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YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity
Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily resp...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046197/ https://www.ncbi.nlm.nih.gov/pubmed/35478181 http://dx.doi.org/10.1038/s41419-022-04847-0 |
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author | Lee, Gwan-Jun Kim, Youn Ju Park, Bongju Yim, Sujin Park, Chansang Roh, Hyunsoo Moon, Yunwon Seong, Je Kyung Park, Hyunsung |
author_facet | Lee, Gwan-Jun Kim, Youn Ju Park, Bongju Yim, Sujin Park, Chansang Roh, Hyunsoo Moon, Yunwon Seong, Je Kyung Park, Hyunsung |
author_sort | Lee, Gwan-Jun |
collection | PubMed |
description | Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy. |
format | Online Article Text |
id | pubmed-9046197 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90461972022-04-29 YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity Lee, Gwan-Jun Kim, Youn Ju Park, Bongju Yim, Sujin Park, Chansang Roh, Hyunsoo Moon, Yunwon Seong, Je Kyung Park, Hyunsung Cell Death Dis Article Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy. Nature Publishing Group UK 2022-04-27 /pmc/articles/PMC9046197/ /pubmed/35478181 http://dx.doi.org/10.1038/s41419-022-04847-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lee, Gwan-Jun Kim, Youn Ju Park, Bongju Yim, Sujin Park, Chansang Roh, Hyunsoo Moon, Yunwon Seong, Je Kyung Park, Hyunsung YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title | YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title_full | YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title_fullStr | YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title_full_unstemmed | YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title_short | YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity |
title_sort | yap-dependent wnt5a induction in hypertrophic adipocytes restrains adiposity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046197/ https://www.ncbi.nlm.nih.gov/pubmed/35478181 http://dx.doi.org/10.1038/s41419-022-04847-0 |
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