The Purinergic P2Y1 Receptor Supports Leptin Secretion in Adipose Tissue

Abstract

Extracellular nucleotides have been shown to trigger intracellular calcium release and influence leptin secretion in differentiated white and brown adipocytes through activation of various but not clearly identified P2 receptors. In the present study, we wished to assess whether or not the P2Y1 ADP receptor is functional in white adipocytes and whether it could affect the secretion of adipocyte-derived hormones. Stromal cells and mature adipocytes were isolated from epididymal adipose tissue from wild-type and P2Y1 knockout (KO) C57-black/six male mice. The expression of the P2Y1 receptor in adipocytes was confirmed by RT-PCR and intracellular calcium measurements with fura 2-AM. KO of P2Y1 receptors did not affect the cell size and lipid content of mature adipocytes or the differentiation of the stromal cell fraction, but the leptin production of mature adipocytes was decreased under basal and insulin-stimulated conditions. A selective P2Y1 antagonist, MRS2500, reduced leptin release in isolated adipocytes. The plasma and adipose tissue mRNA levels of leptin were also lower in P2Y1 KO mice as compared with wild-type animals. However, in mice fed a high-fat diet, the plasma leptin levels were greatly enhanced and the inhibitory effect of P2Y1 KO was not observed. These results show that the P2Y1 receptor supports leptin production in isolated white adipocytes through a transcriptional mechanism. This function of the receptor may regulate plasma leptin in lean mice but is overcome in obese animals.

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

“…All of the three P2Y receptors that are preferentially activated by ADP (P2Y 1 , P2Y 12 and P2Y 13 ) have been found to be coupled to ecto-F 1 -ATPase activity and display different functions depending on the cell type [32]. For instance, in hepatocytes the apoA-I/ecto-F 1 -ATPase/P2Y 13 axis activates an intracellular RhoA/ROCKI signaling pathway that stimulates HDL uptake and appears to have atheroprotective properties by promoting reverse cholesterol transport [21-24, 30, 44, 45], and in adipocytes HDL-apoA-I, ecto-F 1 -ATPase and P2Y signaling are all involved in lipid metabolism [46-50]. In endothelial cells, apoA-I/ecto-F 1 -ATPase has been previously shown to stimulate HDL transcytosis via activation of P2Y 12 ADP receptors [20].…”

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…Most illustrative are studies on mice. 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).…”

Purinergic signalling and diabetes

“…Although adipocytes express several P2 receptors (P2Y 1,2,4,6,11 ), the leptin effect may be due to P2Y 1 receptors, since specific antagonist reduced leptin release in isolated adipocytes and circulating levels of leptin was lower in P2Y 1 knockout mice [217]. High ATP dosages stimulated inflammatory responses and insulin resistance in rat adipocytes [218].…”