Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5523-8. Epub 2012 Mar 16


Sebastián D*, Hernández-Alvarez MI*, Segalés J*, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Oresic M, Pich S, Burcelin R, Palacín M, Zorzano A. *El primer autor es compartido entre 3 personas


Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo.


Una característica común en estados de obesidad y diabetes de tipo 2 es la presencia de resistencia a la insulina en tejidos periféricos, asociada a una menor función mitocondrial. En los últimos años la dinámica mitocondrial ha emergido como un aspecto crucial para el buen funcionamiento de la mitocondria. En este sentido, en nuestro grupo se describió que la expresión de Mitofusina 2, una proteína involucrada en la fusión mitocondrial, se encontraba disminuida en individuos obesos y/o diabéticos. Con el objetivo de elucidar si esta proteína tenía un papel importante en la sensibilidad a la insulina, decidimos generar dos modelos animales con pérdida de función de Mfn2 en hígado y en músculo. Los resultados obtenidos sugieren que Mfn2 coordina la correcta función de la mitocondria y del retículo endoplasmático, conduciendo su deficiencia a una alteración de la vía de señal de la insulina y a la aparición de intolerancia a la glucosa y resistencia a la insulina. En conjunto, estos resultados validan a Mfn2 como una posible diana en el tratamiento de la resistencia a la insulina y la diabetes de tipo 2.

imagen mayo


Nuestro grupo tiene como objetivo central determinar los mecanismos moleculares implicados en el desarrollo de resistencia a la insulina y, más concretamente, identificar nuevos genes de susceptibilidad a la obesidad y la diabetes de tipo 2. Este objetivo se estructura en tres niveles:

1. Identificar los genes responsables del desarrollo de resistencia a la insulina asociada a la obesidad o a la diabetes de tipo 2, con especial énfasis en los genes implicados en nuevos mecanismos de regulación mitocondrial, como la dinámica de la mitocondria, en genes que codifican por proteínas implicadas en la regulación de la expresión génica nuclear, o por proteínas implicadas en nuevas vías de señalización intracelular.

2. Análisis de los mecanismos moleculares que intervienen en la regulación del transporte de la glucosa a los músculos y a las células adiposas, y en el desarrollo de la lipotoxicidad.

3. Identificación de nuevos objetivos y desarrollo de nuevos compuestos para el tratamiento del síndrome metabólico.

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