{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T03:17:42Z","timestamp":1779333462136,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health grants","award":["HD094952"],"award-info":[{"award-number":["HD094952"]}]},{"name":"National Institutes of Health grants","award":["HD093701"],"award-info":[{"award-number":["HD093701"]}]},{"name":"National Institutes of Health grants","award":["HD111557"],"award-info":[{"award-number":["HD111557"]}]},{"name":"National Institutes of Health grants","award":["2021-67034-34969"],"award-info":[{"award-number":["2021-67034-34969"]}]},{"DOI":"10.13039\/100000199","name":"United States Department of Agriculture","doi-asserted-by":"publisher","award":["HD094952"],"award-info":[{"award-number":["HD094952"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"United States Department of Agriculture","doi-asserted-by":"publisher","award":["HD093701"],"award-info":[{"award-number":["HD093701"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"United States Department of Agriculture","doi-asserted-by":"publisher","award":["HD111557"],"award-info":[{"award-number":["HD111557"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"United States Department of Agriculture","doi-asserted-by":"publisher","award":["2021-67034-34969"],"award-info":[{"award-number":["2021-67034-34969"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to \u03b2 cell activity.<\/jats:p>","DOI":"10.3390\/ijms25094780","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T08:02:22Z","timestamp":1714723342000},"page":"4780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9303-3607","authenticated-orcid":false,"given":"Victoria C.","family":"Kennedy","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cameron S.","family":"Lynch","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia R.","family":"Tanner","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"},{"name":"University of Colorado School of Medicine, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quinton A.","family":"Winger","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9741-2105","authenticated-orcid":false,"given":"Ahmed","family":"Gad","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul J.","family":"Rozance","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-626X","authenticated-orcid":false,"given":"Russell V.","family":"Anthony","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1053\/j.semperi.2008.02.007","article-title":"Nutrient transport across the intrauterine growth-restricted placenta","volume":"32","author":"Marconi","year":"2008","journal-title":"Semin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1210\/en.2005-0900","article-title":"Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction","volume":"147","author":"Limesand","year":"2006","journal-title":"Endocrinology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E1716","DOI":"10.1152\/ajpendo.00459.2007","article-title":"Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction","volume":"293","author":"Limesand","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tanner, A.R., Lynch, C.S., Kennedy, V.C., Ali, A., Winger, Q.A., Rozance, P.J., and Anthony, R.V. (2021). CSH RNA interference reduces global nutrient uptake and umbilical blood flow resulting in intrauterine growth restriction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158150"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.placenta.2004.09.013","article-title":"Localisation of glucose transport in the ruminant placenta: Implications for sequential use of transporter isoforms","volume":"26","author":"Wooding","year":"2005","journal-title":"Placenta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1113\/jphysiol.2002.026831","article-title":"Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction","volume":"547","author":"Limesand","year":"2003","journal-title":"J. Physiol."},{"key":"ref_7","first-page":"321","article-title":"Placental-fetal glucose exchange and fetal glucose metabolism","volume":"117","author":"Hay","year":"2006","journal-title":"Trans. Am. Clin. Climatol. Assoc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"702","DOI":"10.2337\/diabetes.54.3.702","article-title":"Beta-cell secretory dysfunction in the pathogenesis of low birth weight associated diabetes: A murine model","volume":"54","author":"Reamer","year":"2005","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/j.1471-0528.1977.tb12486.x","article-title":"The endocrine pancreas in small-for-dates infants","volume":"84","author":"Aerts","year":"1977","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lynch, C.S., Kennedy, V.C., Tanner, A.R., Ali, A., Winger, Q.A., Rozance, P.J., and Anthony, R.V. (2022). Impact of placental SLC2A3 deficiency during the first-half of gestation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012530"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0002-9378(89)90453-5","article-title":"Blood glucose and oxygen tension levels in small-for-gestational-age fetuses","volume":"160","author":"Economides","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1530\/JOE-17-0076","article-title":"The impact of IUGR on pancreatic islet development and \u03b2-cell function","volume":"235","author":"Boehmer","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/19382014.2015.1075687","article-title":"Transcription factor regulation of pancreatic organogenesis, differentiation and maturation","volume":"8","author":"Dassaye","year":"2016","journal-title":"Islets"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ydbio.2008.10.024","article-title":"Developmental biology of the pancreas: A comprehensive review","volume":"326","author":"Gittes","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1242\/dev.127.22.4905","article-title":"Regulation of pancreas development by hedgehog signaling","volume":"127","author":"Hebrok","year":"2000","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R867","DOI":"10.1152\/ajpregu.00072.2018","article-title":"Fetal undernutrition, placental insufficiency, and pancreatic \u03b2-cell development programming in utero","volume":"315","author":"Mohan","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-cellbio-101512-122405","article-title":"Pancreas organogenesis: From lineage determination to morphogenesis","volume":"29","author":"Shih","year":"2019","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1126\/science.1089769","article-title":"Control of pancreas and liver gene expression by HNF transcription