Nuria Matesanz, Edgar Bernardo, Rebeca Acín-Pérez, Elisa Manieri, Sonia Pérez-Sieira, Lourdes Hernández-Cosido, Valle Montalvo-Romeral, Alfonso Mora, Elena Rodríguez, Luis Leiva-Vega, Ana Victoria Lechuga-Vieco, Jesús Ruiz-Cabello, Jorge L. Torres, María Crespo-Ruiz, Francisco Centeno, Clara V. Álvarez, Miguel Marcos, José Antonio Enríquez, Rubén Nogueiras & Guadalupe Sabio.
Increasing the thermogenic capacity of adipose tissue to enhance organismal energy expenditure is considered a promising therapeutic strategy to combat obesity. Here, we report that expression of MKK6, a p38MAPK activator, is elevated in white adipose tissue of obese individuals.
Using knockout animals and shRNA, we show that Mkk6 deletion increases energy expenditure and thermogenic capacity of white adipose tissue, protecting mice against diet-induced obesity and the development of diabetes. Deletion of Mkk6 increases T3-stimulated UCP1 expression in adipocytes, thereby increasing their thermogenic capacity. Mechanistically we demonstrate that, in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK and TAB.
Our results identify MKK6 in adipocytes as a potential therapeutic target to reduce obesity.