{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:00:44Z","timestamp":1790168444781,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":83,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/PR41478\/MED\/97\/511\/2020"],"award-info":[{"award-number":["BT\/PR41478\/MED\/97\/511\/2020"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/PR41478\/MED\/97\/511\/2020"],"award-info":[{"award-number":["BT\/PR41478\/MED\/97\/511\/2020"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/PR41478\/MED\/97\/511\/2020"],"award-info":[{"award-number":["BT\/PR41478\/MED\/97\/511\/2020"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research","doi-asserted-by":"publisher","award":["09\/141(0215)\/2019-EMR-I"],"award-info":[{"award-number":["09\/141(0215)\/2019-EMR-I"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nutr. Diabetes"],"DOI":"10.1038\/s41387-026-00448-4","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:38:10Z","timestamp":1783006690000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paternal folate deficiency induces hepatic insulin resistance in offspring mice"],"prefix":"10.1038","volume":"16","author":[{"given":"Parampal","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divika","family":"Sapehia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himanshi","family":"Goyal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0284-4517","authenticated-orcid":false,"given":"Jyotdeep","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"448_CR1","first-page":"52","volume":"4","author":"JA Greenberg","year":"2011","unstructured":"Greenberg JA, Bell SJ, Guan Y, Yu YH. Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4:52\u20139.","journal-title":"Rev Obstet Gynecol"},{"key":"448_CR2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00125-007-0793-y","volume":"51","author":"CS Yajnik","year":"2008","unstructured":"Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ, et al. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia. 2008;51:29\u201338.","journal-title":"Diabetologia"},{"key":"448_CR3","doi-asserted-by":"publisher","first-page":"e160845","DOI":"10.1001\/jamapediatrics.2016.0845","volume":"170","author":"G Wang","year":"2016","unstructured":"Wang G, Hu FB, Mistry KB, Zhang C, Ren F, Huo Y, et al. Association between maternal prepregnancy body mass index and plasma folate concentrations with child metabolic health. JAMA Pediatr. 2016;170:e160845.","journal-title":"JAMA Pediatr"},{"key":"448_CR4","doi-asserted-by":"publisher","first-page":"112","DOI":"10.4162\/nrp.2011.5.2.112","volume":"5","author":"HW Kim","year":"2011","unstructured":"Kim HW, Choi YJ, Kim KN, Tamura T, Chang N. Effect of paternal folate deficiency on placental folate content and folate receptor alpha expression in rats. Nutr Res Pract. 2011;5:112\u20136.","journal-title":"Nutr Res Pract"},{"key":"448_CR5","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/mnfr.201200558","volume":"57","author":"HW Kim","year":"2013","unstructured":"Kim HW, Kim KN, Choi YJ, Chang N. Effects of paternal folate deficiency on the expression of insulin-like growth factor-2 and global DNA methylation in the fetal brain. Mol Nutr Food Res. 2013;57:671\u20136.","journal-title":"Mol Nutr Food Res"},{"key":"448_CR6","first-page":"1","volume":"737","author":"BG Swayne","year":"2012","unstructured":"Swayne BG, Kawata A, Behan NA, Williams A, Wade MG, Macfarlane AJ, et al. Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb\/c mice. Mutat Res. 2012;737:1\u20137.","journal-title":"Mutat Res"},{"key":"448_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3889","volume":"4","author":"R Lambrot","year":"2013","unstructured":"Lambrot R, Xu C, Saint-Phar S, Chountalos G, Cohen T, Paquet M, et al. Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun. 2013;4:2889.","journal-title":"Nat Commun"},{"key":"448_CR8","first-page":"20191653","volume":"286","author":"S Wu","year":"2019","unstructured":"Wu S, Guo W, Li X, Liu Y, Li Y, Lei X, et al. Paternal chronic folate supplementation induced the transgenerational inheritance of acquired developmental and metabolic changes in chickens. Proc Biol Sci. 2019;286:20191653.","journal-title":"Proc Biol Sci"},{"key":"448_CR9","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1093\/jn\/123.11.1939","volume":"123","author":"PG Reeves","year":"1993","unstructured":"Reeves PG, Nielsen FH, Fahey GC Jr. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr. 1993;123:1939\u201351.","journal-title":"J Nutr"},{"key":"448_CR10","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/BF00280883","volume":"28","author":"DR Matthews","year":"1985","unstructured":"Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412\u20139.","journal-title":"Diabetologia"},{"key":"448_CR11","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s12986-018-0318-3","volume":"15","author":"S Wei","year":"2018","unstructured":"Wei S, Han R, Zhao J, Wang S, Huang M, Wang Y, et al. Intermittent administration of a fasting-mimicking diet intervenes in diabetes progression, restores beta cells and reconstructs gut microbiota in mice. Nutr Metab (Lond). 