RESUMEN
BACKGROUND: Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling. METHODS: Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05. RESULTS: Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei. CONCLUSIONS: Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.
Asunto(s)
Regulación del Apetito , Núcleo Arqueado del Hipotálamo/metabolismo , Conducta Alimentaria , Hipotiroidismo/metabolismo , Leptina/metabolismo , Neuropéptido Y/metabolismo , Proopiomelanocortina/metabolismo , Transducción de Señal , Animales , Núcleo Arqueado del Hipotálamo/fisiopatología , Modelos Animales de Enfermedad , Ingestión de Alimentos , Metabolismo Energético , Hipotiroidismo/inducido químicamente , Hipotiroidismo/genética , Hipotiroidismo/fisiopatología , Hipotiroidismo/psicología , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Leptina/genética , Masculino , Metimazol , Neuropéptido Y/genética , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiopatología , Fosforilación , Proopiomelanocortina/genética , Ratas Wistar , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Hormona Liberadora de Tirotropina/genética , Hormona Liberadora de Tirotropina/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Núcleo Hipotalámico Ventromedial/fisiopatología , Pérdida de Peso , Yodotironina Deyodinasa Tipo IIRESUMEN
Neuropeptide Y (NPY) inhibits TRH neurons in fed state, and hypothalamic NPY higher expression during fasting has been proposed to be involved in fasting-induced suppression of the hypothalamus-pituitary-thyroid (HPT) axis. We investigated the role of central Y5 receptors in the control of thyrotropin (TSH) and thyroid hormone (TH) secretion. Fed and fasting rats received twice daily central injections (3rd ventricle) of Y5 receptor antagonist (CGP71683; 15nmol/rat) for 72h. Fasted rats also received a single central injection of CGP71683 (15nmol/rat) at the end of 72h of fasting. In fed rats, Y5 receptor blockade reduced total food intake by 32% and body mass by almost 10% (p<0.01), corroborating the role of this receptor in food intake control. 72h-fasted rats exhibited a 4-fold increase in serum TSH (p<0.001), 1h after a single injection of Y5 antagonist. Also with multiple injections during 72h of fasting, Y5 blockade resulted in activation of thyroid axis, as demonstrated by a 3-times rise in serum T4 (p<0.001), accompanied by unchanged TSH and T3. In fed rats, the chronic central administration of CGP71683 resulted in reduced total serum T4 without changes in free T4 and TSH. Serum leptin and PYY were not altered by the NPY central blockade in both fed and fasted rats, suggesting no role of these hormones in the alterations observed. Therefore, the inhibition of central Y5 neurotransmission resulted in activation of thyroid axis during fasting suggesting that NPY-Y5 receptors contribute to fasting-induced TSH and TH suppression.
Asunto(s)
Ayuno/metabolismo , Sistema Hipófiso-Suprarrenal/patología , Receptores de Neuropéptido Y/metabolismo , Hormonas Tiroideas/metabolismo , Tirotropina/metabolismo , Animales , Ayuno/efectos adversos , Hipotálamo/metabolismo , Hipotálamo/patología , Leptina/sangre , Naftalenos/farmacología , Neuropéptido Y/antagonistas & inhibidores , Neuropéptido Y/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Pirimidinas/farmacología , Ratas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Hormonas Tiroideas/sangre , Tirotropina/sangreRESUMEN
We examined the acute effects of endocannabinoid, anandamide, and of synthetic cannabinoid receptor antagonist, AM251[N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], on TSH, thyroxine (T(4)), and triiodothyronine (T(3)) secretions. Euthyroid male rats showed a 42% decrease in serum TSH, 2 h after a single i.p. injection of 0.02, but not 0.2 mg/kg body weight (BW), anandamide, accompanied by a 39% reduction in serum T(4), without alteration in serum T(3). At 0.5 and 1 h, these serum hormones showed no significant change. Hypothyroid rats showed a 35% reduction in serum TSH (P<0.01), 2 h after anandamide injection, which had no effect on hyperthyroid rats. In both thyroid states, no modification of serum thyroid hormones was observed. Intraperitoneal injection of 0.17 or 1.7 mg/kg BW AM251 in euthyroid rats caused, 1.5 h later, 1.7-fold or 4.3-fold increase in serum TSH respectively, without changing thyroid hormones. Stimulatory effect of 0.17 mg/kg BW AM251 and inhibitory effect of anandamide was abolished in the group injected with AM251 followed by an anandamide injection, 30 min later. Intracerebroventricular injection of 20 ng (but not 200 ng) anandamide induced a decrease in serum TSH at 60 min after injection, which tended to disappear at 120 min. Anterior pituitary explants presented significant reduction in TSH release in the presence of 10(-7) M anandamide in incubation medium, which was blocked by 10(-7) M AM251. In conclusion, anandamide has the ability to acutely inhibit TSH release in eu- and hypothyroid rats, acting at the hypothalamus-pituitary axis. Since, in addition, the cannabinoid receptor antagonist AM251 increased TSH release, we suggest that endocannabinoid system has a role as negative regulator of TSH secretion.
