RESUMEN
Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cronoterapia de Medicamentos , Gluconeogénesis/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hígado/efectos de los fármacos , Nicotina/administración & dosificación , Orexinas/agonistas , Animales , Cruzamientos Genéticos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , Hiperglucemia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Hipotálamo/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Nicotina/uso terapéutico , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/uso terapéutico , Obesidad/complicaciones , Obesidad/etiología , Orexinas/genética , Orexinas/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMEN
The extract of the stem bark of Siberian ginseng, Acanthopanax senticosus Harms (ASH), is believed to play a body-coping role in stress through a brain noradrenergic mechanism. The present study was carried out to investigate the effect of ASH on the neuronal activation patterns of c-Fos expression in the rat brain. With ASH administration, c-Fos accumulated in both the supraoptic nuclei (SON) and paraventricular nuclei (PVN), which regulate stress response. Only the caudal regions in the nucleus of the solitary tract (NTS), a locus innervating both the SON and PVN, were activated. Such a neuro-anatomical pattern associated with ASH suggests the possible involvement of these stress-related brain loci.