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PLoS Biol. 2018 Jul 6;16(7):e2004455. doi: 10.1371/journal.pbio.2004455. eCollection 2018 Jul.

p38α blocks brown adipose tissue thermogenesis through p38δ inhibition.

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Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain.
Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Department of Medicine, University of Salamanca, Salamanca, Spain.
Facultad de Ciencias, University of Extremadura, Grupo GIEN (Grupo de Investigación en Enfermedades Neurodegenerativas), Badajoz, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
ICREA, Barcelona, Spain.
CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain.


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. 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 (p38δ Fab-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.

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