p38α blocks brown adipose tissue thermogenesis through p38δ inhibition

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / enzymology
  • Adipose Tissue, Brown / enzymology*
  • Adipose Tissue, Brown / physiology*
  • Adult
  • Animals
  • Body Mass Index
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / prevention & control
  • Diet
  • Energy Metabolism
  • Enzyme Activation
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 13 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 13 / metabolism
  • Mitogen-Activated Protein Kinase 14 / metabolism*
  • Models, Biological
  • Obesity / enzymology
  • Obesity / prevention & control
  • Thermogenesis*
  • Uncoupling Protein 1 / metabolism

Substances

  • UCP1 protein, human
  • Uncoupling Protein 1
  • Mitogen-Activated Protein Kinase 13
  • Mitogen-Activated Protein Kinase 14

Grant support

EFSD/Lilly Reseach Fellowship. Received by IN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CNIC IPP FP7 Marie Curie Programme (grant number PCOFUND-2012-600396). Received by IN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MINECO -FEDER (grant number SAF2015-74112-JIN). Received by ML. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ramón y Cajal Programme (grant number RYC-2011-07826). Received by RAP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MINECO FPI-FEDER (grant number FPI BES-2011-043428 and FPI-SO BES-2016-077635). Received by EB and AS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. European Union's Seventh Framework Programme (FP7/2007-2013) (grant number ERC 260464). Received by GS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EFSD/Lilly European Diabetes Research Programme (grant number Dr Sabio, 2017). Received by GS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (grant number Investigadores-BBVA-2017 IN[17]_BBM_BAS_0066). Received by GS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MINECO-FEDER (grant number SAF2016-79126-R). Received by GS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Comunidad de Madrid-FEDER (grant number IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733). Received by GS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ISCIII and FEDER (grant number PI16/01548). Received by MM. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Junta de Castilla y León (grant number GRS 1362/A/16, INT/M/17/17, GRS 1356/A/16). Received by MM and JLT. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. MINECO -FEDER (grant number BFU2015-70664-R). Received by RN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Xunta de Galicia (grant number 2015-CP080 and PIE13/00024). Received by RN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. European grants (grant number ERC281408, UE0/MCA1108, UE0/MCA1201). Received by RN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Junta de Extremadura-FEDER (grant number BR15164). Received by FC. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministerio de Economía, Industria y Competitividad (MEIC) and the Pro CNIC Foundation (grant number SEV-2015-0505). The CNIC is supported by the Ministerio de Economía, Industria y Competitividad (MEIC) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.