Constitutive P2Y₂ receptor activity regulates basal lipolysis in human adipocytes

White adipocytes are key regulators of metabolic homeostasis, which release stored energy as free fatty acids via lipolysis. Adipocytes possess both basal and stimulated lipolytic capacity, but limited information exists regarding the molecular mechanisms that regulate basal lipolysis. Here, we describe a mechanism whereby autocrine purinergic signaling and constitutive P2Y₂ receptor activation suppresses basal lipolysis in primary human in vitro differentiated adipocytes. We found that human adipocytes possess cytoplasmic calcium tone due to ATP secretion and constitutive P2Y₂ receptor activation. Pharmacological antagonism or knockdown of P2Y₂ receptors increases intracellular cAMP levels and enhances basal lipolysis. P2Y₂ receptor antagonism works synergistically with phosphodiesterase inhibitors in elevating basal lipolysis, but is dependent upon adenylate cyclase activity. Mechanistically, we suggest that the increased calcium tone exerts an anti-lipolytic effect by suppression of calcium-sensitive adenylate cyclase isoforms. We also observed that acute enhancement of basal lipolysis following P2Y₂ receptor antagonism alters the profile of secreted adipokines leading to longer term adaptive decreases in basal lipolysis. Our findings reveal that basal lipolysis and adipokine secretion are controlled by autocrine purinergic signaling in human adipocytes.