Interleukin-6 from the adipose secretome potentiates differentiation of adipose progenitors through the activation of redox signaling

Under obesogenic conditions, it is thought that a signal arising from the adipose microenvironment triggers differentiation of adipose progenitor cells (APCs); yet the identity and source of this signal remain unknown. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacological agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide ([Formula: see text]) and hydrogen peroxide (H₂O₂) via redox cyclers amplified APC differentiation, while differentiation was blunted with ROS scavengers and antioxidants. Protein was concentrated from conditioned media of adipose tissue explants cultured ex vivo to capture secreted factors. Differentiation was enhanced in APCs cultured in the presence of the adipose protein secretome, an effect that was diminished with scavenging of ROS and amplified when the secretome was collected from mice fed a high-fat diet. Proteomic analysis revealed that the adipose secretome from animals on a high-fat diet was enriched in pathways involved in immune cell responses and contained higher levels of cytokines, including interleukin 6 (IL-6). A multiplex assay confirmed higher IL-6, which was predicted as a central regulator of differential levels of secretome proteins. Exposure of APCs to IL-6 increased adipogenesis, while treatment of APCs with an IL-6 blocking antibody diminished the adipogenic effect of the adipose secretome. Together, these findings substantiate a role for redox signaling in the regulation of adipogenesis and identify IL-6 as a potential secreted factor that may mediate activation of adipogenesis via ROS generation under obesogenic conditions.<b>NEW & NOTEWORTHY</b> This study identified IL-6 as an adipose-secreted factor that is increased in obesity and potentiates differentiation of APCs. Redox signaling is involved in APC differentiation and mediates the proadipogenic effect of IL-6. Thus, IL-6 may be a paracrine regulator of APC differentiation in the setting of obesity.