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Methods: Tissue biopsies were collected from patients with normal weight (NW) and obesity (OBS). Adipocytes were isolated via enzymatic digestion and density separation. Each group was divided into control (standard medium) and folic acid treatment (2 mg\/24 h for 48 h) conditions. After treatment, DNA methylation levels were analyzed using the Infinium Methylation EPIC v2.0 Kit, and gene expression analyses were performed by RT-qPCR. A pathway enrichment analysis was conducted using the KEGG database for functional insight. Results: Folic acid induced differential methylation at 755 CpG sites in NW adipocytes, which were associated with immune regulation, including MAPK signaling. Also, OBS adipocytes showed methylation changes at 92 CpG sites, affecting pathways related to metabolic regulation, such as cAMP signaling. LEP gene expression was upregulated (5.2-fold) in OBS adipocytes, while CREM2 expression was increased (2.8-fold) in NW adipocytes after treatment. These gene expression differences underscore weight-dependent responses to folic acid, with LEP upregulation in OBS cells suggesting links to metabolic dysregulation and CREM2 upregulation in NW cells potentially contributing to immune modulation. Conclusions: Folic acid treatment exerts distinct epigenetic and gene expression effects in adipocytes of SLE patients, modulated by obesity status. This weight-dependent response, marked by changes in pathways relevant to immune and metabolic function, highlights the need for further investigation into how nutrient-based interventions might support SLE management. From a clinical perspective, this study underscores the potential of targeted nutrient-based interventions to address immunometabolic dysfunctions in SLE patients. Further research could explore folic acid supplementation as a complementary approach to personalized treatment strategies, particularly for patients with obesity.<\/jats:p>","DOI":"10.3390\/nu17061086","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T05:03:59Z","timestamp":1742447039000},"page":"1086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genome-Wide Impact of Folic Acid on DNA Methylation and Gene Expression in Lupus Adipocytes: An In Vitro Study on Obesity"],"prefix":"10.3390","volume":"17","author":[{"given":"Leticia L.","family":"Souza","sequence":"first","affiliation":[{"name":"Applied Physiology and Nutrition Research Group, School of Physical Education and Sport and Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Center of Lifestyle Medicine, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-4868","authenticated-orcid":false,"given":"Jhulia C. N. L.","family":"da Mota","sequence":"additional","affiliation":[{"name":"Applied Physiology and Nutrition Research Group, School of Physical Education and Sport and Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Center of Lifestyle Medicine, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1633-1405","authenticated-orcid":false,"given":"Lucas M.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Applied Physiology and Nutrition Research Group, School of Physical Education and Sport and Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Center of Lifestyle Medicine, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8915-9357","authenticated-orcid":false,"given":"Amanda A.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Applied Physiology and Nutrition Research Group, School of Physical Education and Sport and Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Center of Lifestyle Medicine, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar A.","family":"Caponi","sequence":"additional","affiliation":[{"name":"Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela A. S.","family":"Pinhel","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Sao Jose do Rio Preto Medical School, Sao Jose do Rio Preto 15090-000, Brazil"},{"name":"Department of Health Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Costa-Fraga","sequence":"additional","affiliation":[{"name":"Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS\/SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angel","family":"Diaz-Lagares","sequence":"additional","affiliation":[{"name":"Epigenomics Unit, Cancer Epigenomics, Translational Medical Oncology Group (ONCOMET), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS\/SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Centro de Investigacion Biomedica en Red Cancer (CIBERONC), ISCIII, 28029 Madrid, Spain"},{"name":"Department of Clinical Analysis, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS\/SERGAS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-8834","authenticated-orcid":false,"given":"Andrea G.","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS\/SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla B.","family":"Nonino","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4392-0301","authenticated-orcid":false,"given":"Ana B.","family":"Crujeiras","sequence":"additional","affiliation":[{"name":"Epigenomics in Endocrinology and Nutrition Group, Epigenomics Unit, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS\/SERGAS), 15706 Santiago de Compostela, Spain"},{"name":"Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina F.","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Applied Physiology and Nutrition Research Group, School of Physical Education and Sport and Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Center of Lifestyle Medicine, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05508-220, Brazil"},{"name":"Rheumatology Division, Hospital das Clinicas, Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rafael-Vidal, C., P\u00e9rez, N., Altab\u00e1s, I., Garcia, S., and Pego-Reigosa, J.M. 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