{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:43:43Z","timestamp":1771339423819,"version":"3.50.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["2019-67015-29448"],"award-info":[{"award-number":["2019-67015-29448"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["2020-67015-30825"],"award-info":[{"award-number":["2020-67015-30825"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1P20GM104320"],"award-info":[{"award-number":["1P20GM104320"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nebraska Agricultural Experiment Station","award":["NIH 1P20GM104320"],"award-info":[{"award-number":["NIH 1P20GM104320"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Intrauterine stress impairs growth and metabolism in the fetus and offspring. We recently found that sustained maternofetal inflammation resulted in intrauterine growth-restricted (MI-IUGR) fetuses with asymmetric body composition, impaired muscle glucose metabolism, and \u03b2-cell dysfunction near term. These fetuses also exhibited heightened inflammatory tone, which we postulated was a fetal programming mechanism for the IUGR phenotype. Thus, the objective of this study was to determine whether poor growth and metabolism persisted in MI-IUGR lambs after birth. Polypay ewes received serial lipopolysaccharide or saline injections in the first 2 wk of the third trimester of pregnancy to produce MI-IUGR (n = 13) and control (n = 12) lambs, respectively. Lambs were catheterized at 25 d of age. \u03b2-Cell function was assessed at 29 d, hindlimb glucose metabolism at 30 d, and daily blood parameters from day 26 to 31. Glucose metabolism was also assessed in flexor digitorum superficialis (FDS) muscle isolated at necropsy on day 31. Asymmetric body composition persisted in MI-IUGR neonates, as these lambs were lighter (P &amp;lt; 0.05) than controls at birth and 31 d, but body and cannon bone lengths did not differ at either age. FDS muscles from MI-IUGR lambs were smaller (P &amp;lt; 0.05) and exhibited reduced (P &amp;lt; 0.05) glucose oxidation and Akt phosphorylation but similar glucose uptake compared with controls when incubated in basal or insulin-spiked media. Similarly, hindlimb glucose oxidation was reduced (P &amp;lt; 0.05) in MI-IUGR lambs under basal and hyperinsulinemic conditions, but hindlimb glucose utilization did not differ from controls. Circulating urea nitrogen and cholesterol were reduced (P &amp;lt; 0.05), and triglycerides, high-density lipoprotein cholesterol, and glucose-to-insulin ratios were increased (P &amp;lt; 0.05) in MI-IUGR lambs. Glucose and insulin concentrations did not differ between groups during basal or hyperglycemic conditions. Although circulating monocyte and granulocyte concentrations were greater (P &amp;lt; 0.05) in MI-IUGR lambs, plasma tumor necrosis factor \u03b1 (TNF\u03b1) was reduced (P &amp;lt; 0.05). FDS muscle contained greater (P &amp;lt; 0.05) TNF receptor 1 (TNFR1) and I\u03baB\u03b1 protein content. These findings indicate that maternofetal inflammation in late pregnancy results in fetal programming that impairs growth capacity, muscle glucose oxidation, and lipid homeostasis in offspring. Inflammatory indicators measured in this study appear to reflect heightened cytokine sensitivity in muscle and compensatory systemic responses to it.<\/jats:p>","DOI":"10.1093\/jas\/skab102","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T20:46:26Z","timestamp":1617050786000},"source":"Crossref","is-referenced-by-count":16,"title":["Maternofetal inflammation induced for 2 wk in late gestation reduced birth weight and impaired neonatal growth and skeletal muscle glucose metabolism in lambs"],"prefix":"10.1093","volume":"99","author":[{"given":"Robert J","family":"Posont","sequence":"first","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin N","family":"Cadaret","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joslyn K","family":"Beard","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca M","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel L","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eileen S","family":"Marks-Nelson","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5438-8555","authenticated-orcid":false,"given":"Jessica L","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin T","family":"Yates","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Nebraska\u2013Lincoln, Lincoln, NE 