A shift in PKM2 oligomeric state instructs adipocyte inflammatory potential.

Area of Science:

• Metabolic disease
• Immunology
• Adipocyte biology

Background:

• White adipocyte inflammatory function is not fully understood.
• Obesity is linked to increased systemic and tissue inflammation.

Purpose of the Study:

• To investigate the role of type I interferon (IFN-I) in adipocyte metabolism and inflammation.
• To explore pyruvate kinase isozyme M2 (PKM2) as a therapeutic target for obesity-related inflammation.

Main Methods:

• Examined the impact of IFN-I on adipocyte glycolysis, NAD+ utilization, and PKM2 function.
• Utilized chemical and genetic inhibition of glycolysis, NAD+ salvage pathways, and PKM2 in vitro and in vivo.
• Analyzed gene expression in white adipose tissue from individuals with and without metabolic disease.
• Tested small molecule targeting of PKM2 in obese mice and primary human adipocytes.

Main Results:

• IFN-I signaling promotes adipocyte glycolysis, NAD+ utilization, and PKM2 function, contributing to inflammation.
• Inhibition of glycolysis, NAD+ salvage, or PKM2 reduced IFN-I-induced inflammatory cytokine production.
• Targeting PKM2 in vivo reduced inflammation and metabolic disease severity in obese mice.
• Human adipose tissue from individuals with obesity and metabolic disease showed increased inflammatory gene expression.
• PKM2 inhibition reduced IFN-I-driven inflammation in primary human adipocytes.

Conclusions:

• The IFN-I/PKM2 axis is implicated in adipocyte inflammation and metabolic dysfunction in obesity.
• Targeting PKM2 presents a potential therapeutic strategy for modulating obesity-related inflammation.