline). However, in 6 LPS rats, ghrelin did not alter these parameters. Central administration of a CB1R antagonist (AM251, 200ng/µl in 5µl/rat) induced hypophagia in 6 LPS animals, suggesting that the endocannabinoid system contributes to preserved food intake during LPS tolerance. In the presence of AM251, the ability of ghrelin to phosphorylate AMPK in the hypothalamus of 6 LPS group was restored, but not its orexigenic effect. Our data highlight that the orexigenic effects of ghrelin require CB1R signaling downstream of AMPK activation. Moreover, CB1R-mediated pathways contribute to the absence of hypophagia during repeated exposure to endotoxin.
Assuntos
Adenilato Quinase/metabolismo , Grelina/metabolismo , Hipotálamo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Animais , Endocanabinoides/metabolismo , Hipotálamo/metabolismo , Masculino , Neuropeptídeo Y/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de Grelina/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Excessive sodium (Na+) intake in modern society has been associated with several chronic disorders such as hypertension. Several studies suggest that early life events can program physiological systems and lead to functional changes in adulthood. Therefore, we investigated behavioral and neuroendocrine responses under basal conditions and after 48 h of water deprivation in adult (60-day-old Wistar rats) male, Wistar rats originating from dams were offered only water or 0.15 mol/L NaCl during pregnancy and lactation. Early life salt exposure induced kidney damage, as shown by a higher number of ED-1 positive cells (macrophages/monocytes), increased daily urinary volume and Na+ excretion, blunted basal water intake and plasma oxytocin levels, and increased plasma corticosterone secretion. When challenged with water deprivation, animals exposed to 0.15 mol/L NaCl during early life showed impaired water intake, reduced salt preference ratio, and vasopressin (AVP) secretion. In summary, our data demonstrate that the perinatal exposure to excessive Na+ intake can induce kidney injury in adult offspring and significantly affect the key mechanisms regulating water balance, fluid intake, and AVP release in response to water deprivation. Collectively, these novel results highlight the impact of perinatal programming on the homeostatic mechanisms regulating fluid and electrolyte balance during exposure to an environmental stress (i.e. dehydration) in later life.
Assuntos
Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Rim/efeitos dos fármacos , Ocitocina/sangue , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Cloreto de Sódio/farmacologia , Animais , Ingestão de Líquidos/efeitos dos fármacos , Feminino , Rim/metabolismo , Lactação/fisiologia , Masculino , Gravidez , Ratos , Ratos Wistar , Micção/efeitos dos fármacos , Micção/fisiologia , Privação de Água/fisiologia , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
CONTEXT: Metabolic syndrome (MetS) shares several similarities with hypercortisolism. OBJECTIVES: To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. DESIGN: Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirão Preto Medical School University Hospital. METHODS: Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα) expression were assessed by quantitative polymerase chain reaction. RESULTS: Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 ± 17.3 vs 37.9 ± 2.6, P = .02, and SF: 4.9 ± 1.7 vs 2.2 ± 0.3, P < .0001). After all DEX doses, a lower number of MetS patients suppressed plasma and salivary cortisol compared with controls. The BclI genotypic frequencies (%) differed between patients (CC:56/CG:44) and controls (CC:50/CG:32.5/GG:17.5) (P = .03). The GRß was overexpressed (fold = 100.0; P = .002) and IL4 (fold = -265.0; P < .0001) was underexpressed in MetS. CONCLUSION: MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GRß overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis.
Assuntos
Sistema Hipotálamo-Hipofisário/patologia , Síndrome Metabólica/fisiopatologia , Sistema Hipófise-Suprarrenal/patologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de Glucocorticoides/metabolismo , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biomarcadores/análise , Estudos de Casos e Controles , Citocinas/metabolismo , Dexametasona/uso terapêutico , Feminino , Seguimentos , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Prognóstico , Estudos Prospectivos , Isoformas de Proteínas , Receptores de Glucocorticoides/genéticaRESUMO
In rodents, kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) of the preoptic area are considered to provide a major stimulatory input to the GnRH neuronal network that is responsible for triggering the preovulatory LH surge. Noradrenaline (NA) is one of the main modulators of GnRH release, and NA fibers are found in close apposition to kisspeptin neurons in the RP3V. Our objective was to interrogate the role of NA signaling in the kisspeptin control of GnRH secretion during the estradiol induced LH surge in ovariectomized rats, using prazosin, an α1-adrenergic receptor antagonist. In control rats, the estradiol-induced LH surge at 17 hours was associated with a significant increase in GnRH and kisspeptin content in the median eminence with the increase in kisspeptin preceding that of GnRH and LH. Prazosin, administered 5 and 3 hours prior to the predicted time of the LH surge truncated the LH surge and abolished the rise in GnRH and kisspeptin in the median eminence. In the preoptic area, prazosin blocked the increases in Kiss1 gene expression and kisspeptin content in association with a disruption in the expression of the clock genes, Per1 and Bmal1. Together these findings demonstrate for the first time that NA modulates kisspeptin synthesis in the RP3V through the activation of α1-adrenergic receptors prior to the initiation of the LH surge and indicate a potential role of α1-adrenergic signaling in the circadian-controlled pathway timing of the preovulatory LH surge.