68583, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"2022032914561896000_CIT0001","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/jcb.26174","article-title":"Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus","volume":"119","author":"Akash","year":"2018","journal-title":"J. Cell. Biochem"},{"key":"2022032914561896000_CIT0039","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/08977190802025024","article-title":"Beneficial synergistic interactions of TNF-\u03b1 and IL-6 in C2 skeletal myoblasts\u2014potential cross-talk with IGF system","volume":"26","author":"Al-Shanti","year":"2008","journal-title":"Growth Factors"},{"key":"2022032914561896000_CIT0002","doi-asserted-by":"crossref","first-page":"4101","DOI":"10.1093\/jas\/skz271","article-title":"Hypertrophic muscle growth and metabolic efficiency were impaired by chronic heat stress, improved by zilpaterol supplementation, and not affected by ractopamine supplementation in feedlot lambs1","volume":"97","author":"Barnes","year":"2019","journal-title":"J. Anim. Sci"},{"key":"2022032914561896000_CIT0003","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1093\/af\/vfz018","article-title":"Real supermodels wear wool: summarizing the impact of the pregnant sheep as an animal model for adaptive fetal programming","volume":"9","author":"Beede","year":"2019","journal-title":"Anim. Front"},{"key":"2022032914561896000_CIT0004","doi-asserted-by":"crossref","first-page":"R63","DOI":"10.1530\/JOE-17-0076","article-title":"The impact of IUGR on pancreatic islet development and beta-cell function","volume":"235","author":"Boehmer","year":"2017","journal-title":"J. Endocrinol"},{"key":"2022032914561896000_CIT0005","doi-asserted-by":"crossref","first-page":"R920","DOI":"10.1152\/ajpregu.00197.2015","article-title":"Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction","volume":"309","author":"Brown","year":"2015","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol"},{"key":"2022032914561896000_CIT0006","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cyto.2017.03.014","article-title":"Acute exposure of primary rat soleus muscle to zilpaterol HCl (\u03b22 adrenergic agonist), TNF\u03b1, or IL-6 in culture increases glucose oxidation rates independent of the impact on insulin signaling or glucose uptake","volume":"96","author":"Cadaret","year":"2017","journal-title":"Cytokine"},{"key":"2022032914561896000_CIT0007","doi-asserted-by":"crossref","first-page":"4822","DOI":"10.1093\/jas\/skz321","article-title":"Sustained maternal inflammation during the early third-trimester yields intrauterine growth restriction, impaired skeletal muscle glucose metabolism, and diminished \u03b2-cell function in fetal sheep1,2","volume":"97","author":"Cadaret","year":"2019","journal-title":"J. Anim. Sci"},{"key":"2022032914561896000_CIT0008","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1093\/tas\/txz037","article-title":"Maternal inflammation at midgestation impairs subsequent fetal myoblast function and skeletal muscle growth in rats, resulting in intrauterine growth restriction at term","volume":"3","author":"Cadaret","year":"2019","journal-title":"Transl. Anim. Sci"},{"key":"2022032914561896000_CIT0009","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1093\/tas\/txz060","article-title":"Intermittent maternofetal O2 supplementation during late gestation rescues placental insufficiency-induced intrauterine growth restriction and metabolic pathologies in the neonatal lamb","volume":"3","author":"Cadaret","year":"2019","journal-title":"Transl. Anim. Sci"},{"key":"2022032914561896000_CIT0010","doi-asserted-by":"crossref","first-page":"R101","DOI":"10.1152\/ajpregu.00068.2017","article-title":"Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction","volume":"313","author":"Camacho","year":"2017","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol"},{"key":"2022032914561896000_CIT0011","doi-asserted-by":"crossref","first-page":"5995","DOI":"10.1073\/pnas.1118355109","article-title":"Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk","volume":"109","author":"Cohen","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A"},{"key":"2022032914561896000_CIT0012","doi-asserted-by":"crossref","first-page":"500","DOI":"10.3390\/nu7010500","article-title":"Fetal adrenal demedullation lowers circulating norepinephrine and attenuates growth restriction but not reduction of endocrine cell mass in an ovine model of intrauterine growth restriction","volume":"7","author":"Davis","year":"2015","journal-title":"Nutrients"},{"key":"2022032914561896000_CIT0013","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1113\/EP088859","article-title":"Hyperlipidic diet affects body composition and induces