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

Abstract

Cardiac adipose tissue-derived stem cells (cASCs) have the ability to differentiate into multiple cell lineages giving them a high potential for use in regenerative medicine. Cardiac fat tissue still raises many 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 nucleotide receptor as a negative regulator of cardiac fat formation and cASC adipogenic differentiation. Higher expression of P2Y receptor in cardiac fat tissue was observed compared to other adipose tissues. P2Y-null mice displayed a higher mass of cardiac adipose tissue specifically. We therefore examined the role of P2Y receptor in cASC adipogenic differentiation. An inhibitory effect of uridine 5'-triphosphate (UTP), ligand of P2Y, 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-null adipocytes could be linked with cardioprotection previously observed in the heart of P2Y-null ischemic mice. We realized here left anterior descending artery ligation on simple and double-knockout mice for P2Y and adiponectin. No cardioprotective effect of P2Y loss was observed in the absence of adiponectin secretion. In addition, P2Y 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 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.

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…P2Y 1 receptor deletion or its inhibition by MRS2500 reduced leptin production and secretion in lean mice, but this effect disappeared in mice on high‐fat diet (Laplante, Monassier, Freund, Bousquet, & Gachet, 2010). Inhibition or deletion of P2Y 4 receptors increased adiponectin secretion in cardiac adipocytes and was cardioprotective (Lemaire et al, 2017). In P2Y 2 receptor knockout (KO) mice on high‐fat diet, there was decreased immune cell infiltration and inflammation of adipose tissue, as well as a lower fat and body weight (Merz et al, 2018).…”

P2Y2 Nucleotide Receptor Is a Regulator of the Formation of Cardiac Adipose Tissue and Its Fat-Associated Lymphoid Clusters

“…Notably, our laboratory previously described an opposite, positive effect of P2Y 4 loss on PAT mass and cardiac adipogenesis [32]. The opposite effect of P2Y 2 and P2Y 4 loss on cardiac fat formation was unexpected.…”

“…receptors share comparable pharmacological responses to their common ligands, UTP and ATP, but they have a different time course of expression during ASC adipogenic differentiation [32]. This difference, the diversity in tissues expression and in coupling with downstream G proteins [38], could explain the opposite effect on preadipocyte differentiation.…”

“…Nucleotide receptors are known regulators of the differentiation process of mesenchymal stem cells [30,31]. Recently, P2Y 4 , a UTP and ATP receptor, was reported as a negative regulator of adipogenic differentiation of ASCs from cardiac AT [32]. The P2Y 2 receptor was never considered for its role in AT.…”

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

“…In addition, the P2Y1 receptor can induce leptin production in murine adipose tissue ( 175 ). On the other hand, activation of the P2Y4 receptor inhibits adiponectin expression, and P2Y4 KO mice show increased adiponectin secretion ( 178 ). P2X7 KO mice have increased body weight and adipocyte hyperplasia in fat pads ( 171 ) ( Table 2 ).…”