Multiple symmetric lipomatosis (MSL) is a rare adipose tissue disease characterized by progressive, non-encapsulated, symmetrical fat accumulation. Its pathophysiology is still not completely understood. Here, we performed the first intraindividual comparison of secretomes of human adipose-derived stem cells (hASCs) isolated from affected and unaffected regions of n = 15 patients (proteomic discovery cohort n = 5). Affected MSL-hASCs tend to show accelerated metabolic signals and higher cell densities with preserved adipogenic differentiation capacity. Secretome transfer of affected MSL-hASCs significantly increased metabolic activity of wt-hASCs after 24 h in 4/7 samples (all explorative Benjamini-Hochberg corrected p = 0.040). Bottom-up proteomic analysis identified 811 proteins, of which 220 were classified as secreted. Thirteen proteins exhibited nominally significant dysregulation of expression, including CALR (p = 0.0061), LAMC1 (p = 0.0241), S100A7 (p = 0.0281) and HDGF (p = 0.0474), but none remained significant after application of the Benjamini-Hochberg (BH) correction to control the False Discovery Rate (FDR) at 0.05. Transcriptional validation by rt-qPCR revealed a trend toward downregulation of hLAMA4 and hCFB (both p = 0.0625). In conclusion, convergent patterns are consistent with extracellular matrix remodeling and PI3K/AKT-ERK-associated proliferative signaling. This model supports a hypothesis of progenitor-level dysregulation rather than a single clonal driver in MSL, which will require further mechanistic validation in larger cohorts.