anxiety-like behaviour in intrauterine growth-restricted adult mice","volume":"105","author":"De Almeida Silva","year":"2020","journal-title":"Exp. Physiol"},{"key":"2022032914561896000_CIT0014","first-page":"56","article-title":"Laboratory medicine in the scope of proteomics and genomics","volume":"21","author":"Demkow","year":"2010","journal-title":"eJIFCC"},{"key":"2022032914561896000_CIT0015","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.3390\/nu7021202","article-title":"Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity","volume":"7","author":"Dunlop","year":"2015","journal-title":"Nutrients"},{"key":"2022032914561896000_CIT0016","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1097\/GRF.0b013e31829e5b29","article-title":"Prenatal programming of insulin secretion in intrauterine growth restriction","volume":"56","author":"Gatford","year":"2013","journal-title":"Clin. Obstet. Gynecol"},{"key":"2022032914561896000_CIT0017","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1093\/tas\/txz059","article-title":"Body composition estimated by bioelectrical impedance analyses is diminished by prenatal stress in neonatal lambs and by heat stress in feedlot wethers","volume":"3","author":"Gibbs","year":"2019","journal-title":"Transl. Anim. Sci"},{"issue":"Suppl 1","key":"2022032914561896000_CIT0018","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1093\/tas\/txaa097","article-title":"Deficits in growth, muscle mass, and body composition following placental insufficiency-induced intrauterine growth restriction persisted in lambs at 60 d of age but were improved by daily clenbuterol supplementation","volume":"4","author":"Gibbs","year":"2020","journal-title":"Transl. Anim. Sci"},{"key":"2022032914561896000_CIT0019","first-page":"183","article-title":"Consequences of nutrition and growth retardation early in life for growth and composition of cattle and eating quality of beef","volume":"15","author":"Greenwood","year":"2005","journal-title":"Recent Advances in Animal Nutrition in Australia"},{"key":"2022032914561896000_CIT0042","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/ije\/dyt133","article-title":"Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. 1992","volume":"42","author":"Hales","year":"2013","journal-title":"Int. J. Epidemiol"},{"key":"2022032914561896000_CIT0020","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1080\/1357650X.2016.1243552","article-title":"Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep","volume":"22","author":"Hunter","year":"2017","journal-title":"Laterality"},{"key":"2022032914561896000_CIT0021","doi-asserted-by":"crossref","first-page":"E770","DOI":"10.1152\/ajpendo.00494.2009","article-title":"Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction","volume":"298","author":"Leos","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab"},{"key":"2022032914561896000_CIT0022","doi-asserted-by":"crossref","first-page":"5103","DOI":"10.1113\/JP273324","article-title":"Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency","volume":"595","author":"Limesand","year":"2017","journal-title":"J. Physiol"},{"key":"2022032914561896000_CIT0023","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":"2022032914561896000_CIT0024","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":"2022032914561896000_CIT0025","doi-asserted-by":"crossref","first-page":"316","DOI":"10.3389\/fnhum.2017.00316","article-title":"Inflammation: the common pathway of stress-related diseases","volume":"11","author":"Liu","year":"2017","journal-title":"Front. Hum. Neurosci"},{"key":"2022032914561896000_CIT0026","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1210\/en.2015-1850","article-title":"Adrenal demedullation and oxygen supplementation independently increase glucose-stimulated insulin concentrations in fetal sheep with intrauterine growth restriction","volume":"157","author":"Macko","year":"2016","journal-title":"Endocrinology"},{"key":"2022032914561896000_CIT0040","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1111\/febs.12338","article-title":"Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?","volume":"280","author":"Mu\u00f1oz-C\u00e1noves","year":"2013","journal-title":"Febs. J"},{"key":"2022032914561896000_CIT0027","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":"2022032914561896000_CIT0028","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1093\/tas\/txy038","article-title":"Changes in myoblast responsiveness to TNFa and IL-6 contribute to decreased skeletal muscle mass in intrauterine growth restricted fetal