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

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dc.contributor.authorMcFadden, Tayloren
dc.contributor.authorGaito, Natashaen
dc.contributor.authorCarucci, Isabellaen
dc.contributor.authorFletchall, Everetten
dc.contributor.authorFarrell, Kaylaen
dc.contributor.authorJarome, Timothy J.en
dc.date.accessioned2023-08-31T17:03:35Zen
dc.date.available2023-08-31T17:03:35Zen
dc.date.issued2023-04en
dc.description.abstractObesity 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.en
dc.description.notesThis work was supported by Virginia Commonwealth Health Research Board grant #208-09-22, with additional support from the National Institutes of Health (NIH) grants MH122414, MH120498, MH120569, MH123742, AG071523 and AG079292 to T.J.J. The funders (NIH, VA-CHRB) had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.description.sponsorshipVirginia Commonwealth Health Research Board [208-09-22]; National Institutes of Health (NIH) [MH122414, MH120498, MH120569, MH123742, AG071523, AG079292]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0284286en
dc.identifier.issn1932-6203en
dc.identifier.issue4en
dc.identifier.pmid37036864en
dc.identifier.urihttp://hdl.handle.net/10919/116177en
dc.identifier.volume18en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmemoryen
dc.subjectdysregulationen
dc.subjecthomeostasisen
dc.subjectstateen
dc.titleControlling hypothalamic DNA methylation at the Pomc promoter does not regulate weight gain during the development of obesityen
dc.title.serialPlos Oneen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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