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Category: Publications (Page 2 of 12)

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

28/07/2022 /

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.

Nat Metab 2022; 4 (7): 901-914

Targeting ERK3/MK5 complex for treatment of obesity and diabetes

08/07/2022 /

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.

Biochem Biophys Res Commun 2022; 612: 119-125.

p38 MAPK priming boosts VSMC proliferation and arteriogenesis by promoting PGC1α-dependent mitochondrial dynamics

08/04/2022 /

Álvaro Sahún-Español, Cristina Clemente, Juan Ignacio Jiménez-Loygorri, Elena Sierra-Filardi, Leticia Herrera-Melle, Aurora Gómez-Durán, Guadalupe Sabio, María Monsalve, Patricia Boya & Alicia G Arroyo.

Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players in this process.

p38 MAPK priming by anisomycin in VSMCs.

We demonstrate that MT4-MMP absence boosted VSMC proliferation in vitro in response to PDGF-BB in a cell-autonomous manner through enhanced p38 MAPK activity. Increased phospho-p38 in basal MT4-MMP-null VSMCs augmented the rate of mitochondrial degradation by promoting mitochondrial morphological changes through the co-activator PGC1α as demonstrated in PGC1α−/− VSMCs. We tested the in vivo implications of this pathway in a novel conditional mouse line for selective MT4-MMP deletion in VSMCs and in mice pre-treated with the p38 MAPK activator anisomycin. Priming of p38 MAPK activity in vivo by the absence of the protease MT4-MMP or by anisomycin treatment led to enhanced arteriogenesis and improved flow recovery after femoral artery occlusion.

These findings may open new therapeutic opportunities for peripheral vascular diseases.

Sci Rep 2022; 12 (1):5938.
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Fundación Princesa de Girona

Asociación Española Contra el Cáncer

Fundación BBVA

European Foundation for the Study of Diabetes

Immunothercan

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