sheep","volume":"2","author":"Posont","year":"2018","journal-title":"Transl. Anim. Sci"},{"key":"2022032914561896000_CIT0029","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.cvfa.2019.02.001","article-title":"Postnatal nutrient repartitioning due to adaptive developmental programming","volume":"35","author":"Posont","year":"2019","journal-title":"Vet. Clin. North Am. Food Anim. Pract"},{"key":"2022032914561896000_CIT0030","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.cvfa.2019.02.006","article-title":"Developmental programming of fetal growth and development","volume":"35","author":"Reynolds","year":"2019","journal-title":"Vet. Clin. North Am. Food Anim. Pract"},{"key":"2022032914561896000_CIT0031","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1113\/JP275230","article-title":"Skeletal muscle protein accretion rates and hindlimb growth are reduced in late gestation intrauterine growth-restricted fetal sheep","volume":"596","author":"Rozance","year":"2018","journal-title":"J. Physiol"},{"key":"2022032914561896000_CIT0041","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1046\/j.1365-201X.2003.01158.x","article-title":"Molecular regulation of individual skeletal muscle fibre types","volume":"178","author":"Spangenburg","year":"2003","journal-title":"Acta. Physiol. Scand"},{"key":"2022032914561896000_CIT0032","doi-asserted-by":"crossref","DOI":"10.1093\/jas\/skaa278.374","article-title":"Heat stress-induced deficits in growth, metabolic efficiency, and cardiovascular function coincided with chronic systemic inflammation and hypercatecholaminemia in ractopamine-supplemented feedlot lambs","author":"Swanson","year":"2020","journal-title":"J. Anim. Sci"},{"key":"2022032914561896000_CIT0033","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1016\/j.bbamcr.2014.05.014","article-title":"Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease","volume":"1843","author":"Turner","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"2022032914561896000_CIT0034","doi-asserted-by":"crossref","first-page":"597675","DOI":"10.3389\/fphys.2020.597675","article-title":"Inflammation and skeletal muscle wasting during Cachexia","volume":"11","author":"Webster","year":"2020","journal-title":"Front. Physiol"},{"key":"2022032914561896000_CIT0035","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1113\/JP278726","article-title":"Postnatal beta2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle","volume":"597","author":"Yates","year":"2019","journal-title":"J. Physiol"},{"key":"2022032914561896000_CIT0036","doi-asserted-by":"crossref","first-page":"5439","DOI":"10.1113\/jphysiol.2012.237347","article-title":"Hypoxaemia-induced catecholamine secretion from adrenal chromaffin cells inhibits glucose-stimulated hyperinsulinaemia in fetal sheep","volume":"590","author":"Yates","year":"2012","journal-title":"J. Physiol"},{"key":"2022032914561896000_CIT0037","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1093\/jas\/sky164","article-title":"ASAS-SSR Triennial Reproduction Symposium: Looking back and moving forward\u2014how reproductive physiology has evolved: fetal origins of impaired muscle growth and metabolic dysfunction: lessons from the heat-stressed pregnant ewe","volume":"96","author":"Yates","year":"2018","journal-title":"J. Anim. Sci"},{"key":"2022032914561896000_CIT0038","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0014-5793(95)01272-9","article-title":"TNF-alpha inhibits glucose-induced insulin secretion in a pancreatic beta-cell line (INS-1)","volume":"377","author":"Zhang","year":"1995","journal-title":"FEBS Lett"}],"container-title":["Journal of Animal Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jas\/advance-article-pdf\/doi\/10.1093\/jas\/skab102\/36788774\/skab102.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jas\/article-pdf\/99\/5\/skab102\/39630365\/skab102.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jas\/article-pdf\/99\/5\/skab102\/39630365\/skab102.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T18:52:21Z","timestamp":1648579941000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jas\/article\/doi\/10.1093\/jas\/skab102\/6199898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3,29]]},"published-print":{"date-parts":[[2021,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jas\/skab102","relation":{},"ISSN":["0021-8812","1525-3163"],"issn-type":[{"value":"0021-8812","type":"print"},{"value":"1525-3163","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5,1]]},"published":{"date-parts":[[2021,3,29]]},"article-number":"skab102"}}