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<p>Toll-like receptor 2 (TLR2) is an innate immune receptor linked to obesity primarily via NF-κB activation. Using a mouse model of overnutrition and in vitro TLR2 stimulation of human peripheral blood mononuclear cells, we show that lipids, advanced glycation end products, and low-density lipoproteins extend TLR2 signaling beyond NF-κB to promote Type I IFN production and signaling, establishing the relevance of this pathway to human obesity. This response was abolished by pharmacologic inhibition of the receptor for advanced glycation end products, which recognizes glycated proteins and lipids. In vivo dietary reversal, metformin, and tirzepatide each reduced diet-induced inflammation, but differed in their metabolic effects: dietary reversal reduced weight gain and LDL, tirzepatide reduced weight without lowering LDL, and metformin exerted anti-inflammatory effects independent of weight or LDL. These findings identify TLR2-Type I IFN signaling as a feature of diet-induced inflammation and highlight the diverse immunomodulatory effects of weight-management therapies.</p>

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Overweight and obesity induce Toll-like receptor 2-induced Type I IFN signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

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  • Megan Elkins,
  • Amer Al-Musa,
  • Marcos Chiñas,
  • Brian Woods,
  • Aleksandra Bourdine,
  • Lena Ludwig-Radtke,
  • Brenna LaBere,
  • Saddiq Habiballah,
  • Alan A. Nguyen,
  • Toshiro K. Ohsumi,
  • Maria Gutierrez-Arcelus,
  • Amy Fleischman,
  • Verena Taudte,
  • Janet Chou

摘要

Toll-like receptor 2 (TLR2) is an innate immune receptor linked to obesity primarily via NF-κB activation. Using a mouse model of overnutrition and in vitro TLR2 stimulation of human peripheral blood mononuclear cells, we show that lipids, advanced glycation end products, and low-density lipoproteins extend TLR2 signaling beyond NF-κB to promote Type I IFN production and signaling, establishing the relevance of this pathway to human obesity. This response was abolished by pharmacologic inhibition of the receptor for advanced glycation end products, which recognizes glycated proteins and lipids. In vivo dietary reversal, metformin, and tirzepatide each reduced diet-induced inflammation, but differed in their metabolic effects: dietary reversal reduced weight gain and LDL, tirzepatide reduced weight without lowering LDL, and metformin exerted anti-inflammatory effects independent of weight or LDL. These findings identify TLR2-Type I IFN signaling as a feature of diet-induced inflammation and highlight the diverse immunomodulatory effects of weight-management therapies.