Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/β-catenin and the planar cell polarity pathways during early trunk formation in mouse

Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, Minatojima-Minami, Chuou-ku, Kobe, Japan.
genesis (Impact Factor: 2.04). 02/2008; 46(2):spcone. DOI: 10.1002/dvg.20489
Source: PubMed

ABSTRACT The secreted frizzled-related protein gene family encodes proteins that regulate Wnt signaling. Msx1 in situ hybridization of 9.5 days post coitus mouse embryos showing normal neural tube development in an Sfrp1; Sfrp2 double mutant (left) but severe neural tube defects in a Looptail (Lp/+); Sfrp1; Sfrp2 triple mutant (right). These findings suggest that Sfrps regulate the Wnt planar cell polarity pathway. See Satoh et al. in this issue.

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    • "SFRPs prevent downstream WNT signalling by binding to and sequestering WNT ligands in the extracellular space (Bovolenta et al. 2008). Among SFRPs, SFRP5 may interact with both canonical and non-canonical WNT signalling pathways (Li et al. 2008, Satoh et al. 2008) and might be an import metabolic regulator (Ouchi et al. 2010, Mori et al. 2012, Carstensen et al. 2014). Results from an in vitro study indicated that SFRP5 impairs insulin signalling under normal conditions, but reduces tumour necrosis factor a-induced inflammation in primary human adipocytes (Carstensen et al. 2014). "
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    ABSTRACT: WNT/beta-catenin signalling is involved in regulating adipogenesis, and its dysregulation occurs in obesity. Secreted frizzled-related protein (SFRP) 5 is a WNT protein inhibitor; however, its role in adipogenesis and obesity is controversial. In the present study, we observed that SFRP5 mRNA levels were increased in the fat tissues of obese humans and mice. Sfrp5 expression was gradually induced during white and brown adipocyte differentiation, and was highly enriched in mature adipocytes rather than preadipocytes. However, the exogenous overexpression of Sfrp5 indicated that Sfrp5 may not directly regulate adipogenesis in vitro under the current conditions. Moreover, SFRP5 did not inhibit the canonical WNT/beta-catenin signalling pathway in preadipocytes. Subsequently, we measured circulating SFRP5 levels of obese patients and nonobese subjects using ELISA, and noted no significant difference. Collectively, these findings indicate that Sfrp5 represents a candidate for mature adipocyte marker genes. Our data provide new evidence concerning the role of SFRP5 in white and brown adipogenesis and obesity.
    Journal of Molecular Endocrinology 10/2014; 53(3). DOI:10.1530/JME-14-0037 · 3.62 Impact Factor
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    ABSTRACT: Research conducted over the last decade has established the Wnt/β-catenin signaling pathway as an important regulator of adipocyte differentiation. It is now known that preadipocytes secrete various Wnt proteins that act through autocrine/paracrine mechanisms to inhibit preadipocyte differentiation. Further complexity arises through the regulated expression of endogenous inhibitors of Wnt/β-catenin signaling, including the family of secreted frizzled-related proteins (sFRPs). sFRPs are thought to prevent downstream Wnt signaling by binding to and sequestering Wnt molecules in the extracellular space, although recent reports have indicated sFRPs can function through mechanisms independent of Wnt inhibition. Here we have sought to characterize a novel function for sFRP5 in adipocyte biology and obesity. We show that sFRP5 expression is strongly induced during adipocyte differentiation in vitro and in various models of obesity. Furthermore, sFRP5 expression is highly correlated with increasing adiposity and adipocyte size. Mice that lack functional sFRP5 resist diet-induced obesity as evidenced by lower total body weight and decreased fat mass. Detailed morphometric analysis revealed that sFRP5Q27stop mice challenged with a high fat diet have fewer large adipocytes than wild type mice. Utilizing a model of adipose tissue transplantation, we show that sFRP5 regulates adipocyte size during obesity in a tissue autonomous manner. In our studies to elucidate the mechanism of action of sFRP5, we found that sFRP5 regulates adipocyte clustering of 3T3-L1 cells, a similar result to that observed upon activation of integrin signaling in adipocytes. Indeed, we show that sFRP5 can functionally interact with integrins in a gel contraction assay, and that activation of the integrin/ERK signaling pathway is altered in two distinct models of sFRP5-deficient adipocytes in culture. Thus we provide evidence that sFRP5 regulates adipocyte expansion during obesity, and that the integrin/ERK cascade may mediate these effects. Finally, we describe additional preliminary results suggesting that sFRP5 may directly or indirectly regulate the seemingly distinct processes governing food intake under specific conditions, bone mass, and mitochondrial oxidative phosphorylation in adipocytes, thus expanding the scope of sFRP5 function and providing insight into the overall impact of this factor in vertebrate biology. Ph.D. Cellular & Molecular Biology University of Michigan, Horace H. Rackham School of Graduate Studies
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