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Introduction: Obesity and its associated comorbidities are characterized by chronic inflammation of visceral adipose tissue. Mechanistically, adipose tissue hypertrophy leads to local hypoxia, adipocyte death and the release of danger-associated molecular patterns (DAMPs). Nucleotides and nucleosides released from dying cells act as such DAMPs, activating purinergic receptors on neighboring cells and modulating immunological processes. Therefore the purinergic receptor repertoir on adipocytes may alter their immunological function during the cause of obesity.

Methods: C57BL6/J mice were fed either a high-fat diet (HFD) or a standard chow diet for 21 weeks. Adipocytes were isolated from both subcutaneous (SAT) and visceral adipose tissue (VAT). Expression of purinergic receptors was analyzed using qPCR and Western blot.

Results: Purinergic receptor profiling revealed distinct expression patterns on adipocytes from VAT compared with SAT in chow-fed mice. Among the Gas-coupled P1 receptors, A1 showed the highest expression, with a two-fold higher expression in SAT compared to VAT. Among the metabotropic P2Y receptors, P2Y2 and P2Y6 were highly expressed, with no depot-specific differences. For ionotropic P2X receptors, P2X4 was the most abundantly expressed and comparable between VAT and SAT in lean mice. In obese mice, P2X4 expression increased two-fold in VAT while decreasing two-fold in SAT. Proteome profiling of adipocytes from VAT and SAT of P2X4+/+ and P2X4-/- mice revealed depot- and receptor-differences in cytokine secretion.

Conclusion: A distinct repertoire of purinergic receptors expressed on adipocytes shapes their immunometabolic function depending on depot and hypertrophic states. Follow-up experiments aim to translate these findings to humans and identify purinergic receptors as potential targets for specific anti-inflammatory interventions in individuals suffering from obesity.