{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:01:51Z","timestamp":1788480111915,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The assessment of sex-specific effects in pre-clinical models is critical for improving the translatability of findings to clinical applications. However, preclinical studies often combine sexes or focus exclusively on one sex, including research utilizing syngeneic cancer models. Considering sex differences is particularly important in metabolic studies, as males and females exhibit distinct body compositions, hormone profiles, and metabolic demands.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study evaluates sex-specific metabolic responses to ketogenic therapies in VM\/Dk mice, including assessments of glucose metabolism, ketone metabolism, and histone modifications linked to metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our findings reveal significant sex differences in body weight, circulating metabolites, blood insulin levels, and histone modification profiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>We demonstrate that male and female VM\/Dk mice respond differently to ketogenic therapies, with responses varying based on the specific type of therapy applied.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2025.1554743","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T01:30:55Z","timestamp":1750296655000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["From glucose to histone modification: sex-specific metabolic responses to ketogenic therapy in VM\/Dk mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Sara E.","family":"Moss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M.","family":"Poff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apryl","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine M.","family":"DeBlasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic P.","family":"D\u2019Agostino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1177\/03063127231168371","article-title":"Making a \u201csex-difference fact\u201d: Ambien dosing at the interface of policy, regulation, women's health, and biology","volume":"53","author":"Zhao","year":"2023","journal-title":"Soc Stud Sci"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"19150","DOI":"10.1038\/s41598-021-98689-z","article-title":"Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem","volume":"11","author":"Yoon","year":"2021","journal-title":"Sci Rep"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1089\/jwh.2018.7396","article-title":"Implementation of the NIH sex-inclusion policy: attitudes and opinions of study section members","volume":"28","author":"Woitowich","year":"2019","journal-title":"J Womens Health (Larchmt)"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1002\/path.1711030410","article-title":"Astrocytomas in an inbred mouse strain","volume":"103","author":"Fraser","year":"1971","journal-title":"J Pathol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1097\/00006123-199712000-00024","article-title":"Characterization of a spontaneous murine astrocytoma and abrogation of its Tumorigenicity by cytokine secretion","volume":"41","author":"Sampson","year":"1997","journal-title":"Neurosurgery"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/ijc.23492","article-title":"Metastatic cancer cells with macrophage properties: evidence from a new murine tumor model","volume":"123","author":"Huysentruyt","year":"2008","journal-title":"Int J Cancer"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1158\/1078-0432.CCR-13-0709","article-title":"EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss","volume":"20","author":"Sampson","year":"2014","journal-title":"Clin Cancer Res"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1215\/15228517-2007-010","article-title":"Inhibiting TGF-beta signaling restores immune surveillance in the SMA-560 glioma model","volume":"9","author":"Tran","year":"2007","journal-title":"Neuro-Oncology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1158\/2326-6066.CIR-16-0156","article-title":"Endogenous Neoantigen-specific CD8 T cells identified in two glioblastoma models using a Cancer Immunogenomics approach","volume":"4","author":"Johanns","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jneuroim.2006.09.016","article-title":"Genetic analysis of intracranial tumors in a murine model of glioma demonstrate a shift in gene expression in response to host immunity","volume":"182","author":"Learn","year":"2007","journal-title":"J Neuroimmunol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1158\/1078-0432.CCR-17-1766","article-title":"NKG2D-dependent antitumor effects of chemotherapy and radiotherapy against glioblastoma","volume":"24","author":"Weiss","year":"2018","journal-title":"Clin Cancer Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e00038","DOI":"10.1042\/AN20100002","article-title":"Calorie restriction as an anti-invasive therapy for malignant brain Cancer in the VM mouse","volume":"2","author":"Shelton","year":"2010","journal-title":"ASN Neuro"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3389\/fnut.2018.00091","article-title":"Nontoxic targeting of energy metabolism in preclinical VM-M3 experimental glioblastoma","volume":"5","author":"Augur","year":"2018","journal-title":"Front Nutr"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e0127407","DOI":"10.1371\/journal.pone.0127407","article-title":"Non-toxic metabolic management of metastatic cancer in VM mice: novel combination of ketogenic diet, ketone supplementation, and hyperbaric oxygen therapy","volume":"10","author":"Poff","year":"2015","journal-title":"PLoS