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Los criptocromos median la represión rítmica del receptor glucocorticoide
Katja A Lamia1, Stephanie J Papp, Ruth T Yu
1Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. klamia@scripps.edu
Nature
|December 16, 2011
Resumen
Los criptocromos 1 y 2 regulan el reloj interno del cuerpo y las respuestas hormonales. La pérdida de estas proteínas interrumpe el metabolismo de la glucosa y altera los niveles de las hormonas del estrés, revelando su papel en la homeostasis metabólica.
Área de la Ciencia:
- Cronobiología cronobiología.
- Endocrinología Molecular La Endocrinología Molecular
- Regulación del metabolismo.
Sus antecedentes:
- El metabolismo de los mamíferos exhibe fuertes ritmos circadianos, con receptores de hormonas nucleares que muestran ciclos diurnos.
- Los mecanismos precisos que coordinan los receptores de hormonas nucleares y el reloj circadiano siguen siendo en gran medida desconocidos.
Objetivo del estudio:
- Para dilucidar la interacción entre los co-reguladores circadianos criptocromos y el receptor glucocorticoide.
- Comprender cómo los criptocromos influyen en la respuesta transcripcional a los glucocorticoides e impactan en la homeostasis metabólica.
Principales métodos:
- Interacciones ligando-dependientes investigadas entre los criptocromos 1/2 y el receptor glucocorticoide en los fibroblastos embrionarios de ratón.
- Analizó los efectos de la deficiencia de criptocromo en la expresión génica y la señalización de glucocorticoides in vivo utilizando modelos de ratón.
- Se examinó la asociación genómica de los criptocromos con el promotor de la carboxicinasa 1 del fosfenol piruvato.
Principales resultados:
- La deficiencia de criptocromo redujo significativamente la represión génica y aumentó la expresión génica inducida por la dexametasona, lo que indica que los criptocromos se oponen a la activación del receptor glucocorticoide.
- Los ratones que carecían de criptocromos mostraron intolerancia a la glucosa y niveles elevados de corticosterona, lo que sugiere una disminución de la supresión del eje hipotálamo-hipófisis-adrenal y un aumento de la transactivación hepática de glucocorticoides.
- Se encontró que los criptocromos 1/2 se asocian con el promotor de la carboxicinasa 1 del fosfenolpiruvato, y su transcripción inducida por la dexametasona se elevó en hígados con deficiencia de criptocromo.
Conclusiones:
- Los criptocromos 1 y 2 proporcionan un vínculo mecánico entre el reloj circadiano y la actividad del receptor de glucocorticoides.
- Estos hallazgos revelan un nuevo papel para los criptocromos en la regulación de la homeostasis metabólica a través de la modulación de los circuitos hormonales.
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