Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue

Gencer, Selin; Döring, Yvonne; Jansen, Yvonne; Bayasgalan, Soyolmaa; Schengel, Olga; Müller, Madeleine; Peters, Linsey J. F.; Weber, Christian; van der Vorst, Emiel P. C. (2021). Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue. Biomedicines, 9(4) MDPI 10.3390/biomedicines9040394

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Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe-/- mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.

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