Secreted frizzled-related protein 1 regulates adipose tissue expansion and is dysregulated in severe obesity.
OBJECTIVE
The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo.


METHODS
We use a combination of human and murine, in vivo and in vitro models of adipogenesis, adipose tissue expansion and obesity-related metabolic syndrome to profile the involvement of SFRP1.


RESULTS
SFRP1 is expressed in both murine and human mature adipocytes. The expression of SFRP1 is induced during in vitro adipogenesis, and SFRP1 is preferentially expressed in mature adipocytes in human adipose tissue. Constitutive ectopic expression of SFRP1 is proadipogenic and inhibits the Wnt/β-catenin signaling pathway. In vivo endogenous levels of adipose SFRP1 are regulated in line with proadipogenic states. However, in longitudinal studies of high-fat-diet-fed mice, we observed a dynamic temporal but biphasic regulation of endogenous SFRP1. In agreement with this profile, we observed that SFRP1 expression in human tissues peaks in patients with mild obesity and gradually falls in morbidly obese subjects.


CONCLUSIONS
Our results suggest that SFRP1 is an endogenous modulator of Wnt/β-catenin signaling and participates in the paracrine regulation of human adipogenesis. The reduced adipose expression of SFRP1 in morbid obesity and its knock-on effect to prevent further adipose tissue expansion may contribute to the development of metabolic complications in these individuals.
Lagathu
C
C
Department of Clinical Biochemistry, Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Christodoulides
C
C
Tan
C Y
CY
Virtue
S
S
Laudes
M
M
Campbell
M
M
Ishikawa
K
K
Ortega
F
F
Tinahones
F J
FJ
Fernández-Real
J-M
JM
Orešič
M
M
Sethi
J K
JK
Vidal-Puig
A
A
D052438:Adipocytes, White / Q000378:metabolism; D050156:Adipogenesis; D052436:Adipose Tissue, White / Q000502:physiology*; D000368:Aged; D000818:Animals; D002454:Cell Differentiation; D005260:Female; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009765:Obesity; D009767:Obesity, Morbid / Q000378:metabolism* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000502:physiology*; D000099274:Frizzled-Related Proteins
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins