{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:01:43Z","timestamp":1791925303151,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JDRF Kickstart grant"},{"name":"Ramsey Research grant"},{"name":"Future Leader Fellowship Level 1 from the National Heart Foundation of Australia","award":["106628"],"award-info":[{"award-number":["106628"]}]},{"name":"Wellcome Trust Career Re-entry Fellowship","award":["221604\/Z\/20\/Z"],"award-info":[{"award-number":["221604\/Z\/20\/Z"]}]},{"name":"Barts Charity Grant","award":["G-002145"],"award-info":[{"award-number":["G-002145"]}]},{"name":"BHF MRes studentship","award":["FS\/4YPhD\/P\/20\/34016 DA, NP"],"award-info":[{"award-number":["FS\/4YPhD\/P\/20\/34016 DA, NP"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: The placenta stands at the maternal\u2013fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Methods: Pre-pregnancy weight loss in C57BL\/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg\/kg\/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18\u201320 of gestation. Results: 1H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p &lt; 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation. Conclusions: These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity.<\/jats:p>","DOI":"10.3390\/cells14242009","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T10:41:23Z","timestamp":1765968083000},"page":"2009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Liraglutide-Driven Weight Loss Modulates Placental Remodeling in Obese Pregnancies in Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Natassia","family":"Rodrigo","sequence":"first","affiliation":[{"name":"Diabetes and Obesity Research Group, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia"},{"name":"North Precinct, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia"},{"name":"Department of Diabetes and Endocrinology, Nepean Hospital, Sydney, NSW 2747, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8480-6727","authenticated-orcid":false,"given":"Dunja","family":"Aksentijevic","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0672-0810","authenticated-orcid":false,"given":"Nikayla","family":"Patel","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Pollock","sequence":"additional","affiliation":[{"name":"Diabetes and Obesity Research Group, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia"},{"name":"North Precinct, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"McClements","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9317-1348","authenticated-orcid":false,"given":"Sarah J.","family":"Glastras","sequence":"additional","affiliation":[{"name":"Diabetes and Obesity Research Group, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia"},{"name":"North Precinct, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","unstructured":"World Health Organisation (2025, December 13). Obesity and Overweight Fact Sheet Geneva: WHO2018. Available online: http:\/\/www.who.int\/news-room\/fact-sheets\/detail\/obesity-and-overweight."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1093\/qjmed\/hcx152","article-title":"Complications of obesity","volume":"111","author":"Kinlen","year":"2017","journal-title":"QJM Int. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/S2213-8587(16)30217-0","article-title":"Preconceptional and maternal obesity: Epidemiology and health consequences","volume":"4","author":"Poston","year":"2016","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rodrigo, N., Saad, S., Pollock, C., and Glastras, S.J. (2022). Diet Modification before or during Pregnancy on Maternal and Foetal Outcomes in Rodent Models of Maternal Obesity. Nutrients, 14.","DOI":"10.3390\/nu14102154"},{"key":"ref_5","first-page":"170","article-title":"The impact of maternal obesity on maternal and fetal health","volume":"1","author":"Leddy","year":"2008","journal-title":"Rev. Obs. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Heslehurst, N., Vieira, R., Akhter, Z., Bailey, H., Slack, E., Ngongalah, L., Pemu, A., and Rankin, J. (2019). The association between maternal body mass index and child obesity: A systematic review and meta-analysis. PLoS Med., 16.","DOI":"10.1371\/journal.pmed.1002817"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"f4539","DOI":"10.1136\/bmj.f4539","article-title":"Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: Follow-up of 1 323 275 person years","volume":"347","author":"Reynolds","year":"2013","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1007\/s00125-019-4891-4","article-title":"Consequences of being overweight or obese during pregnancy on diabetes in the offspring: A record linkage study in Aberdeen, Scotland","volume":"62","author":"Bhattacharya","year":"2019","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Brunton, N., Dufault, B., Dart, A., Azad, M.B., and McGavock, J.M. (2020). Maternal obesity before pregnancy predicts offspring blood pressure at 18 years of age: A causal mediation analysis. medRxiv.","DOI":"10.1101\/2020.11.22.20236398"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1530\/JOE-21-0399","article-title":"Preconception weight loss improves fertility and maternal outcomes in obese mice","volume":"253","author":"Rodrigo","year":"2022","journal-title":"J. