Wnt10b Inhibits Development of White and Brown Adipose Tissues

Abstract

Wnt is a family of secreted signaling proteins that regulate diverse developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits differentiation of preadipocytes in vitro. To determine whether Wnt signaling blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs development of this tissue throughout the body, with a decline of ϳ50% in total body fat and a reduction of ϳ60% in weight of epididymal and perirenal depots. FABP4-Wnt10b mice resist accumulation of adipose tissue when fed a high fat diet. Furthermore, transgenic mice are more glucose-tolerant and insulin-sensitive than wild type mice. Expression of Wnt10b from the FABP4 promoter also blocks development of brown adipose tissue. Interscapular tissue of FABP4-Wnt10b mice has the visual appearance of white adipose tissue but expresses neither brown (e.g. uncoupling protein 1) nor white adipocyte markers. Transgenic mice are unable to maintain a core body temperature when placed in a cold environment, providing further evidence that Wnt10b inhibits development of brown adipose tissue. Although food intake is not altered in FABP4-Wnt10b mice, oxygen consumption is decreased. Thus, FABP4-Wnt10b mice on a chow diet gain more weight than controls, largely because of an increase in weight of skin. In summary, inhibition by Wnt10b of white and brown adipose tissue development results in lean mice without lipodystrophic diabetes.The program followed by preadipocytes as they differentiate into adipocytes has been well characterized (1-3). Activation of a cascade of transcription factors, including PPAR␥ 1 and members of the C/EBP family, results in global changes in gene expression that cause the loss of preadipocyte characteristics and the acquisition of the adipocyte phenotype. Whether preadipocytes remain quiescent, divide, or differentiate is influenced by both inhibitory and stimulatory factors (4). One of the endogenous factors proposed to repress adipogenesis is Wnt10b, which belongs to a large family of secreted, cysteine-rich proteins that regulate diverse cellular processes, including development. Although Wnt regulates cell fate through several signaling pathways (5, 6), activation of the canonical Wnt/␤-catenin pathway is sufficient to inhibit differentiation and apoptosis of preadipocytes (7-11). A model for the canonical signaling pathway has arisen from extensive genetic and biochemical studies. In the absence of Wnt, glycogen synthase kinase-3 phosphorylates ␤-catenin, which targets this protein for ubiquitin-mediated degradation by the proteasome. In the presence of Wnt, activation of Frizzled receptors and low density lipoprotein receptor-related protein coreceptors disrupts the complex of proteins that contain glycogen synthase kinase-3 and ␤-catenin. Hypophosphorylated ␤-catenin then accumulates in the cytosol, translocates to the nucleus, and binds to T-cell factor/lymphoid-enhancing factor transcription factors to mediate the eff...

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