Paracrine Signalling in Thermogenesis
A new study has shown that itaconate, a metabolite derived from macrophages, has a paracrine signalling role in the negative regulation of thermogenesis.
This paper discusses the mechanisms underlying adipose thermogenesis and the role of itaconate in regulating thermogenesis. The authors used a range of techniques to determine how itaconate might be regulating thermogenesis. Levels of itaconate in the extracellular fluid of brown adipose tissue (BAT) decreased after cold exposure. The researchers found that this decrease was under the control of cold-sensitive cytokines, and that monocyte-derived macrophages were the most likely source of itaconate. The study suggests that itaconate binds directly to monocarboxylate transporter 1 (MCT1) and competes with succinate for MCT1 engagement, thereby limiting succinate uptake into brown adipocytes and BAT to impair thermogenesis. The cellular thermal shift assay, which examines ligand–protein interactions in a cell system, was critical in demonstrating that both itaconate and succinate can bind to MCT1 in cells and that itaconate binds more potently than succinate.