Assuntos
Regulação da Expressão Gênica , Kisspeptinas/agonistas , Hormônio Luteinizante/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Área Pré-Óptica/metabolismo , Regulação para Cima , Fatores de Transcrição ARNTL/agonistas , Fatores de Transcrição ARNTL/antagonistas & inibidores , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Fase Folicular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Kisspeptinas/antagonistas & inibidores , Kisspeptinas/genética , Kisspeptinas/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Ovariectomia/efeitos adversos , Proteínas Circadianas Period/agonistas , Proteínas Circadianas Period/antagonistas & inibidores , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Prazosina/farmacologia , Área Pré-Óptica/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
The aim of the present work was to establish a time-course correlation between vascular and autonomic changes that contribute to the development of hypertension during ethanol ingestion in rats. For this, male Wistar rats were subjected to the intake of increasing ethanol concentrations in their drinking water during four weeks. Ethanol effects were investigated at the end of each week. Mild hypertension was already observed at the first week of treatment, and a progressive blood pressure increase was observed along the evaluation period. Increased pressor response to phenylephrine was observed from first to fourth week. α1-Adrenoceptor protein in the mesenteric bed was enhanced at the first week, whereas ß2-adrenoceptor protein in the aorta was reduced after the second week. In the third week, ethanol intake facilitated the depressor response to sodium nitroprusside, whereas in the fourth week it reduced nitrate content in aorta and increased it plasma. The bradycardic component of the baroreflex was impaired, whereas baroreflex tachycardia was enhanced at the third and fourth weeks. AT1A receptor and C-type natriuretic peptide (CNP) mRNAs in the nucleus tractus solitarius were increased at the fourth week. These findings suggest that increased vascular responsiveness to vasoconstrictor agents is possibly a link factor in the development and maintenance of the progressive hypertension induced by ethanol consumption. Additionally, baroreflex changes are possibly mediated by alterations in angiotensinergic mechanisms and CNP content within the brainstem, which contribute to maintaining the hypertensive state in later phases of ethanol ingestion. Facilitated vascular responsiveness to nitric oxide seems to counteract ethanol-induced hypertension.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Hipertensão/etiologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Peptídeo Natriurético Tipo C/genética , Óxido Nítrico/fisiologia , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
Anorexia is a common clinical manifestation of primary adrenal gland failure. Adrenalectomy (ADX)-induced hypophagia is reversed by oxytocin (OT) receptor antagonist and is associated with increased activation of satiety-related responses in the nucleus of the solitary tract (NTS). This study evaluated OT projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS after ADX and the effect of pretreatment with intracerebroventricular injection of an OT receptor antagonist ([d(CH2)5,Tyr(Me)(2),Orn(8)]-vasotocin; OVT) on the activation of NTS neurons induced by feeding in adrenalectomized rats. Adrenalectomized animals showed higher OT labelling in the NTS than the sham and the ADX with corticosterone replacement (ADX + B) groups. Adrenalectomized animals exhibited co-localization of the anterograde tracer Phaseolus vulgaris leucoagglutinin and OT in axons in the NTS as well as OT fibres apposing NTS neurons activated by refeeding. After vehicle pretreatment, compared with fasting, refeeding increased the numbers of Fos- and Fos + TH-immunoreactive neurons in the NTS in sham, ADX and ADX + B groups, with a higher number of these immunolabelled neurons in adrenalectomized animals. Compared with fasting conditions, refeeding also increased the activation of NTS neurons in OVT-pretreated sham, ADX and ADX + B groups, but there was no difference among the three experimental groups. These data demonstrate that OT is upregulated in projections to the NTS following ADX and that OT receptor antagonist reverses the greater activation of NTS neurons induced by feeding after ADX. The data indicate that OT pathways to the NTS contribute to higher satiety-related responses and, thus, to reduce meal size in primary adrenal insufficiency.