One"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1002\/ijc.28809","article-title":"Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer","volume":"135","author":"Poff","year":"2014","journal-title":"Int J Cancer"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1002\/jcsm.12554","article-title":"Ketone bodies attenuate wasting in models of atrophy","volume":"11","author":"Koutnik","year":"2020","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.3390\/nu16172921","article-title":"Sex-specific variation in metabolic responses to diet","volume":"16","author":"Andrews","year":"2024","journal-title":"Nutrients"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1161\/01.ATV.0000092326.00725.ED","article-title":"Gender differences in postprandial ketone bodies in normolipidemic subjects and in untreated patients with familial combined hyperlipidemia","volume":"23","author":"Halkes","year":"2003","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.2337\/db18-1884-P","article-title":"Sex differences in the response of C57BL\/6 mice to ketogenic diets","volume":"67","author":"Cochran","year":"2018","journal-title":"Diabetes"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.semcancer.2017.12.011","article-title":"Targeting the Warburg effect for cancer treatment: ketogenic diets for management of glioma","volume":"56","author":"Poff","year":"2017","journal-title":"Semin Cancer Biol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s10863-017-9704-1","article-title":"Estrogens regulate life and death in mitochondria","volume":"49","author":"Klinge","year":"2017","journal-title":"J Bioenerg Biomembr"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s13293-020-00291-x","article-title":"Sex differences in cancer mechanisms","volume":"11","author":"Rubin","year":"2020","journal-title":"Biol Sex Differ"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1111\/j.1467-789X.2008.00529.x","article-title":"Sex differences in obesity and the regulation of energy homeostasis","volume":"10","author":"Lovejoy","year":"2009","journal-title":"Obes Rev"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1016\/j.metabol.2009.05.008","article-title":"Effect of adipose tissue on the sexual dimorphism in metabolic flexibility","volume":"58","author":"Sparks","year":"2009","journal-title":"Metabolism"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1016\/j.cmet.2023.05.008","article-title":"Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia","volume":"35","author":"Ferrer","year":"2023","journal-title":"Cell Metab"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.3390\/nu16162731","article-title":"Sex-and age-specific differences in mice fed a ketogenic diet","volume":"16","author":"Sprankle","year":"2024","journal-title":"Nutrients"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1002\/oby.23106","article-title":"Sex differences in insulin sensitivity are related to muscle tissue Acylcarnitine but not subcellular lipid distribution","volume":"29","author":"Broussard","year":"2021","journal-title":"Obesity (Silver Spring)"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"7845","DOI":"10.3390\/cimb45100496","article-title":"Gender differences in insulin resistance: new knowledge and perspectives","volume":"45","author":"Ciarambino","year":"2023","journal-title":"Curr Issues Mol Biol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.3390\/biomedicines9101363","article-title":"Genome profiling of H3k4me3 histone modification in human adipose tissue during obesity and insulin resistance","volume":"9","author":"Castellano-Castillo","year":"2021","journal-title":"Biomedicines"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"355","DOI":"10.5698\/1535-7597-14.6.355","article-title":"The new ketone alphabet soup: BHB, HCA, and HDAC","volume":"14","author":"Hartman","year":"2014","journal-title":"Epilepsy Curr"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"47","DOI":"10.4161\/epi.4.1.7288","article-title":"Sex differences in histone modifications in the neonatal mouse brain","volume":"4","author":"Tsai","year":"2009","journal-title":"Epigenetics"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1007\/s11914-020-00628-w","article-title":"Sex differences in Cancer Cachexia","volume":"18","author":"Zhong","year":"2020","journal-title":"Curr Osteoporos Rep"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3390\/biomedicines10010126","article-title":"Impact of physical activity and exercise on the epigenome in skeletal muscle and effects on systemic metabolism","volume":"10","author":"Plaza-Diaz","year":"2022","journal-title":"Biomedicines"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1016\/j.ajcnut.2024.09.020","article-title":"Sex differences in clinical presentation, treatment response, and side effects of nutritional therapy among patients at nutritional risk: a secondary analysis of the randomized clinical trial EFFORT","volume":"120","author":"Wunderle","year":"2024","journal-title":"Am J Clin Nutr"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"16465","DOI":"10.1038\/s41598-023-43587-9","article-title":"Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet","volume":"13","author":"Smolensky","year":"2023","journal-title":"Sci Rep"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2025.1554743\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T01:30:56Z","timestamp":1750296656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2025.1554743\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":35,"alternative-id":["10.3389\/fnut.2025.1554743"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2025.1554743","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]},"article-number":"1554743"}}