| First Author | Qian S | Year | 2024 |
| Journal | J Biol Chem | Volume | 300 |
| Issue | 2 | Pages | 105589 |
| PubMed ID | 38141758 | Mgi Jnum | J:345657 |
| Mgi Id | MGI:7579990 | Doi | 10.1016/j.jbc.2023.105589 |
| Citation | Qian S, et al. (2023) The P2Y(2) receptor mediates terminal adipocyte differentiation and insulin resistance: Evidence for a dual G-protein coupling mode. J Biol Chem 300(2):105589 |
| abstractText | Several P2Y nucleotide receptors have been shown to be involved in the early stage of adipocyte differentiation in vitro and insulin resistance in obese mice; however, the exact receptor subtype(s) and its underlying molecular mechanism in relevant human cells are unclear. Here, using human primary visceral preadipocytes as a model, we found that during preadipocyte-to-mature adipocyte differentiation, the P2Y(2) nucleotide receptor (P2Y(2)R) was the most upregulated subtype among the eight known P2Y receptors and the only one further dramatically upregulated after inflammatory TNFalpha treatment. Functional studies indicated that the P2Y(2)R induced intracellular Ca(2+), ERK1/2, and JNK signaling but not the p38 pathway. In addition, stimulation of the P2Y(2)R suppressed basal and insulin-induced phosphorylation of AKT, accompanied by decreased GLUT4 membrane translocation and glucose uptake in mature adipocytes, suggesting a role of P2Y(2)R in insulin resistance. Mechanistically, we found that activation of P2Y(2)R did not increase lipolysis but suppressed PIP(3) generation. Interestingly, activation of P2Y(2)R triggered G(i)-protein coupling, and pertussis toxin pretreatment largely inhibited P2Y(2)R-mediated ERK1/2 signaling and cAMP suppression. Further, treatment of the cells with AR-C 118925XX, a selective P2Y(2)R antagonist, significantly inhibited adipogenesis, and P2Y(2)R knockout decreased mouse body weight gain with smaller eWAT mass infiltrated with fewer macrophages as compared to WT mice in response to a Western diet. Thus, we revealed that terminal adipocyte differentiation and inflammation selectively upregulate P2Y(2)R expression and that P2Y(2)R mediates insulin resistance by suppressing the AKT signaling pathway, highlighting P2Y(2)R as a potential new drug target to combat obesity and type-2 diabetes. |
