Overnutrition induces TLR2-Type I IFN signaling, with tirzepatide and metformin showing distinct anti-inflammatory and metabolic effects.

Obesity is strongly linked to chronic low-grade inflammation, a key driver of metabolic dysfunction and associated comorbidities. Toll-like receptor 2 (TLR2), an innate immune receptor, is implicated in obesity primarily through NF-κB activation. However, the full scope of TLR2 signaling in the context of overnutrition, particularly its potential to extend beyond NF-κB to other inflammatory pathways, remains underexplored. Understanding these broader TLR2-mediated inflammatory cascades could reveal novel therapeutic targets for diet-induced inflammation.

Researchers utilized a mouse model of overnutrition and in vitro human peripheral blood mononuclear cells (PBMCs) to investigate TLR2 signaling. They stimulated TLR2 with various obesity-associated factors, including lipids, advanced glycation end products (AGEs), and low-density lipoproteins (LDL). In the in vivo model, they assessed the impact of dietary reversal, metformin, and tirzepatide on diet-induced inflammation and metabolic parameters. Pharmacologic inhibition of the receptor for advanced glycation end products (RAGE) was also employed to dissect specific mechanistic pathways.

The study found that lipids, advanced glycation end products, and low-density lipoproteins significantly extended TLR2 signaling beyond NF-κB activation, promoting robust Type I IFN production and signaling. This established the relevance of this pathway to human obesity. Importantly, this Type I IFN response was abolished by pharmacologic inhibition of the RAGE. In the in vivo mouse model, dietary reversal, metformin, and tirzepatide each reduced diet-induced inflammation, but their metabolic effects differed significantly. Dietary reversal reduced weight gain and LDL levels. Tirzepatide reduced weight without lowering LDL. Conversely, metformin exerted its anti-inflammatory effects independently of changes in weight or LDL. These findings highlight TLR2-Type I IFN signaling as a key feature of diet-induced inflammation.

The Type I IFN response was abolished by pharmacologic inhibition of the receptor for advanced glycation end products (RAGE), which recognizes glycated proteins and lipids.