RESUMEN
Thyroid hormone regulates food intake. We previously reported that rats with triiodothyronine (T3)-induced thyrotoxicosis display hyperphagia associated with suppressed circulating leptin levels, increased hypothalamic neuropeptide Y (NPY) mRNA and decreased hypothalamic pro-opiomelanocortin (POMC) mRNA. AMP-activated kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular energy is depleted. We hypothesized that T3 causes an increase in hypothalamic AMPK activity, which in turn contributes to the development of T3-induced hyperphagia. Rats that were given s.c. injections of T3 (4.5 nmol/kg) had increased food intake 2 h later without alterations in NPY and POMC mRNA levels, but with increased hypothalamic phosphorylated AMPK (169%) and phosphorylated acetyl-CoA carboxylase (194%). To determine the more chronic effects of T3, rats were given 6 daily s.c. injection of T3 or the vehicle. Food intake was significantly increased. Multiple T3 injections increased hypothalamic phosphorylated AMPK (278%) and phosphorylated acetyl-CoA carboxylase (335%) compared to the controls. Intracerebroventricular administration of compound C, an AMPK inhibitor, blocked the food intake induced by a single or multiple injections of T3. Taken together, these results suggest that enhanced hypothalamic AMPK phosphorylation contributes to T3-induced hyperphagia. Hypothalamic AMPK plays an important role in the regulation of food intake and body weight.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Hipotálamo/efectos de los fármacos , Hipotálamo/enzimología , Triyodotironina/farmacología , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Adiposidad/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Masculino , Neuropéptido Y/genética , Fosforilación , Proopiomelanocortina/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Triyodotironina/administración & dosificaciónAsunto(s)
Hipotálamo/fisiología , Neuropéptido Y/biosíntesis , Hormonas Tiroideas/fisiología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ghrelina , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Insulina/sangre , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leptina/sangre , Melaninas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/metabolismo , Orexinas , Hormonas Peptídicas/metabolismo , Hormonas Hipofisarias/metabolismo , Proopiomelanocortina/metabolismo , Ratas , Hormonas Tiroideas/farmacología , Tirotoxicosis/sangre , Tirotoxicosis/fisiopatología , Triyodotironina/administración & dosificaciónRESUMEN
Growth hormone (GH) synthesis and release from pituitary somatotropes is controlled by the opposing actions of the hypothalamic neuropeptides, GH-releasing hormone (GHRH) in the arcuate nucleus (ARC), and somatostatin in the periventricular nucleus (PeV) and ARC. There is a striking sex difference in the pattern of GH secretion in rats. We have previously demonstrated in male rats that 70% of GHRH neurons in the ARC contain the estrogen receptor alpha (ER alpha) gene, whereas less than 5% of somatostatin neurons in the ARC and PeV expressed the ER alpha or ER beta gene. In addition, it has been reported that the PeV somatostatin neurons of neither sex possess ER immunoreactivity. However, there is no available data about colocalization of ERs and GHRH and/or somatostatin in the ARC of female rats. In this study, we used in situ hybridization in the adult female rat brain to determine whether GHRH neurons and/or somatostatin neurons in the ARC coexpress the ER alpha or ER beta gene. In the ARC, ER alpha mRNA was seen in the ventrolateral region where GHRH mRNA signals were also observed, and in the dorsomedial region where somatostatin mRNA signals were also observed. From studies using adjacent sections through these areas, the distribution of these cells appeared to overlap in part with that of cells containing ER alpha mRNA. On the other hand, few positive cells for ER beta mRNA were observed in the ARC. The double-label in situ hybridization studies showed that in the ARC, 73.4% of GHRH neurons contain ER alpha mRNA, whereas less than 5% of somatostatin neurons express the ER alpha gene. These results indicated that the majority of the GHRH neurons in ARC have ER alpha, but not ER beta, and few somatostatin neurons in ARC have ER alpha or ER beta in either adult female or male rats, suggesting that colocalization with ERs in GHRH and/or somatostatin neurons is not an important determinant of the gender specific pattern of GH secretion.
