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La ausencia de S6K1 protege contra la obesidad inducida por la edad y la dieta al tiempo que mejora la sensibilidad a
Sung Hee Um1, Francesca Frigerio, Mitsuhiro Watanabe
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Nature
|August 13, 2004
Resumen
La deficiencia de S6 Kinasa 1 (S6K1) protege contra la obesidad al mejorar la descomposición de las grasas. Sin embargo, S6K1 regula negativamente la señalización de la insulina, particularmente en condiciones de alto contenido de grasa, ofreciendo nuevos objetivos terapéuticos para la diabetes.
Área de la Ciencia:
- Las vías de señalización metabólica.
- La obesidad y la investigación de la diabetes.
- El objetivo mamífero de la vía de la rapamicina (mTOR)
Sus antecedentes:
- La obesidad afecta la acción de la insulina, lo que contribuye a la diabetes.
- La S6 Kinasa 1 (S6K1) integra las señales de nutrientes y insulina.
- La deficiencia de S6K1 en ratones muestra fenotipos metabólicos complejos, incluida la intolerancia a la glucosa y la sensibilidad a la insulina alterada.
Objetivo del estudio:
- Para investigar el papel de S6K1 en la regulación metabólica y la sensibilidad a la insulina.
- Determinar el impacto de la deficiencia de S6K1 en la obesidad y la respuesta a las dietas altas en grasas.
- Para dilucidar los mecanismos moleculares que vinculan S6K1 a la resistencia a la insulina.
Principales métodos:
- Análisis de ratones con deficiencia de S6K1 bajo condiciones de dieta normal y alta en grasas.
- Evaluación de la homeostasis de la glucosa, los niveles de ácidos grasos libres y la beta-oxidación.
- Investigación de la fosforilación del sustrato 1 del receptor de insulina (IRS1) en sitios clave de resistencia a la insulina (S307 y S636/S639).
Principales resultados:
- Los ratones con deficiencia de S6K1 están protegidos contra la obesidad inducida por la dieta debido a una mayor beta-oxidación.
- A pesar de la protección, las dietas altas en grasas conducen a hiperglucemia y desensibilización del receptor de insulina en ratones con deficiencia de S6K1.
- La deficiencia de S6K1 impide la fosforilación de IRS1 en S307 y S636/S639, lo que indica una sensibilidad a la insulina preservada a través de un bucle de retroalimentación negativa interrumpido.
- Los modelos obesos de tipo salvaje y de obesidad genética exhiben una actividad elevada de S6K1 y un aumento de la fosforilación de IRS1.
Conclusiones:
- S6K1 juega un papel crítico en la regulación negativa de la señalización de la insulina en condiciones ricas en nutrientes.
- La interrupción del bucle de retroalimentación negativa S6K1-IRS1 contribuye a la sensibilidad a la insulina.
- Dirigir la actividad de S6K1 puede ofrecer estrategias terapéuticas para la obesidad y la diabetes tipo 2.
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