at the CNIC

Month: December 2020

Uncovering the role of p38 family members in adipose tissue physiology

Magdalena Leiva, Nuria Matesanz, Marta Pulgarín-Alfaro, Ivana Nikolić & Guadalupe Sabio.

The complex functions of adipose tissue have been a focus of research interest over the past twenty years. Adipose tissue is not only the main energy storage depot, but also one of the largest endocrine organs in the body and carries out crucial metabolic functions. Moreover, brown and beige adipose depots are major sites of energy expenditure through the activation of adaptive, non-shivering thermogenesis.

p38-mediated adipose tissue secretome
The p38-mediated adipose tissue secretome.

In recent years, numerous signaling molecules and pathways have emerged as critical regulators of adipose tissue, in both homeostasis and obesity-related disease. Among the best characterized are members of the p38 kinase family. The activity of these kinases has emerged as a key contributor to the biology of the white and brown adipose tissues, and their modulation could provide new therapeutic approaches against obesity.

Here, we give an overview of the roles of the distinct p38 family members in adipose tissue, focusing on their actions in adipogenesis, thermogenic activity, and secretory function.

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

María Crespo, Barbara Gonzalez-Teran, Ivana Nikolic, Alfonso Mora, Cintia Folgueira, Elena Rodríguez, Luis Leiva-Vega, Aránzazu Pintor-Chocano, Macarena Fernández-Chacón, Irene Ruiz-Garrido, Beatriz Cicuéndez, Antonia Tomás-Loba, Noelia A-Gonzalez, Ainoa Caballero-Molano, Daniel Beiroa, Lourdes Hernández-Cosido, Jorge L Torres, Norman J Kennedy, Roger J Davis, Rui Benedito, Miguel Marcos, Ruben Nogueiras, Andrés Hidalgo, Nuria Matesanz, Magdalena Leiva & Guadalupe Sabio.

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains unexplored.

3-D image of liver section showing the distribution on infiltrated neutrophils in red (Image: Magdalena Leiva).

Here, we demonstrated that in steady state, neutrophils infiltrated the mouse liver following a circadian pattern and regulated hepatocyte clock-genes by neutrophil elastase (NE) secretion. NE signals through c-Jun NH2-terminal kinase (JNK) inhibiting fibroblast growth factor 21 (FGF21) and activating Bmal1 expression in the hepatocyte. Interestingly, mice with neutropenia, defective neutrophil infiltration or lacking elastase were protected against steatosis correlating with lower JNK activation, reduced Bmal1 and increased FGF21 expression, together with decreased lipogenesis in the liver. Lastly, using a cohort of human samples we found a direct correlation between JNK activation, NE levels and Bmal1 expression in the liver.

This study demonstrates that neutrophils contribute to the maintenance of daily hepatic homeostasis through the regulation of the NE/JNK/Bmal1 axis.

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