Activation of Noncanonical Wnt Signaling Through WNT5A in Visceral Adipose Tissue of Obese Subjects Is Related to Inflammation

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 8; pp. E1407 - E1417
• Main Authors: Catalán, Victoria, Gómez-Ambrosi, Javier, Rodríguez, Amaia, Pérez-Hernández, Ana I., Gurbindo, Javier, Ramírez, Beatriz, Méndez-Giménez, Leire, Rotellar, Fernando, Valentí, Víctor, Moncada, Rafael, Martí, Pablo, Sola, Iosu, Silva, Camilo, Salvador, Javier, Frühbeck, Gema
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.08.2014; Copyright by The Endocrine Society
• Subjects: Adipocytes; Adipose tissue; Adult; Body fat; Cells, Cultured; Comorbidity; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Down-regulation; Eye Proteins - physiology; Female; Frizzled protein; Frizzled-related protein; Gastric Bypass; Gelatinase A; Gelatinase B; Gene expression; Humans; Inflammation; Inflammation - complications; Inflammation - genetics; Inflammation - metabolism; Intra-Abdominal Fat - metabolism; Intra-Abdominal Fat - pathology; Lipopolysaccharides; Male; Membrane Proteins - physiology; Obesity; Obesity, Morbid - complications; Obesity, Morbid - genetics; Obesity, Morbid - metabolism; Obesity, Morbid - surgery; Proto-Oncogene Proteins - blood; Proto-Oncogene Proteins - physiology; Signal transduction; Thinness - genetics; Thinness - metabolism; Tumor necrosis factor-α; Up-Regulation - genetics; Weight Loss - physiology; Wnt protein; Wnt Proteins - blood; Wnt Proteins - physiology; Wnt Signaling Pathway - genetics; Wnt-5a Protein
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2014-1191

Context:Wingless-type mouse mammary tumor virus integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the noncanonical 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 noncanonical Wnt signaling.Objective:The aim of the study 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 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 TNF-α and lipopolysaccharide on the 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 < .05) were decreased (P < .001) after gastric bypass. In this line, WNT5A mRNA in visceral adipose tissue was increased (P < .05) in obese patients with gene expression levels of SFRP5 being down-regulated (P < .05). WNT5A mRNA expression was significantly enhanced (P < .01) by lipopolysaccharide and TNF-α treatment, whereas no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P < .05) IL-6, IL1B, MMP2, MMP9, and SSP1 mRNA expression in human adipocyte cultures.Conclusions:Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.