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p38α blocks brown adipose tissue thermogenesis through p38δ inhibition.
PLoS Biol. 2018 07; 16(7):e2004455.PB

Abstract

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.

Authors+Show Affiliations

Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.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.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, 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.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain. CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), 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.Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Department of Medicine, University of Salamanca, Salamanca, Spain.Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29979672

Citation

Matesanz, Nuria, et al. "P38α Blocks Brown Adipose Tissue Thermogenesis Through P38δ Inhibition." PLoS Biology, vol. 16, no. 7, 2018, pp. e2004455.
Matesanz N, Nikolic I, Leiva M, et al. P38α blocks brown adipose tissue thermogenesis through p38δ inhibition. PLoS Biol. 2018;16(7):e2004455.
Matesanz, N., Nikolic, I., Leiva, M., Pulgarín-Alfaro, M., Santamans, A. M., Bernardo, E., Mora, A., Herrera-Melle, L., Rodríguez, E., Beiroa, D., Caballero, A., Martín-García, E., Acín-Pérez, R., Hernández-Cosido, L., Leiva-Vega, L., Torres, J. L., Centeno, F., Nebreda, A. R., Enríquez, J. A., ... Sabio, G. (2018). P38α blocks brown adipose tissue thermogenesis through p38δ inhibition. PLoS Biology, 16(7), e2004455. https://doi.org/10.1371/journal.pbio.2004455
Matesanz N, et al. P38α Blocks Brown Adipose Tissue Thermogenesis Through P38δ Inhibition. PLoS Biol. 2018;16(7):e2004455. PubMed PMID: 29979672.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p38α blocks brown adipose tissue thermogenesis through p38δ inhibition. AU - Matesanz,Nuria, AU - Nikolic,Ivana, AU - Leiva,Magdalena, AU - Pulgarín-Alfaro,Marta, AU - Santamans,Ayelén M, AU - Bernardo,Edgar, AU - Mora,Alfonso, AU - Herrera-Melle,Leticia, AU - Rodríguez,Elena, AU - Beiroa,Daniel, AU - Caballero,Ainoa, AU - Martín-García,Elena, AU - Acín-Pérez,Rebeca, AU - Hernández-Cosido,Lourdes, AU - Leiva-Vega,Luis, AU - Torres,Jorge L, AU - Centeno,Francisco, AU - Nebreda,Angel R, AU - Enríquez,José Antonio, AU - Nogueiras,Rubén, AU - Marcos,Miguel, AU - Sabio,Guadalupe, Y1 - 2018/07/06/ PY - 2017/10/07/received PY - 2018/06/15/accepted PY - 2018/07/18/revised PY - 2018/7/7/pubmed PY - 2019/5/7/medline PY - 2018/7/7/entrez SP - e2004455 EP - e2004455 JF - PLoS biology JO - PLoS Biol. VL - 16 IS - 7 N2 - 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. SN - 1545-7885 UR - https://www.unboundmedicine.com/medline/citation/29979672/p38α_blocks_brown_adipose_tissue_thermogenesis_through_p38δ_inhibition_ L2 - http://dx.plos.org/10.1371/journal.pbio.2004455 DB - PRIME DP - Unbound Medicine ER -