Our preliminary findings lead us to propose bone marrow adipocyte secretions as new actors of bone loss. Indeed using an in vitro coculture model based on human skeletal stem cells (SSCs), we previously showed that soluble factors secreted by adipocytes induced the conversion of osteoblasts towards an adipocyte-like phenotype.This change in fate was further confirmed by microarray gene expression profiling showing profound transcriptomic changes in osteoblasts following coculture with an enrichment in the adipocyte gene signature. Furthermoredouble immunofluorescence staining demonstrated the co-expression of adipogenic and osteoblast specific markers at the single cell level providing evidence for a transdifferentiation event.The objectives of the present work are to identify adipocyte-secreted factor(s) implicated in the transdifferentiation of osteoblasts into adipocyte-like cells, and the molecular mechanisms underlying their actions. To this aim, we used proteomics techniques to analyze and compare stimulatory and non-stimulatory adipocyte culture supernatants and identified a set of adipocyte-secreted proteins potentially regulators of osteoblast differentiation. In parallel, through transcriptomic analysis of the osteoblastic population, gene expression changes induced by adipocyte secretion products in the osteoblastic cells were identified at two early stages of coculture.We then employed an original integrative bioinformatics approach to correlate the selected adipocyte-secreted proteins to the genes whose expression was detected in the first few hours of coculture. By linking these results with genes whose expression was subsequently modified in cells, we were able to determine the potential signalling pathways leading to osteoblast transdifferentiation, and to deduce the mechanism underlying the effects of secreted factors on osteogenesis and adipogenesis. Our findings provide new insights into the crosstalk between adipocytes and osteoblasts in the bone marrow and demonstrate the powerfulness of our integrative omics strategy to decipher cell-cell communication events.