Brown adipocytes are defined based on a distinct morphology and genetic signature that includes, amongst others, the expression of the Purinergic 2 Receptor X5 (P2RX5). However, the role of P2RX5 in brown adipocyte and brown adipose tissue function is poorly characterized. In the present study, we conducted a metabolic characterization of P2RX5 knockout male mice; next, we characterized this purinergic pathway in a cell-autonomous context in brown adipocytes. We then tested the role of the P2RX5 receptor agonism in metabolic responses in vivo in conditions of minimal adaptive thermogenesis requirements. Our data show that loss of P2RX5 causes reduced brown adipocyte differentiation in vitro, and browning in vivo. Lastly, we unravel a previously unappreciated role for P2RX5 agonism to exert an anti-obesity effect in the presence of enhanced brown adipose tissue recruitment in male mice housed at thermoneutrality. Altogether, our data support a role for P2RX5 in mediating brown adipocyte differentiation and function that could be further targeted for benefits in the context of adipose tissue pathology and metabolic diseases.
