{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T22:01:13Z","timestamp":1778796073214,"version":"3.51.4"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FP7-HEALTH-DORIAN","award":["278603"],"award-info":[{"award-number":["278603"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Maternal high-fat diet (HFD) affects metabolic and immune development. We aimed to characterize the effects of maternal HFD, and the subsequent diet-normalization of the mothers during a second pregnancy, on the liver and thymus metabolism in their offspring, in minipigs. Offspring born to high-fat (HFD) and normal diet (ND) fed mothers were studied at week 1 and months 1, 6, 12 of life. Liver and thymus glucose uptake (GU) was measured with positron emission tomography during hyperinsulinemic-isoglycemia. Histological analyses were performed to quantify liver steatosis, inflammation, and hepatic hematopoietic niches (HHN), and thymocyte size and density in a subset. The protocol was repeated after maternal-diet-normalization in the HFD group. At one week, HFDoff were characterized by hyperglycemia, hyperinsulinemia, severe insulin resistance (IR), and high liver and thymus GU, associating with thymocyte size and density, with elevated weight-gain, liver IR, and steatosis in the first 6 months of life. Maternal diet normalization reversed thymus and liver hypermetabolism, and increased HHN at one week. It also normalized systemic insulin-sensitivity and liver fat content at all ages. Instead, weight-gain excess, hyperglycemia, and hepatic IR were still observed at 1 month, i.e., end-lactation. We conclude that intra-uterine HFD exposure leads to time-changing metabolic and immune-correlated abnormalities. Maternal diet-normalization reversed most of the effects in the offspring.<\/jats:p>","DOI":"10.3390\/metabo11120800","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T05:42:10Z","timestamp":1638250930000},"page":"800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Maternal High-Fat Feeding Affects the Liver and Thymus Metabolic Axis in the Offspring and Some Effects Are Attenuated by Maternal Diet Normalization in a Minipig Model"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1671-6057","authenticated-orcid":false,"given":"Federica","family":"La Rosa","sequence":"first","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3330-3238","authenticated-orcid":false,"given":"Letizia","family":"Guiducci","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-5088","authenticated-orcid":false,"given":"Maria Angela","family":"Guzzardi","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Cacciato Insilla","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, Division of Pathology, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Burchielli","sequence":"additional","affiliation":[{"name":"Gabriele Monasterio Foundation, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-9152","authenticated-orcid":false,"given":"Maurizia Rossana","family":"Brunetto","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy"},{"name":"Hepatology Unit, Department of Medical Specialties, Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, 56124 Pisa, Italy"},{"name":"Institute of Biostructure and Bioimaging (IBB), National Research Council (CNR), 80145 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9942-0328","authenticated-orcid":false,"given":"Ferruccio","family":"Bonino","sequence":"additional","affiliation":[{"name":"Institute of Biostructure and Bioimaging (IBB), National Research Council (CNR), 80145 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5987-734X","authenticated-orcid":false,"given":"Daniela","family":"Campani","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, Division of Pathology, Pisa University Hospital, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Iozzo","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6184","DOI":"10.3390\/ijms15046184","article-title":"Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease","volume":"15","author":"Jung","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.jcmg.2017.08.024","article-title":"Maternal obesity and cardiac development in the offspring: Study in human neonates and minipigs","volume":"11","author":"Guzzardi","year":"2018","journal-title":"J. Am. Coll. Cardiol. Cardiovasc. Imaging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s00125-015-3848-5","article-title":"Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: Positron emission tomography study in a porcine model","volume":"59","author":"Sanguinetti","year":"2016","journal-title":"Diabetologia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1136\/bmj.311.6998.171","article-title":"A Fetal origins of coronary heart disease","volume":"311","author":"Barker","year":"1995","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.3109\/07853890.2014.919728","article-title":"Long-term consequences of maternal overweight in pregnancy on offspring later health: Findings from the Helsinki birth cohort study","volume":"46","author":"Eriksson","year":"2014","journal-title":"Ann. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1177\/0300985811432344","article-title":"Extramedullary hematopoiesis: A new look at the underlying stem cell niche, theories of development, and occurrence in animals","volume":"49","author":"Johns","year":"2012","journal-title":"Vet. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"587","DOI":"10.3892\/mmr.2015.4621","article-title":"Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review)","volume":"13","author":"Yamamoto","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s11427-018-9313-4","article-title":"Fetal liver: An ideal niche for hematopoietic stem cell expansion","volume":"61","author":"Gao","year":"2018","journal-title":"Sci. China Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1080\/14767058.2017.1297400","article-title":"Four stages of hepatic hematopoiesis in human embryos and fetuses","volume":"31","author":"Fanni","year":"2018","journal-title":"J. Matern.-Fetal Neonatal Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1172\/JCI66027","article-title":"Hepatic stem cell niches","volume":"123","author":"Kordes","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.4049\/jimmunol.158.7.3118","article-title":"Hemopoietic progenitors in the murine fetal liver capable of rapidly generating T cells","volume":"158","author":"Kawamoto","year":"1997","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/aogs.12790","article-title":"Assessment of first-trimester thymus size and correlation with maternal diseases and fetal outcome","volume":"95","author":"Borgelt","year":"2016","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/00007890-198301000-00009","article-title":"T cell progenitors in the mouse fetal liver","volume":"35","author":"Rabinowich","year":"1983","journal-title":"Transplantation"},{"key":"ref_14","first-page":"25","article-title":"Maternal high-fat diet and obesity compromise fetal hematopoiesis","volume":"4","author":"Krasnow","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1600-065X.2010.00911.x","article-title":"The metabolic life and times of a T-cell","volume":"236","author":"Michalek","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1093\/jn\/138.6.1153","article-title":"Increased glucose availability activates chicken thymocyte metabolism and survival","volume":"138","author":"Humphrey","year":"2008","journal-title":"J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s40618-015-0307-6","article-title":"Assessment of human lymphocyte proliferation associated with metabolic syndrome","volume":"38","year":"2015","journal-title":"J. Endocrinol. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R528","DOI":"10.1152\/ajpregu.00316.2007","article-title":"Maternal obesity at conception programs obesity in the offspring","volume":"294","author":"Shankar","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.jnutbio.2010.12.011","article-title":"Maternal high-fat feeding through pregnancy and lactation predisposes mouse offspring to molecular insulin resistance and fatty liver","volume":"23","author":"Ashino","year":"2012","journal-title":"J. Nutr. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"792934","DOI":"10.1155\/2012\/792934","article-title":"Fetal programming of the neuroendocrine-immune system and metabolic disease","volume":"2012","author":"Fisher","year":"2012","journal-title":"J. Pregnancy"},{"key":"ref_21","first-page":"1653","article-title":"Maternal and post-weaning exposure to a high fat diet promotes visceral obesity and hepatic steatosis in adult rats","volume":"32","author":"Couto","year":"2015","journal-title":"Nutr. Hosp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1002\/hep.23205","article-title":"Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression","volume":"50","author":"Bruce","year":"2009","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/jn\/138.2.397","article-title":"The development of porcine models of obesity and the metabolic syndrome","volume":"138","author":"Spurlock","year":"2008","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E449","DOI":"10.1152\/ajpendo.00487.2011","article-title":"Multiparity leads to obesity and inflammation in mothers and obesity in male offspring","volume":"302","author":"Rebholz","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.2337\/dc08-2077","article-title":"Fetuses of obese mothers develop insulin resistance in utero","volume":"32","author":"Catalano","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Li, M., Reynolds, C.M., Sloboda, D.M., Gray, C., and Vickers, M.H. (2013). Effects of taurine supplementation on hepatic markers of inflammation and lipid metabolism in mothers and offspring in the setting of maternal obesity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076961"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1038\/oby.2009.513","article-title":"The influence of a high-fat dietary environment in the fetal period on postnatal metabolic and immune function","volume":"18","author":"Odaka","year":"2010","journal-title":"Obesity"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1159\/000362656","article-title":"Developmental ORIgins of Healthy and Unhealthy AgeiNg: The role of maternal obesity-introduction to DORIAN","volume":"7","author":"Iozzo","year":"2014","journal-title":"Obes. Facts"},{"key":"ref_29","first-page":"421","article-title":"Involution of the mammalian thymus, one of the leading regulators of aging","volume":"11","author":"Bodey","year":"1997","journal-title":"In Vivo"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1098-3597(08)60025-3","article-title":"Obesity, abdominal obesity, and insulin resistance","volume":"9","author":"Westphal","year":"2008","journal-title":"Clin. Cornerstone"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1023\/A:1026336505343","article-title":"Adaptations of Glucose Metabolism during Pregnancy and