Mouse P2Y4 Nucleotide Receptor Is a Negative Regulator of Cardiac Adipose-Derived Stem Cell Differentiation and Cardiac Fat Formation

Cardiac adipose tissue-derived stem cells (cASCs) have the ability to differentiate into multiple cell lineages giving thema high potential for use in regenerativemedicine. Cardiac fat tissue still raisesmany unsolved questions related to its formation and features. P2Y nucleotide receptors have already been described as regulators of differentiation of bone-marrow derived stem cells, but remain poorly investigated in cASCs. We defined, in this study, the P2Y(4) nucleotide receptor as a negative regulator of cardiac fat formation and cASC adipogenic differentiation. Higher expression of P2Y4 receptor in cardiac fat tissue was observed compared to other adipose tissues. P2Y(4-) null mice displayed a higher mass of cardiac adipose tissue specifically. We therefore examined the role of P2Y(4) receptor in cASC adipogenic differentiation. An inhibitory effect of uridine 5 '-triphosphate (UTP), ligand of P2Y(4), was observed on the maturation state of differentiated cASCs, and on the expression of adipogenesis-linked genes and adiponectin, a cardioprotective adipokine. Higher adiponectin secretion by P2Y(4)- null adipocytes could be linked with cardioprotection previously observed in the heart of P2Y(4)- null ischemic mice. We realized here left anterior descending artery ligation on simple and double- knockoutmice for P2Y(4) and adiponectin. No cardioprotective effect of P2Y(4) loss was observed in the absence of adiponectin secretion. In addition, P2Y(4) loss was correlated with higher expression of UCP- 1 (uncoupling protein- 1) and CD137, two markers of brown/ beige cardiac adipocytes. Our data highlight the P2Y(4) receptor as an inhibitor of cardiac fat formation and cASC adipogenic differentiation, and as a potential therapeutic target in the regulation of cardioprotective function of cardiac fat.