Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis
- PMID: 38730210
- PMCID: PMC11169359
- DOI: 10.1038/s44319-024-00149-y
Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis
Abstract
Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established. Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients. Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.
Keywords: Adipose Tissue; Obesity; T Regulatory Cells; Thermogenesis; p38 Stress Kinases.
© 2024. The Author(s).
Conflict of interest statement
The authors declare no competing interests.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig1_HTML.gif)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig2_HTML.gif)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig3_HTML.gif)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig4_HTML.gif)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig5_HTML.gif)
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig6_HTML.gif)
![Figure 7](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig7_HTML.gif)
![Figure 8](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig8_HTML.gif)
![Figure EV1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig9_ESM.gif)
![Figure EV2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig10_ESM.gif)
![Figure EV3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig11_ESM.gif)
![Figure EV4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig12_ESM.gif)
![Figure EV5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/11169359/bin/44319_2024_149_Fig13_ESM.gif)
Similar articles
-
Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.Hepatology. 2023 Mar 1;77(3):874-887. doi: 10.1002/hep.32581. Epub 2023 Feb 17. Hepatology. 2023. PMID: 35592906 Free PMC article.
-
Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway.J Exp Med. 2021 Jun 7;218(6):e20201203. doi: 10.1084/jem.20201203. J Exp Med. 2021. PMID: 33856409 Free PMC article.
-
GDF5 Promotes White Adipose Tissue Thermogenesis via p38 MAPK Signaling Pathway.DNA Cell Biol. 2019 Nov;38(11):1303-1312. doi: 10.1089/dna.2019.4724. Epub 2019 Sep 25. DNA Cell Biol. 2019. PMID: 31553232
-
-Lapachone Regulates Obesity through Modulating Thermogenesis in Brown Adipose Tissue and Adipocytes: Role of AMPK Signaling Pathway.Am J Chin Med. 2019;47(4):803-822. doi: 10.1142/S0192415X19500423. Epub 2019 May 16. Am J Chin Med. 2019. PMID: 31094212
-
miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice.Cell Rep. 2017 May 9;19(6):1229-1246. doi: 10.1016/j.celrep.2017.04.035. Cell Rep. 2017. PMID: 28494871 Free PMC article.
References
-
- Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol. 2004;24:3057–3067. doi: 10.1128/MCB.24.7.3057-3067.2004. - DOI - PMC - PubMed
-
- Cereijo R, Gavaldà-Navarro A, Cairó M, Quesada-López T, Villarroya J, Morón-Ros S, Sánchez-Infantes D, Peyrou M, Iglesias R, Mampel T, et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab. 2018;28:750–763.e756. doi: 10.1016/j.cmet.2018.07.015. - DOI - PubMed
MeSH terms
Substances
Grants and funding
- 2017-2019/European Foundation for the Study of Diabetes (EFSD)
- Rising Star award/European Foundation for the Study of Diabetes (EFSD)
- EFSD/Lilly European Diabetes Research Programme/European Foundation for the Study of Diabetes (EFSD)
- PCOFUND-2012-600396/EC | FP7 | People | FP7 People: Marie-Curie Actions (FP7 People)
- IJC2018-035390-I/Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (MINECO)
- BES-2017-079711/Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (MINECO)
- SAF2015-74112-JIN/Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (MINECO)
- PRE2020-092784/Ministerio de Ciencia e Innovación (MCIN)
- PID2019-104399RB-I00/Ministerio de Ciencia e Innovación (MCIN)
- PGC2018-097019-B-I00/Ministerio de Ciencia e Innovación (MCIN)
- SAF2016-79126-R/Ministerio de Ciencia e Innovación (MCIN)
- IMPACT-2021. Instituto de Salud Carlos III./Ministerio de Ciencia e Innovación (MCIN)
- PDC2021-121147-I00/Ministerio de Ciencia e Innovación (MCIN)
- RED2022-134397-T/Ministerio de Ciencia e Innovación (MCIN)
- Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033)/Ministerio de Ciencia e Innovación (MCIN)
- FPU17/03847/Ministerio de Universidades (MU)
- INVES20026LEIV/Fundación Científica Asociación Española Contra el Cáncer (AECC)
- AECC PROYE19047SABI/Fundación Científica Asociación Española Contra el Cáncer (AECC)
- EMBO YIP/European Molecular Biology Organization (EMBO)
- YIP/European Molecular Biology Organization (EMBO)
- FP7/2007-2013 (ERC 260464)/EC | European Research Council (ERC)
- (Investigadores-BBVA-2017) IN[17]_BBM_BAS_0066/BBVA | Fundación BBVA (FBBVA)
- IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733/Comunidad de Madrid (Community of Madrid)
- PID2022-138525OB-I00 2023- 26/Ministerio de Ciencia, Innovación y Universidades (MCIU)
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous