DATA FASEB SUBMISSION 202302438

Obesity presents a significant global health challenge, as the excessive accumulation of adipose tissue (AT) is associated with various systemic disruptions. The expansion of the adipose microenvironment, enriched with immune cells, triggers a release of inflammatory mediators and growth factors that disturb tissues, including bones. While the contribution of obesity to bone loss is widely acknowledged, the direct impact of obese AT on osteoblast maturation remains uncertain. This study investigates the influence of the secretome from obese and non-obese AT on osteoblast differentiation and activity. For that, SAOS-2 cells were exposed to conditioned media (CM) from cultures of human subcutaneous AT explants obtained from individuals with obesity (OCM) and lean patients (LCM), and their effects on osteoblasts were assessed. In the presence of OCM, mature osteoblasts undergo dedifferentiation, exhibiting increased proliferation accompanied by a morphological shift towards a mesenchymal phenotype, with detrimental effects on osteogenic markers and calcification capacity. Concurrently, OCM promotes the expression of mesenchymal and adipogenic markers, inducing the formation of cytoplasmic lipid droplets in SAOS-2 cells exposed to an adipogenic differentiation medium. Additionally, TGF-β1 emerges as a key player in mediating these effects, as OCM is enriched with this growth factor. Treatment of SAOS-2 cells with hrTGF-β1 reproduces the effects observed with OCM, and the use of a TGF-βR antagonist reverses OCM-induced changes. Our data shed light on the intricate mechanisms by which obese AT can adversely impact bone physiology, and highlights potential therapeutic targets to mitigate the detrimental effects of obesity on bone health.