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Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis
DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feed...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9150890/ https://www.ncbi.nlm.nih.gov/pubmed/35635747 http://dx.doi.org/10.7554/eLife.72359 |
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author | Tovy, Ayala Reyes, Jaime M Zhang, Linda Huang, Yung-Hsin Rosas, Carina Daquinag, Alexes C Guzman, Anna Ramabadran, Raghav Chen, Chun-Wei Gu, Tianpeng Gupta, Sinjini Ortinau, Laura Park, Dongsu Cox, Aaron R Rau, Rachel E Hartig, Sean M Kolonin, Mikhail G Goodell, Margaret A |
author_facet | Tovy, Ayala Reyes, Jaime M Zhang, Linda Huang, Yung-Hsin Rosas, Carina Daquinag, Alexes C Guzman, Anna Ramabadran, Raghav Chen, Chun-Wei Gu, Tianpeng Gupta, Sinjini Ortinau, Laura Park, Dongsu Cox, Aaron R Rau, Rachel E Hartig, Sean M Kolonin, Mikhail G Goodell, Margaret A |
author_sort | Tovy, Ayala |
collection | PubMed |
description | DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity. |
format | Online Article Text |
id | pubmed-9150890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-91508902022-05-31 Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis Tovy, Ayala Reyes, Jaime M Zhang, Linda Huang, Yung-Hsin Rosas, Carina Daquinag, Alexes C Guzman, Anna Ramabadran, Raghav Chen, Chun-Wei Gu, Tianpeng Gupta, Sinjini Ortinau, Laura Park, Dongsu Cox, Aaron R Rau, Rachel E Hartig, Sean M Kolonin, Mikhail G Goodell, Margaret A eLife Developmental Biology DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity. eLife Sciences Publications, Ltd 2022-05-30 /pmc/articles/PMC9150890/ /pubmed/35635747 http://dx.doi.org/10.7554/eLife.72359 Text en © 2022, Tovy et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Tovy, Ayala Reyes, Jaime M Zhang, Linda Huang, Yung-Hsin Rosas, Carina Daquinag, Alexes C Guzman, Anna Ramabadran, Raghav Chen, Chun-Wei Gu, Tianpeng Gupta, Sinjini Ortinau, Laura Park, Dongsu Cox, Aaron R Rau, Rachel E Hartig, Sean M Kolonin, Mikhail G Goodell, Margaret A Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title | Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title_full | Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title_fullStr | Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title_full_unstemmed | Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title_short | Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis |
title_sort | constitutive loss of dnmt3a causes morbid obesity through misregulation of adipogenesis |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9150890/ https://www.ncbi.nlm.nih.gov/pubmed/35635747 http://dx.doi.org/10.7554/eLife.72359 |
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