Asunto(s)
Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Hormona Liberadora de Hormona del Crecimiento/genética , Hipotálamo/fisiología , Neuronas/fisiología , Animales , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Expresión Génica , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Hibridación in Situ , ARN Mensajero/análisis , Ratas , Caracteres Sexuales , Somatostatina/metabolismoRESUMEN
Food intake is regulated by hypothalamic neuropeptides which respond to peripheral signals. Plasma ghrelin and leptin levels reflect peripheral energy balance and regulate hypothalamic neuropeptides such as neuropeptide Y (NPY), pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and orexins. Thyroid hormone stimulates food intake in humans and rodents. However, the mechanisms responsible for this stimulation have not been fully elucidated. To investigate the hyperphagic response to triiodothyronine (T(3))-induced thyrotoxicosis, adult male rats were studied 7 days after daily intraperitoneal injections of T(3) or vehicle. T(3)-treated rats were markedly hyperphagic. During this hyperphagia, plasma leptin levels were markedly decreased. However, the expression of the ghrelin gene in the stomach and the plasma ghrelin concentrations did not differ between the 2 groups. Hypothalamic NPY mRNA levels were significantly increased and associated with a marked decreased in both hypothalamic POMC and CART mRNA levels in the T(3)-treated rats. Hypothalamic MCH and orexin mRNA levels did not differ between the 2 groups. In addition, hyperphagia was partially reversed by intracerebroventricular administration of the NPY Y1 receptor antagonist BIBO3304. Therefore, the decreased plasma leptin levels could contribute to hyperphagia in T(3)-induced thyrotoxicosis. However, plasma ghrelin levels did not contribute to this hyperphagia.
Asunto(s)
Arginina/análogos & derivados , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Leptina/sangre , Hormonas Peptídicas/sangre , Receptores de Neuropéptido Y/metabolismo , Tirotoxicosis/metabolismo , Animales , Arginina/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/fisiología , Mucosa Gástrica/metabolismo , Expresión Génica , Ghrelina , Hiperfagia/inducido químicamente , Masculino , Proteínas del Tejido Nervioso/genética , Neuropéptido Y/genética , Proopiomelanocortina/genética , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/antagonistas & inhibidores , Tirotoxicosis/inducido químicamente , Triyodotironina/sangre , Triyodotironina/farmacologíaRESUMEN
Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor, was originally purified from the rat stomach. We have previously reported that central administration of ghrelin increases food intake and body weight. To investigate the role of ghrelin in the hyperphagic response to uncontrolled diabetes, adult male rats were studied 14 days after administration of streptozotocin (STZ) or vehicle. STZ-treated diabetic rats were markedly hyperphagic. This hyperphagia was accompanied by hyperglycemia, hypoinsulinemia, and reduced plasma GH levels. Treatment of diabetic rats with insulin reversed these changes. Plasma ghrelin concentrations in untreated diabetic rats were significantly higher than in control rats and were normalized by insulin treatment. The ghrelin gene expression in the stomach was also higher in STZ diabetic rats than in control rats, but this difference was not significant. In contrast, plasma leptin was markedly reduced in STZ diabetic rats. This reduction in plasma leptin levels was reversed by insulin treatment. In addition, hypothalamic NPY mRNA levels were increased in STZ-treated diabetic rats and were reversed by insulin treatment. Furthermore, the hyperphagia was partially reversed by the administration of a ghrelin-receptor antagonist. Therefore, we conclude that the elevated plasma ghrelin levels, along with decreased plasma leptin levels, could contribute to the diabetic hyperphagia in part by increasing hypothalamic NPY. This is the first report to show the pathophysiological significance of ghrelin in diabetes.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Hiperfagia/etiología , Hormonas Peptídicas/fisiología , Receptores Acoplados a Proteínas G , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/tratamiento farmacológico , Mucosa Gástrica/metabolismo , Expresión Génica , Ghrelina , Hormona del Crecimiento/sangre , Hiperfagia/tratamiento farmacológico , Hipotálamo/química , Hipotálamo/metabolismo , Insulina/sangre , Insulina/uso terapéutico , Leptina/sangre , Masculino , Neuropéptido Y/genética , Neuropéptido Y/fisiología , Hormonas Peptídicas/sangre , Hormonas Peptídicas/genética , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de GhrelinaRESUMEN
Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.