at the CNIC

Category: Publications (Page 1 of 11)

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation

Rafael Romero-Becerra, Alfonso Mora, Elisa Manieri, Ivana Nikolic, Ayelén Melina Santamans, Valle Montalvo-Romeral, Francisco Miguel Cruz, Elena Rodríguez, Marta León, Luis Leiva-Vega, Laura Sanz, Víctor Bondía, David Filgueiras-Rama, Luis Jesús Jiménez-Borreguero, José Jalife, Barbara Gonzalez-Teran & Guadalupe Sabio.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6.

Cardiac hypertrophy under the microscope.
Cardiac hypertrophy in a heart lacking MKK6 (Image: Bárbara González-Terán).

Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin.

In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

Veronica Pena-Leon, Cintia Folgueira, Silvia Barja-Fernández, Raquel Pérez-Lois, Natália Da Silva Lima, Marion Martin, Violeta Heras, Sara Martinez-Martinez, Paola Valero, Cristina Iglesias, Mannon Duquenne, Omar Al-Massadi, Daniel Beiroa, Yara Souto, Miguel Fidalgo, Rasika Sowmyalakshmi, Diana Guallar, Juan Cunarro, Cecilia Castelao, Ana Senra, Patricia González-Saenz, Rocío Vázquez-Cobela, Rosaura Leis, Guadalupe Sabio, Helge Mueller-Fielitz, Markus Schwaninger, Miguel López, Sulay Tovar, Felipe F Casanueva, Emmanuel Valjent, Carlos Diéguez, Vincent Prevot, Rubén Nogueiras & Luisa M Seoane.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown.

Prolonged breastfeeding increases interscapular temperature (Image: Cintia Folgueira).

Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta.

Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

Targeting ERK3/MK5 complex for treatment of obesity and diabetes

Angel Loza-Valdes, Rabih El-Merahbi, Toufic Kassouf, Agnieszka Demczuk, Saskia Reuter, Jonathan Trujillo Viera, Till Karwen, Minhe Noh, Mona C. Löffler, Rafael Romero-Becerra, Jorge L. Torres, Miguel Marcos, Guadalupe Sabio, Urszula Wojda & Grzegorz Sumar.

Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored.

MK5 mRNA levels in subcutaneous adipose tissue in healthy lean subjects obese subjects.

Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes.

Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.

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