{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T23:25:17Z","timestamp":1778801117022,"version":"3.51.4"},"reference-count":82,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-130286"],"award-info":[{"award-number":["MOP-130286"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2016\u201306639"],"award-info":[{"award-number":["RGPIN-2016\u201306639"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Folic acid (synthetic folate, FA) is consumed in excess in North America and may interact with common pathogenic variants in methylenetetrahydrofolate reductase (MTHFR); the most prevalent inborn error of folate metabolism with wide-ranging obesity-related comorbidities. While preclinical murine models have been valuable to inform on diet\u2013gene interactions, a recent Folate Expert panel has encouraged validation of new animal models. In this study, we characterized a novel zebrafish model of mthfr deficiency and evaluated the effects of genetic loss of mthfr function and FA supplementation during embryonic development on energy homeostasis and metabolism. mthfr-deficient zebrafish were generated using CRISPR mutagenesis and supplemented with no FA (control, 0FA) or 100\u00a0\u03bcm FA (100FA) throughout embryonic development (0\u20135\u00a0days postfertilization). We show that the genetic loss of mthfr function in zebrafish recapitulates key biochemical hallmarks reported in MTHFR deficiency in humans and leads to greater lipid accumulation and aberrant cholesterol metabolism as reported in the Mthfr murine model. In mthfr-deficient zebrafish, energy homeostasis was also impaired as indicated by altered food intake, reduced metabolic rate and lower expression of central energy-regulatory genes. Microglia abundance, involved in healthy neuronal development, was also reduced. FA supplementation to control zebrafish mimicked many of the adverse effects of mthfr deficiency, some of which were also exacerbated in mthfr-deficient zebrafish. Together, these findings support the translatability of the mthfr-deficient zebrafish as a preclinical model in folate research.<\/jats:p>","DOI":"10.1093\/hmg\/ddac308","type":"journal-article","created":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T01:33:52Z","timestamp":1673660032000},"page":"1575-1588","source":"Crossref","is-referenced-by-count":7,"title":["Methylenetetrahydrofolate reductase deficiency and high-dose FA supplementation disrupt embryonic development of energy balance and metabolic homeostasis in zebrafish"],"prefix":"10.1093","volume":"32","author":[{"given":"Rebecca","family":"Simonian","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5131-9543","authenticated-orcid":false,"given":"Emanuela","family":"Pannia","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Biology, Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rola","family":"Hammoud","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology , Lunenfeld-Tanenbaum Research Institute, , Toronto ON, M5G 1X5 , Canada"},{"name":"Mount Sinai Hospital , Lunenfeld-Tanenbaum Research Institute, , Toronto ON, M5G 1X5 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-5682","authenticated-orcid":false,"given":"Ramil R","family":"Noche","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine , Yale Zebrafish Research Core, , New Haven, CT 06511 , USA"},{"name":"Yale School of Medicine , Yale Zebrafish Research Core, , New Haven, CT 06511 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiucheng","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Biology, Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Kranenburg","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruslan","family":"Kubant","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Ashcraft","sequence":"additional","affiliation":[{"name":"Baylor Scott & White Research Institute , Institute of Metabolic Disease, Dallas, TX 75204 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandi","family":"Wasek","sequence":"additional","affiliation":[{"name":"Baylor Scott & White Research Institute , Institute of Metabolic Disease, Dallas, TX 75204 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[{"name":"Baylor Scott & White Research Institute , Institute of Metabolic Disease, Dallas, TX 75204 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-4169","authenticated-orcid":false,"given":"James J","family":"Dowling","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genome Biology, Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G Harvey","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"Department of Physiology , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"},{"name":"University of Toronto , Faculty of Medicine, , Toronto, ON M5S 1A8 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"2023042013362527000_ref1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"One-carbon metabolism in health and disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cell Metab."},{"key":"2023042013362527000_ref2","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1084\/jem.20181965","article-title":"Toward a better understanding of folate metabolism in health and disease","volume":"216","author":"Zheng","year":"2019","journal-title":"J. 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