Paracrine signalling in thermogenesis

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Evidence suggests that adipose thermogenesis is regulated by a range of different mechanisms, but the precise details of many of these pathways are unclear. Now, a new study has shown that itaconate (a metabolite derived from macrophages) has a paracrine signalling role in the negative regulation of thermogenesis.

Next, the researchers used a range of techniques to determine how itaconate might be regulating thermogenesis. Levels of itaconate in the extracellular fluid of BAT decreased after cold exposure. Their findings suggested that this decrease was under the control of cold-sensitive cytokines, and that monocyte-derived macrophages were the most likely source of itaconate. “Mechanistically, 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,” explains Mills. “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.”