Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

EMBO Rep. 2024 Jun;25(6):2635-2661. doi: 10.1038/s44319-024-00149-y. Epub 2024 May 10.

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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Humans
  • Inflammation / metabolism
  • Interleukins* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity* / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Thermogenesis*
  • p38 Mitogen-Activated Protein Kinases* / metabolism

Substances

  • Interleukins
  • p38 Mitogen-Activated Protein Kinases
  • interleukin-35, mouse
  • TOR Serine-Threonine Kinases
  • interleukin-35, human

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