2436-P: Loss of the Oncostatin M Receptor Distal C-terminus Uncouples Adipogenic Gene Expression from Lipid Accumulation

Introduction and Objective: Impaired adipocyte differentiation contributes to adipose tissue dysfunction and insulin resistance, yet the receptor signaling domains coordinating these processes are incompletely understood. Oncostatin M signals through the oncostatin M receptor (OSMR)-gp130 heterodimer, but the ligand-independent role of the OSMR C-terminus in adipocyte differentiation is unknown. Our objective was to determine whether OSMR C-terminus deletion alters adipogenesis in vitro. Methods: 3T3-L1 preadipocytes expressing wild type OSMR (WT) or an OSMR C-terminus deletion (ΔCT) were induced to differentiate under standard conditions. Differentiation was assessed at day 7 by quantification of Oil Red O staining. Expression of canonical adipogenic and metabolic genes was measured by quantitative RT-PCR. Global protein abundances were quantified by mass spectrometry. Total protein data from WT and ΔCT cells were log2-transformed, analyzed by principal component analysis and linear modeling with empirical Bayes moderation for differential abundance, and interpreted using gene set enrichment and pathway over-representation analyses. Results: WT cells underwent robust lipid accumulation and induction of canonical adipogenic genes. In contrast, ΔCT cells exhibited a significant reduction in lipid accumulation at day 7 while retaining modest expression of key adipogenic genes, such as Pparg and Cebpa, relative to WT cells. Proteomic profiling revealed broad suppression of adipocyte structural and metabolic proteins in ΔCT cells, indicating impaired progression to a mature adipocyte phenotype despite partial transcriptional activation. Conclusion: Deletion of the distal OSMR C-terminus impairs adipocyte differentiation and lipid accumulation and uncouples adipogenic gene expression from functional maturation. These findings identify the OSMR C-terminus as a critical regulator of adipocyte maturation and suggest that disruption of receptor signaling domains can contribute to adipose tissue dysfunction. Disclosure N. Lewis: None. J. Bailey: None. S. Ghosh: None. P. Javvadi: None. E. Westin: None. R.A. Kesterson: None. C.M. Elks: None. Funding National Institutes of Health/NIDDK (R01DK134469 and P30DK072476)