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Reversal of Hyperactive Wnt Signaling-Dependent Adipocyte

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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. We adipocytes in vivo (22), and mutations in the human WNT10B show that the suppressive effect of peptide boronic acids on hyper- gene are associated with early onset of obesity (23). Although active Wnt signaling is dependent on α-catenin; the rescue effect is these findings support the idea that Wnt signaling inhibits adi- completely abolished with the depletion of α-catenin in adipocytes. pogenesis, less is known about the roles of the canonical Wnt These results indicate that rather than targeting the canonical Wnt pathway in regulating different aspects of fat metabolism, in- signaling pathway directly, pharmacologic modulation of β-catenin cluding lipogenesis, lipolysis, and fatty acid β-oxidation. This may activity through α-catenin is a potentially attractive approach to be due to the intertwined nature of these metabolic and cellular CELL BIOLOGY attenuating Wnt signaling in vivo. processes in mammalian adipocytes (14, 24). Drosophila represents a powerful model system for studying axin | catenin | adipocyte | peptide boronic acid | Drosophila mechanisms that control lipid metabolism (25–27), for several reasons. First, there is high conservation in the enzymes, regula- he Wnt signaling pathway controls many fundamental aspects tory factors, pathways, tissues, and organs that regulate lipogenesis Tof normal development and tissue homeostasis in metazoans and adipogenesis between Drosophila and mammals. For example, by regulating cell differentiation, proliferation, migration, and the lipogenic enzymes found in mammals, including fatty acid metabolism (1–4). A key downstream effector of the canonical Wnt synthase, acetyl-CoA carboxylase, and Acyl-CoA synthetase, have signaling pathway is β-catenin, which functions as a cofactor for the virtually the same biochemical activities as the homologous en- T-cell factor and lymphoid-enhancing factor (TCF/LEF) family of zymes in Drosophila. At the tissue level, mature adipocytes in transcription factors in nucleus. In addition, β-catenin also mediates Drosophila fat bodies contain numerous lipid droplets and store cell–cell adhesion by serving as a component of adherens junctions most of the TG, mimicking the role of mammalian adipose tissues. at the cell membrane. β-catenin links adherens junctions and cy- toskeleton by binding to the transmembrane protein cadherin, as Significance wellasmicrofilamentsthrough the adaptor protein α-catenin (α-Cat) (5–7). Membrane-associated β-catenin is stable and may Deregulated Wnt signaling is often observed in diverse human represent the major subcellular pool of β-catenin. In contrast, the diseases, including cancers, and is a potential therapeutic target. soluble cytoplasmic pool of β-catenin is actively degraded by the Here we report that hyperactivated Wnt/Wg signaling disrupts proteasome in the absence of a Wnt signal. This is accomplished by fat metabolism in Drosophila larvae, and that peptide boronic the β-catenin destruction complex, which includes adenomatous acids, a unique class of proteasome inhibitors, can potently polyposis coli (APC), the scaffolding protein Axin (Axn), the Ser/ rescue the fat defects by inhibiting Wg signaling through sta- Thr kinase glycogen synthase kinase 3 (GSK3), and its priming bilization of α-catenin. We show that Axn127 mutant is an at- kinase casein kinase 1 (CK1) (8–10). The destruction complex is tractive system for screening for and optimizing small molecules inhibited on Wnt stimulation, allowing β-catenin to accumulate and that target Wnt signaling and proteasome in vivo. This work translocate into the nucleus, thereby activating expression of the suggests that pharmacologic strategies for stabilizing α-catenin Wnt target genes (4). Mutations of certain components of the Wnt may represent an attractive approach to attenuate Wnt sig- signaling pathway have been implicated in abnormal development naling, rather than directly targeting components of the Wnt and various diseases, including diabetes and a variety of human signaling pathway. cancers, particularly colorectal cancer (1–4, 11). Despite consider- able efforts, the development of inhibitory compounds that can Author contributions: T.Z., F.-N.H., X.-J.X., W.D., and J.-Y.J. designed research; T.Z., F.-N.H., target the Wnt signaling pathway for therapeutics remains an at- X.-J.X., X.L., M.L., X.G., Y.L., and J.-Y.J. performed research; X.P. contributed new re- tractive but elusive goal (12, 13). To our knowledge, there is no agents/analytic tools; T.Z., F.-N.H., X.-J.X., X.L., W.D., and J.-Y.J. analyzed data; and T.Z., F.-N.H., X.-J.X., W.D., and J.-Y.J. wrote the paper. currently Food and Drug Administration (FDA)-approved drug to treat diseases by inhibiting Wnt signaling activities. The authors declare no conflict of interest. Adipocytes play critical roles in maintenance of fat and energy This article is a PNAS Direct Submission. 1 homeostasis in animals. Adipogenesis refers to the cellular pro- T.Z., F.-N.H., and X.-J.X. contributed equally to this work. 2 cess of adipocyte differentiation, whereas lipogenesis is defined To whom correspondence may be addressed. Email: [email protected] or ji@medicine. tamhsc.edu. as fatty acid and triglyceride (TG) biosynthesis from acetyl-CoA This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (14, 15). Multiple lines of evidence have shown that activation of 1073/pnas.1621048114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1621048114 PNAS | Published online August 21, 2017 | E7469–E7478 Downloaded by guest on September 23, 2021 Similarly, the function and regulation of the key regulators, such To analyze the defective fat metabolism at the cellular level, we as the insulin and Wnt signaling pathways, are highly conserved stained the abdominal adipocytes in WT and Axn127 mutant larvae but simpler in Drosophila than in mammals. Second, Drosophila using boron-dipyrromethene (BODIPY). The control adipocytes provides a plethora of sophisticated genetic tools and molecular were largely uniform in size, with numerous oil droplets accu- markers for the functional analysis of adipocyte biology, which mulated within each cell (Fig. 1G and Fig. S2A); however, many of 127 facilitates analyses that are difficult to perform in other experi- the adipocytes in the Axn mutants were smaller and with fewer mental systems. Third, recent studies have identified Drosophila as oil droplets compared with WT (yellow arrow in Fig. 1H and Fig. an excellent model for screening small molecule compounds and S2C), mixed with occasional large adipocytes (red arrow in Fig. subsequent mechanistic studies (28–31). 1H). The strikingly reduced number of oil droplets and size of 127 Here we report our characterization of Axn mutants as a adipocytes in Axn mutants are consistent with the reduced TG unique Drosophila model that propagates a hyperactive Wnt levels of whole larvae as described above. signaling pathway, leading to dysregulated fat metabolism. This Defective Fat Accumulation in Axn127 Mutants Is Caused by a Gain in adipocyte defect was potently restored by three peptide boronic 127 acids, and the underlying mechanism was found to be mediated Wg Signaling. Exon 11 of the Axn allele is replaced by a re- petitive heterochromatin sequence, resulting in a mutant Axn by α-Cat. protein that lacks part of the DIX domain in the C terminus (32). Results The DIX domain is required for homopolymerization and het- Axn127 127 eropolymerization of Axn and Dishevelled (Dsh, or Dvl in Mutant Larvae Are Defective in Fat Metabolism. The Axn – homozygous mutants (genotype: w1118; +;FRT82BAxn127)survive mammals) (10, 33 35). We also observed significantly lower levels of Axn protein in Axn127
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