SPARC Inhibits Adipogenesis by Its Enhancement of β-Catenin Signaling*
- 2 To whom correspondence should be addressed: Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101. Tel.: 206-341-1311; Fax: 206-341-1375; E-mail: hsage{at}benaroyaresearch.org.
Abstract
SPARC (secreted protein acidic and rich in cysteine) modulates interactions between cells and extracellular matrix and is enriched in white adipose tissue. We have reported that SPARC-null mice accumulate significantly more fat than wild-type mice and maintain relatively high levels of serum leptin. We now show that SPARC inhibits adipogenesis in vitro. Specifically, recombinant SPARC inhibited (a) adipocyte differentiation of stromal-vascular cells isolated from murine white adipose tissue and (b) the expression of adipogenic transcription factors and adipocyte-specific genes. SPARC induced the accumulation and nuclear translocation of β-catenin and subsequently enhanced the interaction of β-catenin and T cell/lymphoid enhancer factor 1. The activity of integrin-linked kinase was required for the effect of SPARC on β-catenin accumulation as well as extracellular matrix remodeling. During adipogenesis, fusiform preadipocytes change into sphere-shaped adipocytes and convert the extracellular matrix from a fibronectin-rich stroma to a laminin-rich basal lamina. SPARC retarded the morphological changes exhibited by preadipocytes during differentiation. In the presence of SPARC, the deposition of fibronectin was enhanced, and that of laminin was inhibited; in parallel, the expression of α5 integrin was enhanced, and that of α6 integrin was inhibited. Lithium chloride, which enhances the accumulation of β-catenin, also inhibited the expression of α6 integrin. These findings demonstrate a role for SPARC in adipocyte morphogenesis and in signaling processes leading to terminal differentiation.
Footnotes
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↵3 The abbreviations used are: WAT, white adipose tissue; ECM, extracellular matrix; GM, growth medium; WT, wild type; C/EBPα, CAAT/enhancer-binding protein α; PPARγ, peroxisome proliferator-activated receptor γ; TCF/LEF, T-cell factor/lymphoid-enhancing factor; GSK3β, glycogen synthase kinase 3β; ILK, integrin-linked kinase; LN, laminin; FN, fibronectin; IBMX, 3-isobutyl-1-methylxanthine; GPDH, glycerol-3-phosphate dehydrogenase; ERK1/2, extracellular signal-regulated kinase 1/2; BSA, bovine serum albumin; RUNX2, runt-related transcription factor 2; DMEM, Dulbecco's modified Eagle's medium; SVC, stromal-vascular cell; RT, reverse transcription.
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant R01-GM40711 (to E. H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.
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↵1 Supported by a postdoctoral fellowship from the American Heart Association, Pacific Mountain Affiliate.
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- Received October 29, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
