RESUMEN
Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this, we studied the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona glomerulosa (zG) and the inner zona fasciculata (zF). These layers have separate functions, are continuously renewed in response to physiological demands, and are regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship, and renewal mechanism, however, remain poorly understood. Cell-fate mapping and gene-deletion studies using zG-specific Cre expression demonstrate that differentiated zG cells undergo lineage conversion into zF cells. In addition, zG maintenance is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF-1), and zG-specific Sf-1 deletion prevents lineage conversion. These findings demonstrate that adrenocortical zonation and regeneration result from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues.
Asunto(s)
Linaje de la Célula , Zona Fascicular/citología , Zona Glomerular/citología , Animales , Diferenciación Celular , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Retroalimentación Fisiológica , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Homeostasis , Hormonas/metabolismo , Ratones , Factor Esteroidogénico 1/genética , Factor Esteroidogénico 1/metabolismo , Transcripción Genética , Zona Fascicular/crecimiento & desarrollo , Zona Fascicular/metabolismo , Zona Glomerular/crecimiento & desarrollo , Zona Glomerular/metabolismoAsunto(s)
Adrenoleucodistrofia/diagnóstico , Glucemia/metabolismo , Glucosa/uso terapéutico , Hipoglucemia/complicaciones , Convulsiones/etiología , Adrenoleucodistrofia/sangre , Adrenoleucodistrofia/complicaciones , Anticonvulsivantes/uso terapéutico , Preescolar , Humanos , Hipoglucemia/diagnóstico , Hipoglucemia/tratamiento farmacológico , Hipoglucemia/etiología , Lorazepam/uso terapéutico , Masculino , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPARgamma mutations have features of the metabolic syndrome (severe insulin resistance, dyslipidemia, and hypertension). We created a knock-in mouse model containing a potent dominant negative PPARgamma L466A mutation, shown previously to inhibit wild-type PPARgamma action in vitro. Homozygous PPARgamma L466A knock-in mice die in utero. Heterozygous PPARgamma L466A knock-in (PPARKI) mice exhibit hypoplastic adipocytes, hypoadiponectinemia, increased serum-free fatty acids, and hepatic steatosis. When subjected to high fat diet feeding, PPARKI mice gain significantly less weight than controls. Hyperinsulinemic-euglycemic clamp studies in PPARKI mice revealed insulin resistance and reduced glucose uptake into skeletal muscle. Female PPARKI mice exhibit hypertension independent of diet. The PPARKI mouse provides a novel model for studying the relationship between impaired PPARgamma function and the metabolic syndrome.
