Category: Publications (Page 18 of 19)

MKK6 controls T3-mediated browning of white adipose tissue

11/10/2017 / Sabio lab

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.

Measure of the thermogenic capacity of brown adipose tissue (Image: Nuria Matesanz)

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.

Nat Commun. 2017; 8 (1): 856.

Elena Rodríguez, Alfonso Mora, Ana Victoria Lechuga-Vieco, María Crespo-Ruiz, Guadalupe Sabio, José Antonio Enríquez, Nuria Matesanz & Luis Leiva-Vega (Photo: CNIC).

Hypothalamic AMPK-ER stress-JNK1 axis mediates the central actions of thyroid hormones on energy balance

05/07/2017 / Sabio lab

Noelia Martínez-Sánchez, Patricia Seoane-Collazo, Cristina Contreras, Luis Varela, Joan Villarroya, Eva Rial-Pensado, Xabier Buqué, Igor Aurrekoetxea, Teresa C. Delgado, Rafael Vázquez-Martínez, Ismael González-García, Juan Roa, Andrew J. Whittle, Beatriz Gomez-Santos, Vidya Velagapudi, Y.C. Loraine Tung, Donald A. Morgan, Peter J. Voshol, Pablo B. Martínez de Morentin, Tania López-González, Laura Liñares-Pose, Francisco Gonzalez, Krishna Chatterjee, Tomás Sobrino, Gema Medina-Gómez, Roger J. Davis, Núria Casals, Matej Oreši?, Anthony P. Coll, Antonio Vidal-Puig, Jens Mittag, Manuel Tena-Sempere, María M. Malagón, Carlos Diéguez, María Luz Martínez-Chantar, Patricia Aspichueta, Kamal Rahmouni, Rubén Nogueiras, Guadalupe Sabio, Francesc Villarroya & Miguel López.

Pathway proposed to modulate lipid metabolism in liver Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT.

The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPK?1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism.

Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.

Cell Metab. 2017; 26(1): 212-229.e12

Hepatic p63 regulates steatosis via IKK?/ER stress

11/05/2017 / Sabio lab

Begoña Porteiro, Marcos F. Fondevila, Teresa C. Delgado, Cristina Iglesias, Monica Imbernon, Paula Iruzubieta, Javier Crespo, Amaia Zabala-Letona, Johan Fernø, Bárbara González-Terán, Nuria Matesanz, Lourdes Hernández-Cosido, Miguel Marcos, Sulay Tovar, Anxo Vidal, Julia Sánchez-Ceinos, Maria M. Malagon, Celia Pombo, Juan Zalvide, Arkaitz Carracedo, Xabier Buque, Carlos Dieguez, Guadalupe Sabio, Miguel López, Patricia Aspichueta, María L. Martínez-Chantar & Ruben Nogueiras.

Pathway proposed to modulate lipid metabolism in liver p53 family members control several metabolic and cellular functions. The p53 ortholog p63 modulates cellular adaptations to stress and has a major role in cell maintenance and proliferation.

Here we show that p63 regulates hepatic lipid metabolism. Mice with liver-specific p53 deletion develop steatosis and show increased levels of p63. Down-regulation of p63 attenuates liver steatosis in p53 knockout mice and in diet-induced obese mice, whereas the activation of p63 induces lipid accumulation. Hepatic overexpression of N-terminal transactivation domain TAp63 induces liver steatosis through IKK? activation and the induction of ER stress, the inhibition of which rescues the liver functions. Expression of TAp63, IKK? and XBP1s is also increased in livers of obese patients with NAFLD. In cultured human hepatocytes, TAp63 inhibition protects against oleic acid-induced lipid accumulation, whereas TAp63 overexpression promotes lipid storage, an effect reversible by IKK? silencing.

Our findings indicate an unexpected role of the p63/IKK?/ER stress pathway in lipid metabolism and liver disease.

Nature Communications 8, doi: 10.1038/ncomms15111