Context: Wingless-type MMTV integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the non-canonical Wnt signaling pathway. Secreted frizzled-related protein (SFRP)-5 acts as a decoy receptor that binds and sequesters WNT5A, preventing activation of frizzled receptors and attenuating the non-canonical Wnt signaling. Objective: The aim was to evaluate the involvement of WNT5A and SFRP5 in obesity and obesity-related comorbidities as well as to explore their effect in visceral adipose tissue (VAT) inflammation. Patients and methods: Samples obtained from 90 subjects were used. Circulating and gene expression levels of WNT5A and SFRP5 were analyzed in different metabolic tissues. The effect of tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) on transcript levels of WNT5A and SFRP5 in adipocytes was explored. We also investigated whether WNT5A itself can activate an inflammatory response. Results: Increased circulating levels of WNT5A in obese patients (P<0.05) were decreased (P<0.001) after gastric bypass. In this line, WNT5A mRNA in VAT was increased (P<0.05) in obese patients with gene expression levels of SFRP5 being downregulated (P<0.05). WNT5A mRNA expression was significantly enhanced (P<0.01) by LPS and TNF-α treatment, while no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P<0.05) interleukin (IL)-6 mRNA expression in human adipocyte cultures. Conclusions: Activation of non-canonical Wnt signaling through the upregulation of WNT5A and downregulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.