Sabio lab

at the CNIC

Category: Publications (page 2 of 4)

p38α blocks brown adipose tissue thermogenesis through p38δ inhibition

Nuria Matesanz, Ivana Nikolić, Magdalena Leiva, Marta Pulgarín-Alfaro, Ayelén M. Santamans, Edgar Bernardo, Alfonso Mora, Leticia Herrera-Melle, Elena Rodríguez, Daniel Beiroa, Ainoa Caballero, Elena Martín-García, Rebeca Acín-Pérez, Lourdes Hernández-Cosido, Luis Leiva-Vega, Jorge L. Torres, Francisco Centeno, Angel R. Nebreda, José Antonio Enríquez, Rubén Nogueiras, Miguel Marcos & Guadalupe Sabio.

Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue.

Regulation of browning and BAT activation by p38 pathway (Image: Ivana Nikolić).

Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ.

Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δFab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI).

Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.


Anti-CD69 therapy induces rapid mobilization and high proliferation of HSPCs through S1P and mTOR

Laura Notario, Elisenda Alari-Pahissa, Almudena Albentosa, Magdalena Leiva, Guadalupe Sabio & Pilar Lauzurica.

CD69 regulates lymphocyte egress from the thymus and lymph nodes through cis-interactions and the downregulation of surface sphingosine-1-phosphate (S1P) receptor-1 (S1P1). However, its role in the regulation of cell egress from bone marrow has not been extensively studied.

mTOR pathway activation

mTOR pathway activation in bone marrow (Image: Magdalena Leiva).

We show here that CD69 targeting induced rapid and massive mobilization of BM leukocytes, which was inhibited by desensitization to S1P with FTY720. This mobilization was reproduced with anti-human CD69 mAb treatment of mice expressing human CD69. In this strain, the mobilization occurred to the same extent as that induced by AMD3100. The anti-human CD69 treatment highly increased LSK and CLP cell proliferation and numbers, both in the periphery and in the BM, and also augmented S1P1 and CXCR4 expression. Additionally, increased mTOR, p70S6K, S6, and 4E-BP1 phosphorylation was detected after in vivo anti-CD69 treatment in the bone marrow. Importantly, mTOR inhibition with rapamycin inhibited anti-huCD69-induced mobilization of hematopoietic stem and progenitor cells (HSPCs).

Together, our results indicated that CD69 targeting induces not only mobilization but also high proliferation of HSPCs, and thus is crucial for precursor cell replenishment over time. These results suggest that anti-CD69 mAbs are putative novel candidates for mobilization strategies.


Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis

Begoña Porteiro, Marcos F. Fondevila, Xabier Buque, Maria J. Gonzalez-Rellan, Uxia Fernandez, Alfonso Mora, Daniel Beiroa, Ana, Senra, Rosalia Gallego, Johan Fernø, Miguel López, Guadalupe Sabio, Carlos Dieguez, Patricia Aspichueta & Rubén Nogueiras.

Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Hematoxylin&eosin and oil red O staining of liver sections.

We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2).

The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability.

These data provide new evidence for targeting p53 as a strategy to treat liver disease


« Older posts Newer posts »

© 2019 Sabio lab

Theme by Anders NorénUp ↑