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1055\/s-0031-1275515","article-title":"Placental dysfunction and fetal programming: The importance of placental size, shape, histopathology, and molecular composition","volume":"29","author":"Longtine","year":"2011","journal-title":"Semin. Reprod. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1055\/s-0035-1570027","article-title":"Obesity and Placental Function","volume":"34","author":"Myatt","year":"2016","journal-title":"Semin. Reprod. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Glastras, S.J., Chen, H., Teh, R., McGrath, R.T., Chen, J., Pollock, C.A., Wong, M.G., and Saad, S. (2016). Mouse Models of Diabetes, Obesity and Related Kidney Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162131"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1111\/bph.15193","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"177","author":"Hurst","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1758-5996-6-3","article-title":"Liraglutide counteracts obesity and glucose intolerance in a mouse model of glucocorticoid-induced metabolic syndrome","volume":"6","author":"Fransson","year":"2014","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.bbalip.2011.09.017","article-title":"Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?","volume":"1821","author":"Semenkovich","year":"2012","journal-title":"Biochim. Biophys Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1023\/B:PHAM.0000041444.06122.8d","article-title":"Peroxisome proliferator-activated receptor (PPAR)-alpha: A pharmacological target with a promising future","volume":"21","author":"Li","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1152\/advan.00052.2006","article-title":"PGC-1alpha: A key regulator of energy metabolism","volume":"30","author":"Liang","year":"2006","journal-title":"Adv. Physiol. Educ."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Aouache, R., Biquard, L., Vaiman, D., and Miralles, F. (2018). Oxidative Stress in Preeclampsia and Placental Diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051496"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kretschmer, T., Schulze-Edinghausen, M., Turnwald, E.M., Janoschek, R., Bae-Gartz, I., Zentis, P., Handwerk, M., Wohlfarth, M., Schauss, A., and Hucklenbruch-Rother, E. (2020). Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis. Nutrients, 12.","DOI":"10.3390\/nu12020296"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1038\/s41467-024-46470-x","article-title":"Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles","volume":"15","author":"Faulkes","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1038\/s41598-022-05120-2","article-title":"Impact of reduced uterine perfusion pressure model of preeclampsia on metabolism of placenta, maternal and fetal hearts","volume":"12","author":"McClements","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E1323","DOI":"10.1152\/ajpendo.90617.2008","article-title":"Evaluating the glucose tolerance test in mice","volume":"295","author":"Andrikopoulos","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"266","DOI":"10.18097\/PBMC20176303266","article-title":"Impairments of placental amino acid metabolism in fetal growth restriction","volume":"63","author":"Pogorelova","year":"2017","journal-title":"Biomed. Khim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1210\/en.2017-00152","article-title":"Effect of Maternal Obesity on Placental Lipid Metabolism","volume":"158","author":"Haghiac","year":"2017","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.1113\/JP278226","article-title":"Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction","volume":"597","author":"McIntyre","year":"2019","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102475","DOI":"10.1016\/j.eclinm.2024.102475","article-title":"Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: A post-treatment analysis of a randomised placebo-controlled trial","volume":"69","author":"Jensen","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1111\/aogs.14450","article-title":"Risk of gestational diabetes mellitus in relation to early pregnancy and gestational weight gain before diagnosis: A population-based cohort study","volume":"101","author":"Xu","year":"2022","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/dme.13523","article-title":"Risk of pre-eclampsia in women taking metformin: A systematic review and