RESUMEN

The biogenesis of dense-core secretory granules (DCGs), organelles responsible for the storage and secretion of neurotransmitters and neuropeptides in chromaffin cells, is poorly understood. Chromogranin A (CgA), which binds catecholamines for storage in the lumen of chromaffin granules, has been shown to be involved in DCG biogenesis in neuroendocrine PC12 cells. Here, we report that downregulation of CgA expression in vivo by expressing antisense RNA against CgA in transgenic mice led to a significant reduction in DCG formation in adrenal chromaffin cells. The number of DCGs formed in CgA antisense transgenic mice was directly correlated with the amount of CgA present in adrenal medulla. In addition, DCGs showed an increase in size, with enlargement in the volume around the dense core, a phenomenon that occurs to maintain constant "free" catecholamine concentration in the lumen of these granules. The extent of DCG swelling was inversely correlated with the number of DCGs formed, as well as the amount of CgA present in the adrenal glands of CgA antisense transgenic mice. These data indicate an essential role of CgA in regulating chromaffin DCG biogenesis and catecholamine storage in vivo.

Asunto(s)

Médula Suprarrenal/patología , Gránulos Cromafines/metabolismo , Gránulos Cromafines/patología , Cromograninas/genética , Cromograninas/metabolismo , Médula Suprarrenal/metabolismo , Animales , Catecolaminas/metabolismo , Cromogranina A , ADN sin Sentido , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Embarazo

RESUMEN

Obesity is a clinical syndrome caused by genetic and environmental factors and has a relatively high heretability. Seven genes, of whose mutations each can independently result in severe human obesity, have been cloned. Six of them are involved in the appetite controlling by the central nervous system, and one is related to the regulation of adipocyte differentiation. Investigations into the genetic basis of human obesity are important for understanding the mechanism of obesity formation and for design and screening of anti-obesity drugs.

Asunto(s)

Obesidad/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Humanos , Leptina/genética , PPAR gamma/genética , Proopiomelanocortina/genética , Proproteína Convertasa 1/genética , Receptor de Melanocortina Tipo 4/genética , Receptores de Superficie Celular/genética , Receptores de Leptina , Proteínas Represoras/genética