factors","volume":"303","author":"Odom","year":"2004","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1101\/gad.8.20.2466","article-title":"Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos","volume":"8","author":"Chen","year":"1994","journal-title":"Genes Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1159\/000109603","article-title":"Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth","volume":"12","author":"Maestro","year":"2007","journal-title":"Endocr. Dev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Peterson, M., Gauvin, M., Pillai, S., Jones, A., McFadden, K., Cameron, K., Reed, S., Zinn, S., and Govoni, K. (2021). Maternal under- and over-nutrition during gestation causes islet hypertrophy and sex-specific changes to pancreas DNA methylation in fetal sheep. Animals, 11.","DOI":"10.3390\/ani11092531"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/cphy.c180014","article-title":"Cholecystokinin (CCK) regulation of pancreatic acinar cells: Physiological actions and signal transduction mechanisms","volume":"9","author":"Williams","year":"2019","journal-title":"Compr. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1677\/joe.0.1690233","article-title":"Cholecystokinin expression in the developing and regenerating pancreas and intestine","volume":"169","author":"Liu","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.2337\/diabetes.48.10.2015","article-title":"Evidence for a functional role of the cholecystokinin-B\/gastrin receptor in the human fetal and adult pancreas","volume":"48","author":"Dufresne","year":"1999","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115653","DOI":"10.1016\/j.taap.2021.115653","article-title":"Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio","volume":"426","author":"Venezia","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4105","DOI":"10.1172\/JCI42127","article-title":"PPAR\u03b2\/\u03b4 affects pancreatic \u03b2 cell mass and insulin secretion in mice","volume":"122","author":"Iglesias","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"956277","DOI":"10.3389\/fendo.2022.956277","article-title":"Free fatty acid receptors in the endocrine regulation of glucose metabolism: Insight from gastrointestinal-pancreatic adipose interactions","volume":"13","author":"Zhao","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12986-016-0119-5","article-title":"Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms","volume":"13","author":"Cen","year":"2016","journal-title":"Nutr. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Je\u017eek, P., Jab\u016frek, M., Holendov\u00e1, B., and Plecit\u00e1-Hlavat\u00e1, L. (2018). Fatty acid-stimulated insulin secretion vs. lipotoxicity. Molecules, 23.","DOI":"10.3390\/molecules23061483"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcp.10187","article-title":"Pleiotropic effects of fatty acids on pancreatic beta-cells","volume":"194","author":"Haber","year":"2002","journal-title":"J Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105269","DOI":"10.1016\/j.chemphyslip.2022.105269","article-title":"Fatty acid transport proteins (FATPs) in cancer","volume":"250","author":"Acharya","year":"2023","journal-title":"Chem. Phys. Lipids"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1113\/jphysiol.2010.200741","article-title":"A dual action of saturated fatty acids on electrical activity in rat pancreatic \u03b2-cells. Role of volume-regulated anion channel and KATP channel currents","volume":"589","author":"Best","year":"2011","journal-title":"J. Physiol."},{"key":"ref_33","first-page":"24","article-title":"Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect\u2014A narrative review","volume":"65","author":"Chueire","year":"2021","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wu, N., Wen, H., Xu, P., Chen, J., Xue, M., Li, J., Wang, M., Song, C., and Li, H. (2023). PPAR signaling maintains metabolic homeostasis under hypothermia in freshwater drum (Aplodinotus grunniens). Metabolites, 13.","DOI":"10.3390\/metabo13010102"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8413","DOI":"10.1074\/jbc.M114.554915","article-title":"A critical role for the neural zinc factor ST18 in pancreatic \u03b2-cell apoptosis","volume":"289","author":"Henry","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.mce.2015.12.016","article-title":"Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production","volume":"435","author":"Wesolowski","year":"2016","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101043","DOI":"10.1016\/j.molmet.2020.101043","article-title":"G6PC2 confers protection against hypoglycemia upon ketogenic diet feeding and prolonged fasting","volume":"41","author":"Bosma","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rahim, M., Nakhe, A.Y., Banerjee, D.R., Overway, E.M., Bosma, K.J., Rosch, J.C., Oeser, J.K., Wang, B., Lippmann, E.S., and Jacobson, D.A. (2022). Glucose-6-phosphatase catalytic subunit 2 negatively regulates glucose oxidation and insulin secretion in pancreatic \u03b2-cells. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101729"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"R837","DOI":"10.1152\/ajpregu.00311.2015","article-title":"Development of ovine chorionic somato-mammotropin hormone-deficient pregnancies","volume":"310","author":"Baker","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_40","unstructured":"National Research Council (2007). Nutrient Requirements of Small Ruminants: Sheep, Goats, Cervids, and New World Camelids, The National Academies Press."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T. (2012). Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/JOE-18-0093","article-title":"Chorionic somatomammotropin impacts early fetal growth and placental gene expression","volume":"237","author":"Jeckel","year":"2018","journal-title":"J. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Robinson, M.D., and Oshlack, A. (2010). A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol., 11.","DOI":"10.1186\/gb-2010-11-3-r25"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/nar\/27.1.29","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"27","author":"Ogata","year":"1999","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:34:35Z","timestamp":1760106875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,27]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094780"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094780","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,27]]}}}