meta-analysis","volume":"35","author":"Alqudah","year":"2018","journal-title":"Diabet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1042\/CS20190266","article-title":"Placental function in maternal obesity","volume":"134","author":"Kelly","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1203\/00006450-199810000-00011","article-title":"Placental Transport of Leucine and Lysine Is Reduced in Intrauterine Growth Restriction","volume":"44","author":"Jansson","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"972562","DOI":"10.1155\/2012\/972562","article-title":"Placental Amino Acids Transport in Intrauterine Growth Restriction","volume":"2012","author":"Avagliano","year":"2012","journal-title":"J. Pregnancy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2585S","DOI":"10.1093\/jn\/131.9.2585S","article-title":"Glutamine in the Fetus and Critically Ill Low Birth Weight Neonate: Metabolism and Mechanism of Action","volume":"131","author":"Neu","year":"2001","journal-title":"J. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1203\/00006450-199609000-00200","article-title":"Is glutamine a conditionally essential amino acid during pregnancy? 177","volume":"40","author":"Neu","year":"1996","journal-title":"Pediatr. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lindsay, K.L., Hellmuth, C., Uhl, O., Buss, C., Wadhwa, P.D., Koletzko, B., and Entringer, S. (2016). Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145794"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1242901","DOI":"10.1155\/2018\/1242901","article-title":"Pregnancy Ketonemia and Development of the Fetal Central Nervous System","volume":"2018","author":"Bronisz","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0248-4900(05)80176-5","article-title":"Positive regulation of the peroxisomal beta-oxidation pathway by fatty acids through activation of peroxisome proliferator-activated receptors (PPAR)","volume":"77","author":"Dreyer","year":"1993","journal-title":"Biol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.21006","article-title":"Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob\/ob mice","volume":"43","author":"Ding","year":"2006","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bbrc.2015.08.092","article-title":"GLP-1 contributes to increases in PGC-1\u03b1 expression by downregulating miR-23a to reduce apoptosis","volume":"466","author":"Wang","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.placenta.2017.06.001","article-title":"Effects of maternal diabetes and fetal sex on human placenta mitochondrial biogenesis","volume":"57","author":"Jiang","year":"2017","journal-title":"Placenta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jri.2012.05.004","article-title":"Interleukin-6 in pregnancy and gestational disorders","volume":"95","author":"Prins","year":"2012","journal-title":"J. Reprod. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e14811","DOI":"10.14814\/phy2.14811","article-title":"Maternal exposure to high-fat diet during pregnancy and lactation predisposes normal weight offspring mice to develop hepatic inflammation and insulin resistance","volume":"9","author":"Saengnipanthkul","year":"2021","journal-title":"Physiol. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Esca\u00f1uela S\u00e1nchez, T., Meaney, S., O\u2019Connor, C., Linehan, L., O\u2019Donoghue, K., Byrne, M., and Matvienko-Sikar, K. (2022). Facilitators and barriers influencing weight management behaviours during pregnancy: A meta-synthesis of qualitative research. BMC Pregnancy Childbirth, 22.","DOI":"10.1186\/s12884-022-04929-z"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.ajog.2015.08.030","article-title":"The placenta is the center of the chronic disease universe","volume":"213","author":"Thornburg","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s11154-014-9289-5","article-title":"Effects of GLP-1 on appetite and weight","volume":"15","author":"Shah","year":"2014","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1053\/plac.2001.0648","article-title":"Key regulatory transcription factors involved in placental trophoblast development--a review","volume":"22","author":"Vasicek","year":"2001","journal-title":"Placenta"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41576-019-0169-4","article-title":"Mechanisms of early placental development in mouse and humans","volume":"21","author":"Hemberger","year":"2020","journal-title":"Nat. Rev. Genet."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/2009\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T10:52:17Z","timestamp":1765968737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/2009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":48,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14242009"],"URL":"https:\/\/doi.org\/10.3390\/cells14242009","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]}}}