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Intrauterine growth restriction (IUGR) is associated with enhanced inflammatory activity, poor skeletal muscle glucose metabolism, and pancreatic \u03b2 cell dysfunction that persist in offspring. We hypothesized that targeting heightened inflammation in IUGR-born neonatal lambs by supplementing anti-inflammatory \u03c9-3 polyunsaturated fatty acids (\u03c9-3 PUFAs) would improve metabolic outcomes. Methods: Maternal heat stress was used to produce IUGR lambs, which received daily oral boluses of \u03c9-3 PUFA Ca2+ salts or placebo for 30 days. Results: Greater circulating TNF\u03b1 and semitendinosus IL6R in IUGR lambs were fully resolved by \u03c9-3 PUFA, and impaired glucose-stimulated insulin secretion, muscle glucose oxidation, and hypertension were partially rescued. Impaired glucose oxidation by IUGR muscle coincided with a greater glycogen content that was completely reversed by \u03c9-3 PUFA and greater lactate production that was partially reversed. Ex vivo O2 consumption was increased in IUGR muscle, indicating compensatory lipid oxidation. This too was alleviated by \u03c9-3 PUFA. Conversely, \u03c9-3 PUFA had little effect on IUGR-induced changes in lipid flux and hematology parameters, did not resolve greater muscle TNFR1, and further reduced muscle \u03b22-adrenoceptor content. Conclusions: These findings show that targeting elevated inflammatory activity in IUGR-born lambs in the early neonatal period improved metabolic outcomes, particularly muscle glucose metabolism and \u03b2 cell function.<\/jats:p>","DOI":"10.3390\/metabo15060346","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T04:32:37Z","timestamp":1747888357000},"page":"346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reducing Systemic Inflammation in IUGR-Born Neonatal Lambs via Daily Oral \u03c9-3 PUFA Supplement Improved Skeletal Muscle Glucose Metabolism, Glucose-Stimulated Insulin Secretion, and Blood Pressure"],"prefix":"10.3390","volume":"15","author":[{"given":"Melanie R.","family":"White","sequence":"first","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7980-1377","authenticated-orcid":false,"given":"Rachel L.","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo C.","family":"Grijalva","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zena M.","family":"Hicks","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley N.","family":"Beer","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen S.","family":"Marks-Nelson","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin T.","family":"Yates","sequence":"additional","affiliation":[{"name":"Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/ije\/31.6.1235","article-title":"Fetal origins of adult disease: Strength of effects and biological basis","volume":"31","author":"Barker","year":"2002","journal-title":"Int. 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