Make or break - PEDS1 and AGMO orchestrate ether lipid homeostasis in human adipocytes and are associated with blood lipid profiles.

[BACKGROUND] Obesity and its associated sequelae have become a major global health concern. While ester-linked lipids are well-established regulators of adipocyte function and energy storage. Emerging evidence from cohort studies suggests that ether-linked lipid levels are also altered during the development of acquired obesity. The genes of two extra-peroxisomal enzymes of ether lipid metabolism, alkylglycerol monooxygenase () and plasmanylethanolamine desaturase (), have recently been identified, but their physiological roles in humans remain poorly understood.

[METHODS] We conducted a monocentric, cross-sectional study analyzing subcutaneous adipose tissue from 30 patients undergoing abdominoplasty. To dissect the function of AGMO and PEDS1, we combined in vitro knockdown experiments in adipocyte-derived stem cells with pulse-chase tracing of a labeled ether lipid precursor. Untargeted lipidomics using liquid chromatography–tandem mass spectrometry was applied to in vivo differentiated adipocytes to assess the impact of AGMO activity on phospholipid composition. To explore a systemic relevance for AGMO and PEDS1 in humans, enzyme activity and gene expression data were correlated with blood lipid and metabolic parameters.

[RESULTS] We demonstrate that AGMO and PEDS1 are critical regulators of ether lipid subclass balance during adipocyte differentiation. Both enzymes maintained plasmanyl- and plasmenylphospholipid homeostasis without altering total ether lipid levels, indicating dynamic remodeling rather than a metabolic bottleneck. In vivo, AGMO activity reshaped the molecular phospholipid composition of primary adipocytes. Importantly, expression and activity of AGMO and PEDS1 correlated with circulating cholesterol, triglycerides, and lipoprotein particle levels, linking adipose ether lipid metabolism to systemic lipid regulation.

[CONCLUSION] This is the first human study highlighting AGMO and PEDS1 as key determinants of adipose ether lipid remodeling with systemic metabolic relevance. By connecting adipocyte ether lipid metabolism to circulating lipid profiles, our findings point to AGMO and PEDS1 as promising candidates for further investigation in the context of obesity and metabolic syndrome, and may warrant further exploration as potential contributors to mitigating metabolic dysregulation.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-026-07728-8.