Referencia

Hepatology. 2011 Mar;53(3):821-32.

Autores

Josep M. Orellana-Gavaldà, Laura Herrero, Maria Ida Malandrino, Astrid Pañeda, María Sol Rodríguez-Peña, Harald Petry, Guillermina Asins, Sander Van Deventer, Fausto G. Hegardt, Dolors Serra.

Resumen

Obesity-induced insulin resistance is associated with both ectopic lipid deposition and chronic, low-grade adipose tissue inflammation. Despite their excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This has raised the question of whether burning off the excess fat could improve the obese metabolic phenotype. Here we used humansafe nonimmunoreactive adeno-associated viruses (AAV) to mediate long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid b-oxidation, or its permanently active mutant form CPT1AM, to high-fat diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater extent, CPT1AM-expressing mice showed an enhanced hepatic FAO which resulted in increased production of CO2, adenosine triphosphate, and ketone bodies. Notably, the increase in hepatic FAO not only reduced liver triacylglyceride content, inflammation, and reactive oxygen species levels but also systemically affected a decrease in epididymal adipose tissue weight and inflammation and improved insulin signaling in liver, adipose tissue, and muscle. Obesity-induced weight gain, increase in fasting blood glucose and insulin levels, and augmented expression of gluconeogenic genes were restored to normal only 3 months after AAV treatment. Thus, CPT1A- and, to a greater extent, CPT1AM-expressing mice were protected against obesity- induced weight gain, hepatic steatosis, diabetes, and obesity-induced insulin resistance. In addition, genetically obese db/db mice that expressed CPT1AM showed reduced glucose and insulin levels and liver steatosis. Conclusion: A chronic increase in liver FAO improves the obese metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be a potential molecular therapy for obesity and diabetes.

Descripción

Un mayor sobrepeso predispone a un aumento a la resistencia a la insulina. A pesar del exceso de grasa los individuos obesos presentan niveles bajos de oxidación de ácidos grasos. Por eso en este trabajo nos planteamos que un aumento de la oxidación de ácidos grasos podría ser un buen método para mejorar el fenotipo metabólico del individuo obeso. Para ello, hemos utilizado virus adenoasociados (AAV) para sobreexpresar a largo plazo la carnitina pamitoiltransferasa 1A (CPT1A) en hígado de ratones obesos. La sobreexpresión de CPT1A fue capaz de reducir el peso, la diabetes y la resistencia a la insulina producidos por una dieta grasa. Los resultados presentados muestran como un incremento a largo plazo de la β-oxidación en hígado podría ser la base de futuros tratamientos de la obesidad.

Foto grupo abril

REFERENCIA DEL GRUPO INVESTIGADOR

Nuestro grupo está especializado en los mecanismos moleculares implicados en la patogénesis de la obesidad y la diabetes tipo 2. En particular, estudiamos el papel de los ácidos grasos en el metabolismo, centrándonos en la carnitina palmitoiltransferasa 1 (CPT1), enzima mitocondrial clave para la oxidación de los ácidos grasos.

Nuestras líneas de investigación incluyen el estudio del metabolismo de los ácidos grasos en: 1) la insulino-resistencia asociada a la obesidad y la diabetes tipo 2, 2) el apetito, y 3) desarrollo de nuevos tratamientos potenciales para la obesidad y la diabetes de tipo 2, mediante estudios estructurales de CPT1.

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