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Tag: mTOR (Page 1 of 3)

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Ivana Nikolić, Irene Ruiz-Garrido, María Crespo, Rafael Romero-Becerra, Luis Leiva-Vega, Alfonso Mora, Marta León, Elena Rodríguez, Magdalena Leiva, Ana Belén Plata-Gómez, Maria Beatriz Alvarez Flores, Jorge L Torres, Lourdes Hernández-Cosido, Juan Antonio López, Jesús Vázquez, Alejo Efeyan, Pilar Martin, Miguel Marcos & Guadalupe Sabio.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established.

Reduction of fat mass of mice lacking MKK3/6 as seen by MRI (Image: Ivana Nikolić).

Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients.

Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

Ana Belén Plata-Gómez, Lucía de Prado-Rivas, Alba Sanz, Nerea Deleyto-Seldas, Fernando García, Celia de la Calle Arregui, Camila Silva, Eduardo Caleiras, Osvaldo Graña-Castro, Elena Piñeiro-Yáñez, Joseph Krebs, Luis Leiva-Vega, Javier Muñoz, Ajay Jain, Guadalupe Sabio & Alejo Efeyan

The metabolic functions of the liver are spatially organized in a phenomenon called zonation, linked to the differential exposure of portal and central hepatocytes to nutrient-rich blood. The mTORC1 signaling pathway controls cellular metabolism in response to nutrients and insulin fluctuations.

Liver zonation (Image: Ana Belén Plata Gómez).

Here we show that simultaneous genetic activation of nutrient and hormone signaling to mTORC1 in hepatocytes results in impaired establishment of postnatal metabolic and zonal identity of hepatocytes. Mutant hepatocytes fail to upregulate postnatally the expression of Frizzled receptors 1 and 8, and show reduced Wnt/β-catenin activation. This defect, alongside diminished paracrine Wnt2 ligand expression by endothelial cells, underlies impaired postnatal maturation. Impaired zonation is recapitulated in a model of constant supply of nutrients by parenteral nutrition to piglets.

Our work shows the role of hepatocyte sensing of fluctuations in nutrients and hormones for triggering a latent metabolic zonation program.

MCJ: A mitochondrial target for cardiac intervention in pulmonary hypertension

Ayelén M. Santamans, Beatriz Cicuéndez, Alfonso Mora , María Villalba-Orero, Sanela Rajlic, María Crespo, Paula Vo, Madison Jerome, Álvaro Macías, Juan Antonio López, Magdalena Leiva, Susana F. Rocha, Marta León, Elena Rodríguez, Luis Leiva, Aránzazu Pintor Chocano, Inés García Lunar, Ana García-Álvarez, Pablo Hernansanz-Agustín, Víctor I. Peinado, Joan Albert Barberá, Borja Ibañez, Jesús Vázquez, Jessica B. Spinelli, Andreas Daiber, Eduardo Oliver & Guadalupe Sabio.

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies.

MCJ stainimg in lungs of patients with chronic obstructive pulmonary disease.

Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure.

These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition

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