RESUMEN
Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.
Asunto(s)
Péptidos y Proteínas de Señalización del Ritmo Circadiano/efectos de los fármacos , Ghrelina/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Páncreas/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Estómago/efectos de los fármacos , Factores de Transcripción ARNTL/efectos de los fármacos , Factores de Transcripción ARNTL/genética , Animales , Proteínas CLOCK/efectos de los fármacos , Proteínas CLOCK/genética , Caprilatos/farmacología , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Criptocromos/efectos de los fármacos , Criptocromos/genética , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Regulación de la Expresión Génica , Ghrelina/genética , Ghrelina/metabolismo , Transportador de Glucosa de Tipo 2/efectos de los fármacos , Transportador de Glucosa de Tipo 2/genética , Hipotálamo/metabolismo , Ratones , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Páncreas/metabolismo , Proteínas Circadianas Period/efectos de los fármacos , Proteínas Circadianas Period/genéticaRESUMEN
Ghrelin, a gastrointestinal peptide, stimulates feeding when administered peripherally. Blockade of the vagal afferent pathway abolishes ghrelin-induced feeding, indicating that the vagal afferent pathway may be a route conveying orexigenic ghrelin signals to the brain. Here, we demonstrate that peripheral ghrelin signaling, which travels to the nucleus tractus solitarius (NTS) at least in part via the vagus nerve, increases noradrenaline (NA) in the arcuate nucleus of the hypothalamus, thereby stimulating feeding at least partially through alpha-1 and beta-2 noradrenergic receptors. In addition, bilateral midbrain transections rostral to the NTS, or toxin-induced loss of neurons in the hindbrain that express dopamine beta hydroxylase (an NA synthetic enzyme), abolished ghrelin-induced feeding. These findings provide new evidence that the noradrenergic system is necessary in the central control of feeding behavior by peripherally administered ghrelin.