{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:49:19Z","timestamp":1790815759549,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T00:00:00Z","timestamp":1745625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Heart Association, Ohio Valley Affiliate","award":["0525318B"],"award-info":[{"award-number":["0525318B"]}]},{"name":"Regina Drury\/Children\u2019s Miracle Network Endowment Fund","award":["0525318B"],"award-info":[{"award-number":["0525318B"]}]},{"name":"University of Kentucky College of Medicine","award":["0525318B"],"award-info":[{"award-number":["0525318B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: The long-term effects of a perinatal high-fat diet on the cardiovascular function of offspring are not well elucidated. We hypothesize that perinatal exposure to a high-fat diet alters adult cardiovascular and immune responses in a sex-specific manner. Methods: Male and female offspring were born to perinatal high-fat (pHFD) or control diet (pCD)-fed C57BL\/6 mothers and weaned to a control diet. Cardiovascular function (baseline and response to an acute isoproterenol stress test) was quantified at 8 weeks of age, and acute blood inflammatory response to a single low dose of lipopolysaccharide at 9 weeks of age. Results: Male pHFD offspring had identical baseline cardiovascular function compared to pCD mice but a blunted response to isoproterenol (20\u201345% reductions in cardiac output, stroke volume, and left ventricular fractional shortening). In contrast, baseline cardiovascular parameters were reduced in female pHFD compared to pCD offspring, but there was no effect of perinatal diet on response to isoproterenol. Concentrations of TNF-\u03b1 and IL-6 in plasma two hours after a low-dose LPS administration were highest in female pCD mice. Conclusions: Perinatal high-fat diet exposure resulted in sex-specific adaptations in cardiovascular function and immune response. Female offspring displayed baseline impairments, whereas male offspring showed latent vulnerability under stress. These differences may reflect underlying hormonal or epigenetic mechanisms that diverge by sex. Future studies should examine the roles of sex hormones and gene regulation pathways to better understand these dimorphic outcomes. These findings emphasize the importance of maternal diet in shaping offspring cardiometabolic risks and highlight potential avenues for nutritional interventions during pregnancy.<\/jats:p>","DOI":"10.3390\/nu17091464","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:21:31Z","timestamp":1745817691000},"page":"1464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Maternal Nutritional Programming: Sex-Specific Cardiovascular and Immune Outcomes Following Perinatal High-Fat Diet Exposure"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5809-7909","authenticated-orcid":false,"given":"Yasir","family":"Alsiraj","sequence":"first","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"},{"name":"Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9972-7677","authenticated-orcid":false,"given":"Robin","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Schanbacher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Giannone","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"},{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Kentucky, 138 Leader Ave, Lexington, KY 40536-0200, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart Disease and Stroke Statistics: A Report of US and Global Data from the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2022060641","DOI":"10.1542\/peds.2022-060641","article-title":"Executive Summary: Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents with Obesity","volume":"151","author":"Hampl","year":"2023","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/s41569-023-00869-z","article-title":"Maternal cardiovascular disorders before and during pregnancy and offspring cardiovascular risk across the life course","volume":"20","author":"Gaillard","year":"2023","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/emph\/eoae002","article-title":"Reconsidering the developmental origins of adult disease paradigm: The \u2018metabolic coordination of childbirth\u2019 hypothesis","volume":"12","author":"Wells","year":"2024","journal-title":"Evol. Med. Public Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1136\/bmj.301.6761.1111","article-title":"The fetal and infant origins of adult disease","volume":"301","author":"Barker","year":"1990","journal-title":"BMJ"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/bmj.311.6998.171","article-title":"Fetal origins of coronary heart disease","volume":"311","author":"Barker","year":"1995","journal-title":"BMJ"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.tem.2024.02.002","article-title":"Placental inflammation, oxidative stress, and fetal outcomes in maternal obesity","volume":"35","author":"Zhang","year":"2024","journal-title":"Trends. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1344S","DOI":"10.1093\/ajcn\/71.5.1344s","article-title":"Fetal nutrition and adult disease","volume":"71","author":"Godfrey","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1159\/000113169","article-title":"The role of growth in heart development","volume":"61","author":"Thornburg","year":"2008","journal-title":"Nestle Nutr. Workshop Ser. Pediatr. Program"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.1210\/en.2014-1383","article-title":"Maternal Diet-induced Obesity Programs Cardiovascular Dysfunction in Adult Male Mouse Offspring Independent of Current Body Weight","volume":"155","author":"Blackmore","year":"2014","journal-title":"Endocrinology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chinas Merlin, A., Gonzalez, K., Mockler, S., Perez, Y., Jia, U.-T.A., Chicco, A.J., Ullevig, S.L., and Chung, E. (2022). Switching to a Standard Chow Diet at Weaning Improves the Effects of Maternal and Postnatal High-Fat and High-Sucrose Diet on Cardiometabolic Health in Adult Male Mouse Offspring. Metabolites, 12.","DOI":"10.3390\/metabo12060563"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"den Harink, T., Roelofs, M.J.M., Limpens, J., Painter, R.C., Roseboom, T.J., and van Deutekom, A.W. (2022). Maternal obesity in pregnancy and children\u2019s cardiac function and structure: A systematic review and meta-analysis of evidence from human studies. PLOS ONE, 17.","DOI":"10.1371\/journal.pone.0275236"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1038\/s41366-022-01210-3","article-title":"Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year olds: Children of the UPBEAT RCT","volume":"46","author":"Taylor","year":"2022","journal-title":"Int. J. Obes."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1093\/aje\/kws224","article-title":"Prevalence, prospective risk markers, and prognosis associated with the presence of left ventricular diastolic dysfunction in young adults: The coronary artery risk de-velopment in young adults study","volume":"177","author":"Desai","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S2213-8587(20)30151-0","article-title":"Maternal obesity and risk of cardiovascular diseases in offspring: A population-based cohort and sibling-controlled study","volume":"8","author":"Razaz","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1210\/en.2015-1227","article-title":"Sex-Specific Placental Responses in Fetal Development","volume":"156","author":"Rosenfeld","year":"2015","journal-title":"Endocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gilardini, L., Croci, M., Cavaggioni, L., Pasqualinotto, L., and Bertoli, S. (2024). Sex differences in cardiometabolic risk factors and in response to lifestyle intervention in prepubertal and pubertal subjects with obesity. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1304451"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jsha.2011.09.002","article-title":"Gender differences in cardiovascular risk factors among adolescents in Aseer Region, southwestern Saudi Arabia","volume":"24","author":"Mahfouz","year":"2012","journal-title":"J. Saudi Hear. Assoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1161\/CIRCULATIONAHA.106.624536","article-title":"Emergence of sex differences in prevalence of high systolic blood pressure: Analysis of a longitudinal adolescent cohort","volume":"114","author":"Dasgupta","year":"2006","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1113\/JP282462","article-title":"Maternal obesity causes fetal cardiac hypertrophy and alters adult offspring myocardial metabolism in mice","volume":"600","author":"Vaughan","year":"2022","journal-title":"J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1476-9255-4-22","article-title":"Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet","volume":"4","author":"Huang","year":"2007","journal-title":"J. Inflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0166-0934(91)90173-W","article-title":"Animal serum factor(s) causing adverse effects on RIAs of human enterovirus IgM","volume":"31","author":"Frisk","year":"1991","journal-title":"J. Virol. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0894-7317(14)80116-8","article-title":"Automated Assessment of Ventricular Volume and Function by Echocardiography: Validation of Automated Border Detection","volume":"7","author":"Morrissey","year":"1994","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/S0024-3205(01)01141-9","article-title":"Diabetes related cardiomyopathy Time dependent echocardiographic evaluation in an experimental rat model","volume":"69","author":"Mihm","year":"2001","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H829","DOI":"10.1152\/ajpheart.00222.2009","article-title":"Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy","volume":"297","author":"Han","year":"2009","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/0002-8703(74)90415-3","article-title":"Evaluation of isoproterenol as a method of stress testing","volume":"87","author":"Combs","year":"1974","journal-title":"Am. Hear. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0024-3205(01)01123-7","article-title":"Non-invasive echocardiographic studies in mice: Influence of anesthetic regimen","volume":"69","author":"Chaves","year":"2001","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1007\/s00404-023-07349-2","article-title":"Maternal and long-term offspring outcomes of obesity during pregnancy","volume":"309","author":"Alves","year":"2024","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.lfs.2019.04.018","article-title":"Postnatal early overfeeding induces cardiovascular dysfunction by oxidative stress in adult male Wistar rats","volume":"226","author":"Junior","year":"2019","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1017\/S2040174420000513","article-title":"Long-term effects of early overfeeding and food restriction during puberty on cardiac remodeling in adult rats","volume":"11","author":"Rosa","year":"2020","journal-title":"J. Dev. Orig. Health Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"H485","DOI":"10.1152\/ajpheart.00176.2021","article-title":"Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency, and diastolic function early in life","volume":"321","author":"Omoto","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1017\/jns.2020.21","article-title":"Overweight during lactation and its implications for biometric, nutritional and cardiovascular parameters of young and adult male and female rats","volume":"9","author":"Farias","year":"2020","journal-title":"J. Nutr. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ferreira, L.A., Ferreira-Junior, M.D., Amaral, K.d.J.V., Cavalcante, K.V.N., Pontes, C.N.R., Cristin, L., Ribeiro, L.C.d.S., dos Santos, B.G., Xavier, C.H., and Mathias, P.C.d.F. (2022). Maternal postnatal early overfeeding induces sex-related cardiac dysfunction and alters sexually hormones levels in young offspring. J. Nutr. Biochem., 103.","DOI":"10.1016\/j.jnutbio.2022.108969"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, W., Huo, Y., Zhang, J., Xu, D., Bai, F., and Gui, Y. (2022). Association between High-Fat Diet during Pregnancy and Heart Weight of the Offspring: A Multivariate and Mediation Analysis. Nutrients, 14.","DOI":"10.3390\/nu14204237"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrcardio.2017.65","article-title":"Epidemiology of heart failure with preserved ejection fraction","volume":"14","author":"Dunlay","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/ejhf.67","article-title":"Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction","volume":"16","author":"Gori","year":"2014","journal-title":"Eur. J. Hear. Fail."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"889","DOI":"10.2174\/1566524023666230605142119","article-title":"Maternal High Fat Diet and its Expressions in the Heart and Liver in the Mice Embryogenesis","volume":"24","author":"Nirala","year":"2024","journal-title":"Curr. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Preston, C.C., Larsen, T.D., Eclov, J.A., Louwagie, E.J., Gandy, T.C.T., Faustino, R.S., and Baack, M.L. (2020). Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.570846"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4161\/viru.26982","article-title":"Gender differences in sepsis: Cardiovascular and immunological aspects","volume":"5","author":"Angele","year":"2014","journal-title":"Virulence"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155934","DOI":"10.1016\/j.metabol.2024.155934","article-title":"Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPAR\u03b4\/NLRP3 signaling","volume":"156","author":"Adekunle","year":"2024","journal-title":"Metabolism"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1124\/jpet.119.264192","article-title":"Pre-eclamptic Fetal Programming Alters Neuroinflammatory and Cardiovascular Consequences of Endotoxemia in Sex-Specific Manners","volume":"373","author":"Abuiessa","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Xerri, A., Gallardo, F., Kober, F., Mathieu, C., Fourny, N., Tran, T.T., Mege, J.-L., Singer, M., Lalev\u00e9e, N., and Bernard, M. (2022). Female hormones prevent sepsis-induced cardiac dysfunction: An experimental randomized study. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-08889-4"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110631","DOI":"10.1016\/j.isci.2024.110631","article-title":"Maternal high-fat diet alters Tet-mediated epigenetic regulation during heart development","volume":"27","author":"Yang","year":"2024","journal-title":"iScience"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1161\/CIRCULATIONAHA.116.023789","article-title":"Female Mice with an XY Sex Chromosome Complement Develop Severe Angiotensin II\u2013Induced Abdominal Aortic Aneurysms","volume":"135","author":"Alsiraj","year":"2017","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1038\/s41467-019-10462-z","article-title":"XX sex chromosome complement promotes atherosclerosis in mice","volume":"10","author":"AlSiraj","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/s44161-025-00622-4","article-title":"Maternal high-fat diet exacerbates atherosclerosis development in offspring through epigenetic memory","volume":"4","author":"Li","year":"2025","journal-title":"Nat. Cardiovasc. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1464\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:13Z","timestamp":1760030533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1464"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,26]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091464"],"URL":"https:\/\/doi.org\/10.3390\/nu17091464","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,26]]}}}