Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by Mmp12+ macrophages

Area of Science:

• Metabolic disease research
• Gut microbiome studies
• Immunometabolism

Background:

• High-fat/high-sugar (HFHS) diets are linked to type 2 diabetes, with gut microbiota implicated.
• The specific organs and molecular pathways affected by diet-induced microbiota changes remain unclear.

Purpose of the Study:

• To identify organs and pathways impacted by microbiota in HFHS diet-induced type 2 diabetes.
• To elucidate the role of specific immune cells and molecules in this process.

Main Methods:

• Multiorgan network analysis
• Transkingdom analysis
• Macrophage characterization (Mmp12+)
• Genetic Mmp12 deficiency and pharmacological inhibition
• In vitro adipocyte studies
• Analysis of TLR2-ligands and bacterial species (Oscillibacter valericigenes)

Main Results:

• Microbiota-dependent impairment of oxidative phosphorylation (OXPHOS)/mitochondria in white adipose tissue (WAT) is key to glucose metabolism disruption.
• Mmp12+ macrophages mediate the link between microbiota-driven inflammation and OXPHOS damage in WAT.
• Mmp12+ macrophage signature correlates with insulin resistance in obese patients.
• MMP12 deficiency/inhibition improves glucose metabolism in conventional mice, while MMP12 induces insulin resistance in adipocytes.
• HFHS-expanded Oscillibacter valericigenes TLR2-ligands induce Mmp12 in WAT macrophages via a MYD88-ATF3 pathway.

Conclusions:

• HFHS diet-induced Mmp12+ macrophages and MMP12 act as a microbiota-dependent bridge between inflammation and mitochondrial dysfunction in WAT.
• This pathway contributes significantly to the development of insulin resistance and type 2 diabetes.