Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors
Edited by Elaine Fuchs, The Rockefeller University, New York, NY, and approved February 28, 2014 (received for review July 9, 2013)
Significance
The synchronized patterns of hair follicle growth and expansion of the dermal adipocyte layer have long been recognized. Although factors secreted by adipocytes are known to regulate the hair growth cycle, it is unclear whether, conversely, the epidermis can regulate adipogenesis. Our study now demonstrates that activation of epidermal Wnt/β-catenin signaling stimulates adipocyte differentiation in vivo and in vitro. The effect can be mediated by secreted factors, including insulin-like growth factor 2 and bone morphogenetic proteins 2 and 6.
Abstract
It has long been recognized that the hair follicle growth cycle and oscillation in the thickness of the underlying adipocyte layer are synchronized. Although factors secreted by adipocytes are known to regulate the hair growth cycle, it is unclear whether the epidermis can regulate adipogenesis. We show that inhibition of epidermal Wnt/β-catenin signaling reduced adipocyte differentiation in developing and adult mouse dermis. Conversely, ectopic activation of epidermal Wnt signaling promoted adipocyte differentiation and hair growth. When the Wnt pathway was activated in the embryonic epidermis, there was a dramatic and premature increase in adipocytes in the absence of hair follicle formation, demonstrating that Wnt activation, rather than mature hair follicles, is required for adipocyte generation. Epidermal and dermal gene expression profiling identified keratinocyte-derived adipogenic factors that are induced by β-catenin activation. Wnt/β-catenin signaling-dependent secreted factors from keratinocytes promoted adipocyte differentiation in vitro, and we identified ligands for the bone morphogenetic protein and insulin pathways as proadipogenic factors. Our results indicate epidermal Wnt/β-catenin as a critical initiator of a signaling cascade that induces adipogenesis and highlight the role of epidermal Wnt signaling in synchronizing adipocyte differentiation with the hair growth cycle.
Acknowledgments
We acknowledge the core services of the Cancer Research UK Cambridge Research Institute, where the project was initiated, and the assistance of Charlotte Collins, Marta Lesko, Maria Mastrogiannaki, and Kai Kretzschmar, who generously provided mice/sections for research. We also thank Asako Nakagawa for technical assistance. G.D. thanks Samuel Woodhouse for daily discussions about this project. This work was supported by grants to F.M.W. from Cancer Research UK, the European Union, the Medical Research Council, and the Wellcome Trust and to H.F. from RIKEN. B.M.L. was the recipient of a Federation of European Biochemical Societies long-term fellowship. We gratefully acknowledge financial support, in the form of access to the flow facility, from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas' National Health Service Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust.
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Published online: March 31, 2014
Published in issue: April 15, 2014
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Acknowledgments
We acknowledge the core services of the Cancer Research UK Cambridge Research Institute, where the project was initiated, and the assistance of Charlotte Collins, Marta Lesko, Maria Mastrogiannaki, and Kai Kretzschmar, who generously provided mice/sections for research. We also thank Asako Nakagawa for technical assistance. G.D. thanks Samuel Woodhouse for daily discussions about this project. This work was supported by grants to F.M.W. from Cancer Research UK, the European Union, the Medical Research Council, and the Wellcome Trust and to H.F. from RIKEN. B.M.L. was the recipient of a Federation of European Biochemical Societies long-term fellowship. We gratefully acknowledge financial support, in the form of access to the flow facility, from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas' National Health Service Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust.
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors, Proc. Natl. Acad. Sci. U.S.A.
111 (15) E1501-E1509,
https://doi.org/10.1073/pnas.1312880111
(2014).
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