Asunto(s)
Ácidos Araquidónicos/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Endocannabinoides , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tirotropina/metabolismo , Animales , Ácidos Araquidónicos/administración & dosificación , Moduladores de Receptores de Cannabinoides/administración & dosificación , Hipertiroidismo/sangre , Hipertiroidismo/tratamiento farmacológico , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Técnicas In Vitro , Masculino , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Alcamidas Poliinsaturadas/administración & dosificación , Radioinmunoensayo , Ratas , Ratas Wistar , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
We investigated the effects of chronic administration of sertraline (SERT; approximately 20 mg kg(-1) day(-1) in drinking water), a selective serotonin reuptake inhibitor, on water and sodium intake and on plasma levels of oxytocin (OT) and vasopressin (AVP) in basal and stimulated conditions. Basal water intake was reduced in SERT-treated rats. After 24 h of water deprivation, rats treated with SERT for 21 days ingested less water than the control rats (9.7 +/- 0.5 versus 20.0 +/- 0.9 ml, respectively, at 300 min after water presentation, P < 0.0001). Subcutaneous injection of 2 m NaCl or isoproterenol evoked a lower dipsogenic response in rats treated with SERT for 21 days. Fluid and food deprivation also induced a weaker dipsogenic response in SERT-treated rats (1.6 +/- 0.5 versus 10.2 +/- 1.2 ml, at 300 min, P < 0.0001) but had no effect on saline intake. Sodium depletion induced a higher natriorexigenic response in the SERT group (5.6 +/- 1.3 versus 1.2 +/- 0.3 ml, at 300 min, P < 0.0002). Higher urinary density and lower plasma sodium levels were observed after SERT treatment. Sertraline also increased plasma levels of vasopressin and oxytocin (AVP, 2.65 +/- 0.36 versus 1.31 +/- 0.16 pg ml(-1), P < 0.005; OT, 17.16 +/- 1.06 versus 11.3 +/- 1.03 pg ml(-1), P < 0.0009, at the third week post-treatment). These data constitute the first evidence that chronic SERT treatment affects water and sodium intake in rats. These effects seem to be related to the hyponatraemia caused by the higher plasma levels of AVP and OT.
Asunto(s)
Oxitocina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología , Cloruro de Sodio Dietético/farmacología , Sed/efectos de los fármacos , Vasopresinas/sangre , Agonistas Adrenérgicos beta/farmacología , Animales , Apetito/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Privación de Alimentos , Isoproterenol/farmacología , Masculino , Presión Osmótica , Ratas , Ratas Wistar , Cloruro de Sodio Dietético/sangre , Orina , Privación de AguaRESUMEN
We describe the occurrence of bone-like formations in the left ventricular wall of infarcted rats treated or not with bone marrow cells injected systemically or locally into the myocardium. The incidence of ectopic calcification in hearts has been reported in rare cases in children with infarcts without previous coronary artery disease. Recently, ventricular calcification has been correlated with unselected bone marrow cell transplantation into infarcted rat hearts. Echocardiographic analysis of large infarction in rats frequently reveals the presence of echogenic structures in the left ventricular wall, sometimes projecting to the lumen of the chamber. The histological examination of these echogenic structures exhibited bone, cartilage, and marrow-like formations extending from the collagen-rich matrix of the ventricle wall. Microanalytical techniques verified the presence of hydroxyapatite in the mineral phase. Ossification was found in 25 out of 30 hearts evaluated 90 days postinfarct, being observed in 14 out of 17 animals submitted to cell therapy and in 11 out of 13 infarcted rats not submitted to cell therapy. Our study indicates that chondro-osteogenic differentiation can take place in the pathological rat heart independent of animal treatment with marrow cells.
