Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue.

Loss of brown adipose tissue (BAT) activity observed during ageing, obesity and living at thermoneutrality is associated with lipid accumulation, fibrosis and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances. Mechanistically, we demonstrate that brown adipocytes secrete ATP in response to imbalanced thermogenic activation, which activates P2X4 and P2X7 of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.