Itaconate Promotes Cold Adaptation and Myocardial Protection by Enhancing Brown Adipose Tissue Metabolism

Area of Science:

• Immunometabolism
• Adipose Tissue Biology
• Cardiovascular Physiology

Background:

• Itaconic acid (ITA) is an immunometabolite with known anti-inflammatory and metabolic roles.
• Its cellular origins and function within brown adipose tissue (BAT) are not well understood.
• Investigating ITA's role in BAT is crucial for understanding metabolic and cardiovascular health.

Purpose of the Study:

• To determine the expression patterns of the ITA synthesis gene, Irg1, in BAT across different developmental stages.
• To examine the impact of cold exposure and exogenous ITA on BAT metabolic function.
• To assess the cardioprotective effects of ITA and its dependence on BAT.

Main Methods:

• Single-cell RNA sequencing of mouse BAT stromal vascular fraction (SVF) at neonatal and adult stages.
• Bioinformatic analysis to identify Irg1-expressing cell types.
• Cold exposure, exogenous ITA administration, and transverse aortic constriction (TAC) model to evaluate BAT function and cardiac outcomes.

Main Results:

• Irg1 expression in neonatal BAT was primarily in macrophages; in adults, it was in neutrophils and macrophages.
• Cold exposure reduced Irg1 in neutrophils and decreased BAT ITA content.
• Exogenous ITA boosted BAT thermogenesis (reduced lipid droplets, increased UCP1, elevated body temperature) and improved cardiac function post-TAC.

Conclusions:

• ITA enhances cold adaptation and mitigates cardiac injury by boosting BAT metabolic function.
• The cardioprotective effects of ITA are dependent on the presence of BAT.
• This research offers novel therapeutic strategies for metabolic cardiovascular diseases.