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Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity

Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as ho...

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Autores principales: McFadden, Taylor, Gaito, Natasha, Carucci, Isabella, Fletchall, Everett, Farrell, Kayla, Jarome, Timothy J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085038/
https://www.ncbi.nlm.nih.gov/pubmed/37036864
http://dx.doi.org/10.1371/journal.pone.0284286
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author McFadden, Taylor
Gaito, Natasha
Carucci, Isabella
Fletchall, Everett
Farrell, Kayla
Jarome, Timothy J.
author_facet McFadden, Taylor
Gaito, Natasha
Carucci, Isabella
Fletchall, Everett
Farrell, Kayla
Jarome, Timothy J.
author_sort McFadden, Taylor
collection PubMed
description Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity.
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spelling pubmed-100850382023-04-11 Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity McFadden, Taylor Gaito, Natasha Carucci, Isabella Fletchall, Everett Farrell, Kayla Jarome, Timothy J. PLoS One Research Article Obesity is a complex medical condition that is linked to various health complications such as infertility, stroke, and osteoarthritis. Understanding the neurobiology of obesity is crucial for responding to the etiology of this disease. The hypothalamus coordinates many integral activities such as hormone regulation and feed intake and numerous studies have observed altered hypothalamic gene regulation in obesity models. Previously, it was reported that the promoter region of the satiety gene, Pomc, has increased DNA methylation in the hypothalamus following short-term exposure to a high fat diet, suggesting that epigenetic-mediated repression of hypothalamic Pomc might contribute to the development of obesity. However, due to technical limitations, this has never been directly tested. Here, we used the CRISPR-dCas9-TET1 and dCas9-DNMT3a systems to test the role of Pomc DNA methylation in the hypothalamus in abnormal weight gain following acute exposure to a high fat diet in male rats. We found that exposure to a high fat diet increases Pomc DNA methylation and reduces gene expression in the hypothalamus. Despite this, we found that CRISPR-dCas9-TET1-mediated demethylation of Pomc was not sufficient to prevent abnormal weight gain following exposure to a high fat diet. Furthermore, CRISPR-dCas9-DNMT3a-mediated methylation of Pomc did not alter weight gain following exposure to standard or high fat diets. Collectively, these results suggest that high fat diet induced changes in Pomc DNA methylation are a consequence of, but do not directly contribute to, abnormal weight gain during the development of obesity. Public Library of Science 2023-04-10 /pmc/articles/PMC10085038/ /pubmed/37036864 http://dx.doi.org/10.1371/journal.pone.0284286 Text en © 2023 McFadden et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
McFadden, Taylor
Gaito, Natasha
Carucci, Isabella
Fletchall, Everett
Farrell, Kayla
Jarome, Timothy J.
Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title_full Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title_fullStr Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title_full_unstemmed Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title_short Controlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesity
title_sort controlling hypothalamic dna methylation at the pomc promoter does not regulate weight gain during the development of obesity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10085038/
https://www.ncbi.nlm.nih.gov/pubmed/37036864
http://dx.doi.org/10.1371/journal.pone.0284286
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