Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation.
BACKGROUND
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.


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.
Metabolic Research Laboratory (V.C., J.G.-A., A.R., A.I.P.-H., J.G., B.R., L.M.-G., G.F.) and Departments of Surgery (F.R., V.V., P.M.), Anesthesia (R.M.), Pathology (I.S.), and Endocrinology and Nutrition (C.S., J.S., G.F.), Clínica Universidad de Navarra, 31008 Pamplona, Spain; and CIBER de la Obesidad y Nutrición (V.C., J.G.-A., A.R., B.R., F.R., V.V., C.S., J.S., G.F.), Instituto de Salud Carlos III, 31008, Pamplona, Spain.
Victoria
V
Catalán
Javier
J
Gómez-Ambrosi
Amaia
A
Rodríguez
Ana I
AI
Pérez-Hernández
Javier
J
Gurbindo
Beatriz
B
Ramírez
Leire
L
Méndez-Giménez
Fernando
F
Rotellar
Víctor
V
Valentí
Rafael
R
Moncada
Pablo
P
Martí
Iosu
I
Sola
Camilo
C
Silva
Javier
J
Salvador
Gema
G
Frühbeck
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000502:physiology; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D009767:Obesity, Morbid / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000502:physiology*; D013851:Thinness / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D015431:Weight Loss / Q000502:physiology; D051153:Wnt Proteins / Q000097:blood / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000071818:Wnt-5a Protein; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D005136:Eye Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C118511:SFRP5 protein, human; D000094742:Secreted Frizzled-Related Proteins; C085389:WNT5A protein, human