{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:18:13Z","timestamp":1792030693292,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["D73C22001670006"],"award-info":[{"award-number":["D73C22001670006"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: In utero exposure to maternal hyperglycemia and obesity can trigger detrimental effects in the newborn through epigenetic programming. We aimed to assess the DNA methylation levels in the promoters of MC4R and LPL genes from maternal blood, placenta, and buccal swab samples collected in children born to mothers with and without obesity and Gestational Diabetes Mellitus (GDM). Methods: A total of 101 Caucasian mother\u2013infant pairs were included in this study. Sociodemographic characteristics, clinical parameters, physical activity, and adherence to the Mediterranean diet were evaluated in the third trimester of pregnancy. Clinical parameters of the newborns were recorded at birth. Results: A negative relationship between MC4R DNA methylation on the fetal side of the GDM placenta and birth weight (r = \u22120.630, p = 0.011) of newborns was found. MC4R DNA methylation level was lower in newborns of GDM women (CpG1: 2.8% \u00b1 3.0%, CpG2: 3.8% \u00b1 3.3%) as compared to those of mothers without GDM (CpG1: 6.9% \u00b1 6.2%, CpG2: 6.8% \u00b1 5.6%; p &lt; 0.001 and p = 0.0033, respectively), and it was negatively correlated with weight (r = \u22120.229; p = 0.035), head circumference (r = \u22120.236; p = 0.030), and length (r = \u22120.240; p = 0.027) at birth. LPL DNA methylation was higher on the fetal side of the placenta in obese patients as compared to normal-weight patients (66.0% \u00b1 14.4% vs. 55.7% \u00b1 15.2%, p = 0.037), and it was associated with maternal total cholesterol (r = 0.770, p = 0.015) and LDL-c (r = 0.783, p = 0.012). Conclusions: These results support the role of maternal MC4R and LPL methylation in fetal programming and in the future metabolic health of children.<\/jats:p>","DOI":"10.3390\/nu16203502","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T04:45:35Z","timestamp":1729485935000},"page":"3502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["From Mother to Child: Epigenetic Signatures of Hyperglycemia and Obesity during Pregnancy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4830-8034","authenticated-orcid":false,"given":"Marica","family":"Franzago","sequence":"first","affiliation":[{"name":"Department of Medicine and Aging, School of Medicine, and Health Sciences, \u201cG. D\u2019Annunzio\u201d University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9389-627X","authenticated-orcid":false,"given":"Paola","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-1931","authenticated-orcid":false,"given":"Marta","family":"Di Nicola","sequence":"additional","affiliation":[{"name":"Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierluigi","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging, School of Medicine, and Health Sciences, \u201cG. D\u2019Annunzio\u201d University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebe","family":"D\u2019Adamo","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, \u201cG. D\u2019Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Di Tizio","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, SS. Annunziata Hospital, \u201cG. D\u2019Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Gazzolo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging, School of Medicine, and Health Sciences, \u201cG. D\u2019Annunzio\u201d University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Neonatal Intensive Care Unit, \u201cG. D\u2019Annunzio\u201d University, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liborio","family":"Stuppia","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1756-661X","authenticated-orcid":false,"given":"Ester","family":"Vitacolonna","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging, School of Medicine, and Health Sciences, \u201cG. D\u2019Annunzio\u201d University, Via dei Vestini, Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. D\u2019Annunzio\u201d University, Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/s41430-023-01333-4","article-title":"Micronutrients in early life and offspring metabolic health programming: A promising target for preventing non-communicable diseases","volume":"77","author":"Maguolo","year":"2023","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kelishadi, R. (2019). Early Life Nutrition and Non Communicable Disease. Primordial Prevention of Non Communicable Disease, Springer.","DOI":"10.1007\/978-3-030-10616-4"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ge, Z.J., Zhang, C.L., Schatten, H., and Sun, Q.Y. (2014). Maternal diabetes mellitus and the origin of non-communicable diseases in offspring: The role of epigenetics. Biol. Reprod., 90.","DOI":"10.1095\/biolreprod.114.118141"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/15592294.2019.1582277","article-title":"Nutrigenetics, epigenetics, and gestational diabetes: Consequences in mother and child","volume":"14","author":"Franzago","year":"2019","journal-title":"Epigenetics"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Franzago, M., Santurbano, D., Vitacolonna, E., and Stuppia, L. (2020). Genes and diet in the prevention of chronic diseases in future generations. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072633"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1159\/000499698","article-title":"Impact of Micronutrient Status during Pregnancy on Early Nutrition Programming","volume":"74","author":"Cetin","year":"2019","journal-title":"Ann. Nutr. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102469","DOI":"10.1016\/j.bpobgyn.2024.102469","article-title":"An overview of diabetes mellitus in pregnant women with obesity","volume":"93","author":"Bashir","year":"2024","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"(2024). Diagnosis and Classification of Diabetes: Standards of Care in Diabetes\u20142024. Diabetes Care., 47, S20\u2013S42.","DOI":"10.2337\/dc24-S002"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Paulo, M.S., Abdo, N.M., Bettencourt-Silva, R., and Al-Rifai, R.H. (2021). Gestational Diabetes Mellitus in Europe: A Systematic Review and Meta-Analysis of Prevalence Studies. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.691033"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.2337\/dc17-2393","article-title":"Gestational Diabetes Mellitus: Does One Size Fit All? A Challenge to Uniform Worldwide Diagnostic Thresholds","volume":"41","author":"McIntyre","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s00592-020-01668-5","article-title":"Fat mass and obesity-associated (FTO) gene epigenetic modifications in gestational diabetes: New insights and possible pathophysiological connections","volume":"58","author":"Franzago","year":"2021","journal-title":"Acta Diabetol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114280","DOI":"10.1016\/j.physbeh.2023.114280","article-title":"Prefrontal cortex melanocortin 4 receptors (MC4R) mediate food intake behavior in male mice","volume":"269","author":"Ross","year":"2023","journal-title":"Physiol. Behav."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R19","DOI":"10.1530\/JOE-12-0157","article-title":"The hypothalamus-adipose axis is a key target of developmental programming by maternal nutritional manipulation","volume":"216","author":"Breton","year":"2013","journal-title":"J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1055\/s-0033-1357182","article-title":"Perinatal nutrition programs the hypothalamic melanocortin system in offspring","volume":"45","author":"Wattez","year":"2013","journal-title":"Horm. Metab. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF03195727","article-title":"High-fat diet leads to a decreased methylation of the Mc4r gene in the obese BFMI and the lean B6 mouse lines","volume":"51","author":"Widiker","year":"2010","journal-title":"J. Appl. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R711","DOI":"10.1152\/ajpregu.00310.2010","article-title":"Maternal obesity and fetal metabolic programming: A fertile epigenetic soil","volume":"299","author":"Heerwagen","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1080\/15592294.2017.1322254","article-title":"Placental lipoprotein lipase DNA methylation alterations are associated with gestational diabetes and body composition at 5 years of age","volume":"12","author":"Houde","year":"2017","journal-title":"Epigenetics"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger, B.E., Gabbe, S.G., Persson, B., Buchanan, T.A., Catalano, P.A., Damm, P., Dyer, A.R., de Leiva, A., and Hod, M. (2010). International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care, 33, 676\u2013682.","DOI":"10.2337\/dc09-1848"},{"key":"ref_19","first-page":"369","article-title":"International physical activity questionnaire: Validation and assessment in an Italian sample","volume":"7","author":"Mannocci","year":"2010","journal-title":"Ital. J. Public Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.3945\/jn.110.135566","article-title":"A short screener is valid for assessing Mediterranean diet adherence among older Spanish men and women","volume":"141","author":"Estruch","year":"2011","journal-title":"J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Gonz\u00e1lez, M.A., Garc\u00eda-Arellano, A., Toledo, E., Salas-Salvad\u00f3, J., Buil-Cosiales, P., Corella, D., Covas, M.I., Schr\u00f6der, H., Ar\u00f3s, F., and G\u00f3mez-Gracia, E. (2012). A 14-item Mediterranean diet assessment tool and obesity indexes among high-risk subjects: The PREDIMED trial. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043134"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1542\/peds.105.5.1141","article-title":"Controversies regarding definition of neonatal hypoglycemia: Suggested operational thresholds","volume":"105","author":"Cornblath","year":"2000","journal-title":"Pediatrics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13072-018-0245-6","article-title":"Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation","volume":"12","author":"Islam","year":"2019","journal-title":"Epigenetics Chromatin"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1161\/CIRCGENETICS.109.913426","article-title":"Associations of lipoprotein lipase gene polymorphisms with longitudinal plasma lipid trends in young adults: The coronary artery risk development in young adults (CARDIA) study","volume":"3","author":"Tang","year":"2010","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1194\/jlr.P007476","article-title":"Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population","volume":"52","author":"Liu","year":"2011","journal-title":"J. Lipid Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s00592-021-01787-7","article-title":"Nutrigenetic variants and response to diet\/lifestyle intervention in obese subjects: A pilot study","volume":"59","author":"Franzago","year":"2022","journal-title":"Acta Diabetol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Franzago, M., Porreca, A., D\u2019ardes, M., Di Nicola, M., Di Tizio, L., Liberati, M., Stuppia, L., and Vitacolonna, E. (2022). The Obesogenic Environment: Epigenetic Modifications in Placental Melanocortin 4 Receptor Gene Connected to Gestational Diabetes and Smoking. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.879526"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lehmann, U., and Tost, J. (2015). PyroMark\u00ae Instruments, Chemistry, and Software for Pyrosequencing\u00ae Analysis. Pyrosequencing. Methods in Molecular Biology, Humana Press.","DOI":"10.1007\/978-1-4939-2715-9"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.placenta.2004.09.009","article-title":"Evaluation of housekeeping genes in placental comparative expression studies","volume":"26","author":"Meller","year":"2005","journal-title":"Placenta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.2217\/epi-2019-0163","article-title":"Epigenetics and human reproduction: The primary prevention of the noncommunicable diseases","volume":"11","author":"Franzago","year":"2019","journal-title":"Epigenomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.2337\/db14-1257","article-title":"Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus","volume":"64","author":"Morgan","year":"2015","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1172\/JCI9238","article-title":"Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity","volume":"106","author":"Vaisse","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cmet.2011.01.010","article-title":"Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis","volume":"13","author":"Rossi","year":"2011","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1146\/annurev.psych.59.103006.093551","article-title":"The brain, appetite, and obesity","volume":"59","author":"Berthoud","year":"2008","journal-title":"Annu. Rev. Psychol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/oby.2011.81","article-title":"Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat","volume":"20","author":"Mul","year":"2012","journal-title":"Obesity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/ijo.2013.80","article-title":"The melanocortin-4 receptor as target for obesity treatment: A systematic review of emerging pharmacological therapeutic options","volume":"38","author":"Fani","year":"2014","journal-title":"Int. J. Obes."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e16424","DOI":"10.1097\/MD.0000000000016424","article-title":"MC4R and HNF4\u03b1 promoter methylation at birth contribute to triglyceride levels in childhood: A prospective cohort study","volume":"98","author":"Kwon","year":"2019","journal-title":"Medicine"},{"key":"ref_38","unstructured":"Wild, R., and Feingold, K.R. (2023). Effect of Pregnancy on Lipid Metabolism and Lipoprotein Levels. Endotext [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK498654\/."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dimasuay, K.G., Boeuf, P., Powell, T.L., and Jansson, T. (2016). Placental Responses to Changes in the Maternal Environment Determine Fetal Growth. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00012"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1093\/nar\/gkt1380","article-title":"Predicting DNA methylation level across human tissues","volume":"42","author":"Ma","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1002\/j.0022-0337.2001.65.12.tb03492.x","article-title":"A revolution in biomedical assessment: The development of salivary diagnostics","volume":"65","author":"Tabak","year":"2001","journal-title":"J. Dent. Educ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1096\/fj.13-238402","article-title":"Global and gene-specific DNA methylation across multiple tissues in early infancy: Implications for children's health research","volume":"28","author":"Armstrong","year":"2014","journal-title":"FASEB J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Parrettini, S., Caroli, A., and Torlone, E. (2020). Nutrition and Metabolic Adaptations in Physiological and Complicated Pregnancy: Focus on Obesity and Gestational Diabetes. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.611929"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12933-023-01774-y","article-title":"Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways","volume":"22","author":"Tejedor","year":"2023","journal-title":"Cardiovasc. Diabetol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/20\/3502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:14:13Z","timestamp":1760112853000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/20\/3502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,16]]},"references-count":44,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["nu16203502"],"URL":"https:\/\/doi.org\/10.3390\/nu16203502","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,16]]}}}