Lactation","volume":"2","author":"Bell","year":"1997","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1017\/S0007114511003187","article-title":"Pregnancy augments hepatic glucose storage in response to a mixed meal","volume":"107","author":"Moore","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4039","DOI":"10.1210\/en.2010-0098","article-title":"Diet-induced obesity model: Abnormal oocytes and persistent growth abnormalities in the offspring","volume":"51","author":"Jungheim","year":"2010","journal-title":"Endocrinology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12958-019-0482-y","article-title":"Effects of high-fat diets on fetal growth in rodents: A systematic review","volume":"17","author":"Christians","year":"2019","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1136\/bmj.320.7240.967","article-title":"Association between postnatal catch-up growth and obesity in childhood: Prospective cohort study","volume":"320","author":"Ong","year":"2000","journal-title":"BMJ"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1203\/PDR.0b013e3182055ede","article-title":"Obesity in pregnancy: Implications for the mother and lifelong health of the child. A consensus statement","volume":"69","author":"Poston","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_37","first-page":"2066","article-title":"Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart","volume":"24","author":"Wang","year":"2010","journal-title":"Fed. Am. Soc. Exp. Biol. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4611","DOI":"10.1113\/JP276372","article-title":"Maternal obesity has sex-dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring","volume":"596","author":"Bautista","year":"2018","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3109\/07435800.2010.534751","article-title":"A dose-response elevation in hepatic glucose uptake is paralleled by liver triglyceride synthesis and release","volume":"36","author":"Guiducci","year":"2011","journal-title":"Endocr. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1210\/jcem.87.7.8736","article-title":"Hepatic steatosis, insulin resistance, and adipose tissue disorders","volume":"87","author":"Garg","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3727\/105221616X692135","article-title":"Enhanced steatosis and fibrosis in liver of adult offspring exposed to maternal high-fat diet","volume":"17","author":"Thompson","year":"2016","journal-title":"Gene Expr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.acthis.2017.09.003","article-title":"Different combinations of maternal and postnatal diet are reflected in changes of hepatic parenchyma and hepatic TNF-alpha expression in male rat offspring","volume":"119","author":"Belovari","year":"2017","journal-title":"Acta Histochem."},{"key":"ref_43","first-page":"323","article-title":"Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates","volume":"119","author":"McCurdy","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1824564","DOI":"10.1080\/19490976.2020.1824564","article-title":"The early life education of the immune system: Moms, microbes and (missed) opportunities","volume":"12","author":"Jain","year":"2020","journal-title":"Gut Microbes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.1073\/pnas.1205129109","article-title":"Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice","volume":"109","author":"Trottier","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.4049\/jimmunol.172.8.4661","article-title":"Regulation of T lymphocyte metabolism","volume":"172","author":"Frauwirth","year":"2004","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/S1672-0229(08)60009-1","article-title":"Transcriptome and proteome expressions involved in insulin resistance in muscle and activated T-lymphocytes of patients with type 2 diabetes","volume":"5","author":"Stentz","year":"2007","journal-title":"Genom. Proteom. Bioinform."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"156","DOI":"10.2337\/db17-1218","article-title":"Senescent T Cells Predict the Development of Hyperglycemia in Humans","volume":"68","author":"Lee","year":"2019","journal-title":"Diabetes"},{"key":"ref_49","first-page":"711","article-title":"Clarification of a fractional uptake concept","volume":"36","author":"Thie","year":"1995","journal-title":"J. Nucl. Med."},{"key":"ref_50","first-page":"E214","article-title":"Glucose clamp technique: A method for quantifying insulin secretion and resistance","volume":"237","author":"DeFronzo","year":"1979","journal-title":"Am. J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"16502","DOI":"10.1038\/s41598-018-34453-0","article-title":"Maternal High-Fat Diet Programs Offspring Liver Steatosis in a Sexually Dimorphic Manner in Association with Changes in Gut Microbial Ecology in Mice","volume":"8","author":"Wankhade","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s42003-020-01513-z","article-title":"Obese mother offspring have hepatic lipidic modulation that contributes to sex-dependent metabolic adaptation later in life","volume":"4","author":"Savva","year":"2021","journal-title":"Commun. Biol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/12\/800\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:10Z","timestamp":1760168170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/12\/800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["metabo11120800"],"URL":"https:\/\/doi.org\/10.3390\/metabo11120800","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]}}}