Reducing Systemic Inflammation in IUGR-Born Neonatal Lambs via Daily Oral ω-3 PUFA Supplement Improved Skeletal Muscle Glucose Metabolism, Glucose-Stimulated Insulin Secretion, and Blood Pressure

Authors

• Melanie R. White, University of Nebraska-Lincoln
• Rachel L. Gibbs, University of Nebraska-Lincoln
• Pablo C. Grijalva, University of Nebraska-Lincoln
• Zena M. Hicks, University of Nebraska-Lincoln
• Haley N. Beer, University of Nebraska-Lincoln
• Eileen S. Marks-Nelson, University of Nebraska-Lincoln
• Dustin T. Yates, University of Nebraska-LincolnFollow

ORCID IDs

Gibbs https://orcid.org/0000-0001-7980-1377

Document Type

Article

Date of this Version

2025

Citation

Metabolites (2025) 33: 13

doi: 10.3390/metabo15060346

Comments

Open access

License: CC BY 4.0

Abstract

Background/Objectives: Intrauterine growth restriction (IUGR) is associated with enhanced inflammatory activity, poor skeletal muscle glucose metabolism, and pancreatic β cell dysfunction that persist in offspring. We hypothesized that targeting heightened inflammation in IUGR-born neonatal lambs by supplementing anti-inflammatory ω-3 polyunsaturated fatty acids (ω-3 PUFAs) would improve metabolic outcomes. Methods: Maternal heat stress was used to produce IUGR lambs, which received daily oral boluses of ω-3 PUFA Ca²⁺ salts or placebo for 30 days. Results: Greater circulating TNFα and semitendinosus IL6R in IUGR lambs were fully resolved by ω-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 ω-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 ω-3 PUFA. Conversely, ω-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 β2-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 β cell function.