2722-LB: Sex-Specific Regulation of Adipose Progenitor Cell Senescence by Lipocalin 2 via Phosphatidic Acid–Dependent mTOR Signaling Pathway

Introduction and Objective: Sexual dimorphism in metabolic regulation is well recognized, yet mechanisms beyond classic estrogen receptor-mediated signaling remain unclear. We showed that the adipokine Lipocalin 2 (LCN2) exhibited sex- and depot-specific expression, as well as a sex-dependent aging effect in subcutaneous fat. We identified LCN2 as a phosphatidic acid (PA)-binding protein, linking it to PA-mediated regulation of mTOR (mammalian target of rapamycin) signaling and metabolism. This study aims to investigate the sexually dimorphic role of LCN2 in adipose progenitor cell senescence through PA-mediated regulation of signaling pathways. Methods: Stromal-vascular (SV) cells from inguinal fat of wild-type (WT) and Lcn2 knockout (KO) male and female mice were treated with PA and mouse recombinant LCN2 (mrLCN2) to assess senescence and PA-regulated mTOR and LIPIN1 pathways. Results: In both male and female WT SV cells, PA (16:0-18:1) treatment reduced senescence, and PA plus mrLCN2 produced the strongest effect. Lcn2 deficiency reduced senescence in female SV cells, whereas in males, the opposite effect was observed. We next assessed the role of LCN2 in mTOR and LIPIN1 pathways. Female Lcn2 KO SV cells showed significantly reduced mTOR activation but increased Cyclin D1 levels compared to WT controls. PA enhanced p70S6K phosphorylation in both sexes. The addition of mrLCN2 further amplified PA-induced p70S6K phosphorylation in male cells but attenuated it in female cells. Blocking mTOR activation with Rapamycin led to increased senescence in female Lcn2 KO cells. Notably, Lcn2 deficiency disrupted Rapamycin regulation of LIPIN 1 and Cyclin D1 in females. Conclusion: Our findings demonstrated PA plays a protective role against cellular senescence, while PA and LCN2 show significant sex dimorphic effect in mTOR signaling. These findings demonstrate a sexually dimorphic interplay between PA and LCN2 in regulating lipid metabolism and cellular aging. Disclosure X. Jin: None. X. Chen: None. Funding NIA/NIH Grant(R21AG093377)