Reversal of Hyperactive Wnt Signaling-Dependent Adipocyte
Reversal of hyperactive Wnt signaling-dependent PNAS PLUS adipocyte defects by peptide boronic acids Tianyi Zhanga,1, Fu-Ning Hsub,1, Xiao-Jun Xieb,1, Xiao Lib, Mengmeng Liub, Xinsheng Gaob, Xun Peia, Yang Liaoa, Wei Dua,2, and Jun-Yuan Jib,2 aBen May Department for Cancer Research, The University of Chicago, Chicago, IL 60637; and bDepartment of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843 Edited by Norbert Perrimon, Harvard Medical School, Boston, MA, and approved July 17, 2017 (received for review December 22, 2016) Deregulated Wnt signaling and altered lipid metabolism have been the Wnt/β-catenin pathway inhibits adipocyte differentiation and linked to obesity, diabetes, and various cancers, highlighting the development (16–19); for example, activation of Wnt signaling in importance of identifying inhibitors that can modulate Wnt signal- cultured mouse preadipocyte 3T3-L1 cells impaired adipogenesis, ing and aberrant lipid metabolism. We have established a Drosophila whereas inhibition of β-catenin activity promoted this process (20). model with hyperactivated Wnt signaling caused by partial loss of In addition, in vivo studies have shown that overexpression of axin, a key component of the Wnt cascade. The Axin mutant larvae Wnt10b or β-catenin in adipose tissue impairs the formation of are transparent and have severe adipocyte defects caused by up- white and brown adipose tissue and causes fibrosis in mice (19, regulation of β-catenin transcriptional activities. We demonstrate 21). Conversely, the loss of β-catenin activity in mouse embryonic pharmacologic mitigation of these phenotypes in Axin mutants by mesenchyme switches the fate of normal uterine smooth muscle to identifying bortezomib and additional peptide boronic acids.
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