Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance

Area of Science:

• Immunology
• Metabolic Diseases
• Molecular Biology

Background:

• Obesity-induced inflammation in metabolic tissues like visceral adipose tissue (VAT) and liver contributes to insulin resistance (IR).
• The precise mechanisms driving this inflammation remain incompletely understood.

Purpose of the Study:

• To investigate the role of nucleic acid-targeting pathways in obesity-related metabolic inflammation and insulin resistance.
• To explore the therapeutic potential of inhibiting these pathways.

Main Methods:

• High-fat diet (HFD)-fed mice models were used to study inflammation in VAT and liver.
• Analysis included extracellular trap (ET) formation, nucleic acid levels, autoantibodies, macrophage activation, and plasmacytoid dendritic cell (pDC) expansion.
• Genetic manipulation (TLR7/9 knockout) and pharmacological inhibition (ET formation inhibitors, TLR7/9 antagonist) were employed.

Main Results:

• HFD-fed mice exhibited increased ET release in VAT, impaired ET clearance, and elevated autoantibodies against nuclear antigens.
• Excess nucleic acids exacerbated metabolic parameters by activating VAT macrophages and expanding liver pDCs.
• Mice lacking TLR7 and TLR9 showed reduced metabolic inflammation and improved glucose homeostasis.
• Inhibition of ET formation or TLR7/9 signaling ameliorated metabolic disease in HFD-fed mice.

Conclusions:

• Nucleic acid-targeting pathways, including those involving extracellular traps and Toll-like receptors (TLR)7/9, are key drivers of metabolic inflammation in insulin resistance.
• Targeting these pathways represents a potential therapeutic strategy for managing obesity-related metabolic disorders.