2018;15:80.","journal-title":"Nutr Metab (Lond)"},{"key":"448_CR12","doi-asserted-by":"publisher","first-page":"2402","DOI":"10.1210\/jcem.85.7.6661","volume":"85","author":"A Katz","year":"2000","unstructured":"Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402\u201310.","journal-title":"J Clin Endocrinol Metab"},{"key":"448_CR13","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.023685","volume":"11","author":"B Xue","year":"2022","unstructured":"Xue B, Yu Y, Beltz TG, Guo F, Wei SG, Johnson AK. Loss of the protective effect of estrogen contributes to maternal gestational hypertension-induced hypertensive response sensitization elicited by postweaning high-fat diet in female offspring. J Am Heart Assoc. 2022;11:e023685.","journal-title":"J Am Heart Assoc"},{"key":"448_CR14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s13287-018-1118-4","volume":"10","author":"C Davegardh","year":"2019","unstructured":"Davegardh C, Hall Wedin E, Broholm C, Henriksen TI, Pedersen M, Pedersen BK, et al. Sex influences DNA methylation and gene expression in human skeletal muscle myoblasts and myotubes. Stem Cell Res Ther. 2019;10:26.","journal-title":"Stem Cell Res Ther"},{"key":"448_CR15","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1002\/ped4.12367","volume":"7","author":"Q Shi","year":"2023","unstructured":"Shi Q, Qi K. Developmental origins of health and disease: impact of paternal nutrition and lifestyle. Pediatr Investig. 2023;7:111\u201331.","journal-title":"Pediatr Investig"},{"key":"448_CR16","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13293-015-0033-y","volume":"6","author":"F Mauvais-Jarvis","year":"2015","unstructured":"Mauvais-Jarvis F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ. 2015;6:14.","journal-title":"Biol Sex Differ"},{"key":"448_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-48120-5","volume":"9","author":"S Paredes","year":"2019","unstructured":"Paredes S, Fonseca L, Ribeiro L, Ramos H, Oliveira JC, Palma I. Novel and traditional lipid profiles in metabolic syndrome reveal a high atherogenicity. Sci Rep. 2019;9:11792.","journal-title":"Sci Rep"},{"key":"448_CR18","doi-asserted-by":"crossref","unstructured":"Yang M, Wang D, Wang X, Mei J, Gong Q. Role of folate in liver diseases. Nutrients. 2024;16:1872.","DOI":"10.3390\/nu16121872"},{"key":"448_CR19","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1002\/biof.1154","volume":"40","author":"RP da Silva","year":"2014","unstructured":"da Silva RP, Kelly KB, Al Rajabi A, Jacobs RL. Novel insights on interactions between folate and lipid metabolism. Biofactors. 2014;40:277\u201383.","journal-title":"Biofactors"},{"key":"448_CR20","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1172\/JCI18581","volume":"112","author":"AM Hennige","year":"2003","unstructured":"Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, et al. Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes. J Clin Investig. 2003;112:1521\u201332.","journal-title":"J Clin Investig"},{"key":"448_CR21","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21:6275.","DOI":"10.3390\/ijms21176275"},{"key":"448_CR22","doi-asserted-by":"crossref","unstructured":"Khalid M, Alkaabi J, Khan MAB, Adem A. Insulin signal transduction perturbations in insulin resistance. Int J Mol Sci. 2021;22:8590.","DOI":"10.3390\/ijms22168590"},{"key":"448_CR23","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/nm.2686","volume":"18","author":"M Lu","year":"2012","unstructured":"Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med. 2012;18:388\u201395.","journal-title":"Nat Med"},{"key":"448_CR24","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1126\/science.292.5522.1728","volume":"292","author":"H Cho","year":"2001","unstructured":"Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001;292:1728\u201331.","journal-title":"Science"},{"key":"448_CR25","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1210\/en.2011-1527","volume":"153","author":"K Zhang","year":"2012","unstructured":"Zhang K, Li L, Qi Y, Zhu X, Gan B, DePinho RA, et al. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice. Endocrinology. 2012;153:631\u201346.","journal-title":"Endocrinology"},{"key":"448_CR26","doi-asserted-by":"publisher","first-page":"6314","DOI":"10.1128\/MCB.00763-08","volume":"28","author":"S Patel","year":"2008","unstructured":"Patel S, Doble BW, MacAulay K, Sinclair EM, Drucker DJ, Woodgett JR. Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol Cell Biol. 2008;28:6314\u201328.","journal-title":"Mol Cell Biol"},{"key":"448_CR27","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.2337\/diabetes.51.10.2903","volume":"51","author":"GW Cline","year":"2002","unstructured":"Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, et al. Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa\/fa) rats. Diabetes. 2002;51:2903\u201310.","journal-title":"Diabetes"},{"key":"448_CR28","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1194\/jlr.M081836","volume":"59","author":"AG Linden","year":"2018","unstructured":"Linden AG, Li S, Choi HY, Fang F, Fukasawa M, Uyeda K, et al. Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. J Lipid Res. 2018;59:475\u201387.","journal-title":"J Lipid Res"},{"key":"448_CR29","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.1074\/jbc.M113.541110","volume":"289","author":"R Ruiz","year":"2014","unstructured":"Ruiz R, Jideonwo V, Ahn M, Surendran S, Tagliabracci VS, Hou Y, et al. Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. J Biol Chem. 2014;289:5510\u20137.","journal-title":"J Biol Chem"},{"key":"448_CR30","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.febslet.2007.07.084","volume":"582","author":"PD Denechaud","year":"2008","unstructured":"Denechaud PD, Dentin R, Girard J, Postic C. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett. 2008;582:68\u201373.","journal-title":"FEBS Lett"},{"key":"448_CR31","doi-asserted-by":"publisher","first-page":"e0151579","DOI":"10.1371\/journal.pone.0151579","volume":"11","author":"JA Sabet","year":"2016","unstructured":"Sabet JA, Park LK, Iyer LK, Tai AK, Koh GY, Pfalzer AC, et al. Paternal B vitamin intake is a determinant of growth, hepatic lipid metabolism and intestinal tumor volume in female Apc1638N mouse offspring. PLoS ONE. 2016;11:e0151579.","journal-title":"PLoS ONE"},{"key":"448_CR32","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1080\/19396368.2021.1954724","volume":"67","author":"Y Zhang","year":"2021","unstructured":"Zhang Y, Yuan H, Peng M, Hu Z, Fan Z, Xu J, et al. Folic acid deficiency damages male reproduction via endoplasmic reticulum stress-associated PERK pathway induced by Caveolin-1 in mice. Syst Biol Reprod Med. 2021;67:383\u201394.","journal-title":"Syst Biol Reprod Med"},{"key":"448_CR33","doi-asserted-by":"publisher","first-page":"6895","DOI":"10.3168\/jds.2021-21754","volume":"105","author":"Z Fang","year":"2022","unstructured":"Fang Z, Gao W, Jiang Q, Loor JJ, Zhao C, Du X, et al. Targeting IRE1alpha and PERK in the endoplasmic reticulum stress pathway attenuates fatty acid-induced insulin resistance in bovine hepatocytes. J Dairy Sci. 2022;105:6895\u2013908.","journal-title":"J Dairy Sci"},{"key":"448_CR34","doi-asserted-by":"publisher","first-page":"782","DOI":"10.3803\/EnM.2023.1738","volume":"38","author":"J Lee","year":"2023","unstructured":"Lee J, Kim MJ, Moon S, Lim JY, Park KS, Jung HS, et al. Partial deletion of perk improved high-fat diet-induced glucose intolerance in mice. Endocrinol Metab (Seoul). 2023;38:782\u20137.","journal-title":"Endocrinol Metab (Seoul)"},{"key":"448_CR35","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.2337\/db15-1637","volume":"65","author":"X Chen","year":"2016","unstructured":"Chen X, Zhang F, Gong Q, Cui A, Zhuo S, Hu Z, et al. Hepatic ATF6 increases fatty acid oxidation to attenuate hepatic steatosis in mice through peroxisome proliferator-activated receptor alpha. Diabetes. 2016;65:1904\u201315.","journal-title":"Diabetes"},{"key":"448_CR36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/hep.24396","volume":"54","author":"A Cinaroglu","year":"2011","unstructured":"Cinaroglu A, Gao C, Imrie D, Sadler KC. Activating transcription factor 6 plays protective and pathological roles in steatosis due to endoplasmic reticulum stress in zebrafish. Hepatology. 2011;54:495\u2013508.","journal-title":"Hepatology"},{"key":"448_CR37","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1093\/molehr\/gax029","volume":"23","author":"L Ly","year":"2017","unstructured":"Ly L, Chan D, Aarabi M, Landry M, Behan NA, MacFarlane AJ, et al. Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation. Mol Hum Reprod. 2017;23:461\u201377.","journal-title":"Mol Hum Reprod"},{"key":"448_CR38","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.molmet.2015.12.002","volume":"5","author":"T de Castro Barbosa","year":"2016","unstructured":"de Castro Barbosa T, Ingerslev LR, Alm PS, Versteyhe S, Massart J, Rasmussen M, et al. High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab. 2016;5:184\u201397.","journal-title":"Mol Metab"},{"key":"448_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46782-y","volume":"15","author":"AJ Crean","year":"2024","unstructured":"Crean AJ, Senior AM, Freire T, Clark TD, Mackay F, Austin G, et al. Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring. Nat Commun. 2024;15:2982.","journal-title":"Nat Commun"},{"key":"448_CR40","unstructured":"Baddam S, Khan KM, Jialal I. Folic Acid Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK535377\/."}],"container-title":["Nutrition & Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00448-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00448-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00448-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:02:19Z","timestamp":1790164939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00448-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["448"],"URL":"https:\/\/doi.org\/10.1038\/s41387-026-00448-4","relation":{},"ISSN":["2044-4052"],"issn-type":[{"value":"2044-4052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]},"assertion":[{"value":"28 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The study was approved by the Institute Animal Ethics Committee, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India (763\/IAEC\/110). All procedures were performed in accordance with the relevant guidelines and regulations for the care and use of laboratory animals. This study did not involve human participants; therefore, informed consent was not applicable.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"38"}}