Asunto(s)
Cicatriz/patología , Infarto del Miocardio/patología , Osificación Heterotópica/patología , Animales , Cicatriz/metabolismo , Colágeno/metabolismo , Ecocardiografía/métodos , Electrocardiografía/métodos , Femenino , Masculino , Microscopía Confocal/métodos , Microscopía Electrónica de Rastreo/métodos , Microscopía Electrónica de Transmisión/métodos , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocardio/patología , Miocardio/ultraestructura , Osificación Heterotópica/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) has been reported to improve cardiac performance by increasing the number of bone marrow stem cell in the peripheral circulation. The aim of this study was to investigate the impact of G-CSF administration on cardiac function in a rat model of acute myocardial infarction. METHODS: Recombinant human G-CSF (Filgrastim, 100 microg/kg, sc) twice a day during seven consecutive days (G-CSF group, n=13) or vehicle (control group, n=10) was administrated three hours after left anterior coronary artery ligation. Cardiac performance was evaluated 19-21 days after myocardial infarction by electro- and echocardiography, hemodynamic and treadmill exercise test. RESULTS: Both infarcted groups exhibit impaired cardiac function compared to sham-operated rats. Moreover, all cardiac functional parameters were not statistically different between G-CSF and infarcted group at resting conditions as well as after treadmill exercise stress test. There was no sign of cardiac regeneration and infarct size was not different on histological analysis between groups. CONCLUSIONS: These data clearly shows that G-CSF treatment was unable to prevent cardiac remodeling or to improve cardiovascular function in a rat model of acute myocardial infarction, by permanent LAD ligation, despite bone marrow stem cell mobilization.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/fisiopatología , Sístole/fisiología , Animales , Antígenos CD34/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Recuento de Leucocitos , Masculino , Infarto del Miocardio/patología , Condicionamiento Físico Animal/fisiología , Ratas , Ratas Wistar , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/prevención & control , Remodelación Ventricular/fisiologíaRESUMEN
We describe the occurrence of bone-like formations in the left ventricular wall of infarcted rats treated or not with bone marrow cells injected systemically or locally into the myocardium. The incidence of ectopic calcification in hearts has been reported in rare cases in children with infarcts without previous coronary artery disease. Recently, ventricular calcification has been correlated with unselected bone marrow cell transplantation into infarcted rat hearts. Echocardiographic analysis of large infarction in rats frequently reveals the presence of echogenic structures in the left ventricular wall, sometimes projecting to the lumen of the chamber. The histological examination of these echogenic structures exhibited bone, cartilage, and marrowlike formations extending from the collagen-rich matrix of the ventricle wall. Microanalytical techniques verified the presence of hydroxyapatite in the mineral phase. Ossification was found in 25 out of 30 hearts evaluated 90 days postinfarct, being observed in 14 out of 17 animals submitted to cell therapy and in 11 out of 13 infarcted rats not submitted to cell therapy. Our study indicates that chondro-osteogenic differentiation can take place in the pathological rat heart independent of animal treatment with marrow cells.
RESUMEN
The main purpose of this study was to investigate whether dipsogenic stimuli influences the sodium appetite of rats with ibotenic acid lesion of the dorsal raphe nucleus (IBO-DRN). Compared to control, rats microinjected with phosphate buffer (PB-DRN), the ingestion of 0.3M NaCl was enhanced in IBO-DRN at 21 and 35 days after DRN lesion under a protocol of fluids and food deprivation. Despite of similar dipsogenic response observed both in IBO-DRN and PB-DRN treated with isoproterenol (ISO, 300 microg/kg, sc), the 0.3M NaCl intake was again significantly enhanced in IBO-DRN at 21 and 35 days post-lesion. Finally, treatment with polyethylene glycol (PEG, MW=20,000, 20%, w/v, 16.7 ml/kg, sc) induced higher dipsogenic response in IBO-DRN than PB-DRN at 21 day after lesion. In addition, IBO-DRN also expressed higher sodium appetite than PB-DRN, concomitantly with a drinking response. These results suggest that ibotenic lesion of DRN promote an increase of the brain angiotensinergic response, possibly settled within the subfornical organ, through paradigms which increase circulating ANG II levels. The current paper supports the hypothesis that the ibotenic lesion of DRN suppresses a serotonergic component implicated on the modulation of the sodium appetite and, therefore, furthering homeostatic restoration of extracellular fluid volume.