Daily Injection of the β2 Adrenergic Agonist Clenbuterol Improved Muscle Glucose Metabolism, Glucose-Stimulated Insulin Secretion, and Hyperlipidemia in Juvenile Lambs Following Heat-Stress-Induced Intrauterine Growth Restriction

Authors

Rachel L. Gibbs, University of Nebraska-Lincoln
James Wilson, University of Nebraska at OmahaFollow
Rebecca M. Swanson, University of Nebraska-Lincoln
Joslyn K. Beard, University of Nebraska-Lincoln
Zena M. Hicks, University of Nebraska-Lincoln
Haley Beer, University of Nebraska-LincolnFollow
Eileen Marks-Nelson, University of Nebraska-LincolnFollow
Ty B. Schmidt, University of Nebraska-LincolnFollow
Jessica Lynn Petersen, University of Nebraska - LincolnFollow
Dustin T. Yates, University of Nebraska LincolnFollow

Document Type

Article

Date of this Version

3-7-2024

Citation

Gibbs, R.L.;Wilson, J.A.; Swanson, R.M.; Beard, J.K.; Hicks, Z.M.; Beer, H.N.; Marks-Nelson, E.S.; Schmidt, T.B.; Petersen, J.L.; Yates, D.T. Daily Injection of the β2 Adrenergic Agonist Clenbuterol Improved Muscle Glucose Metabolism, Glucose-Stimulated Insulin Secretion, and Hyperlipidemia in Juvenile Lambs Following Heat-Stress-Induced Intrauterine Growth Restriction. Metabolites 2024, 14, 156. https:// doi.org/10.3390/metabo14030156

Comments

Open access.

Abstract

Stress-induced fetal programming diminishes β2 adrenergic tone, which coincides with intrauterine growth restriction (IUGR) and lifelong metabolic dysfunction. We determined if stimulating β2 adrenergic activity in IUGR-born lambs would improve metabolic outcomes. IUGR lambs that received daily injections of saline or the β2 agonist clenbuterol from birth to 60 days were compared with controls from pair-fed thermoneutral pregnancies. As juveniles, IUGR lambs exhibited systemic inflammation and robust metabolic dysfunction, including greater (p < 0.05) circulating TNF, IL-6, and non-esterified fatty acids, increased (p < 0.05) intramuscular glycogen, reduced (p < 0.05) circulating IGF-1, hindlimb blood flow, glucose-stimulated insulin secretion, and muscle glucose oxidation. Daily clenbuterol fully recovered (p < 0.05) circulating TNF, IL-6, and nonesterified fatty acids, hindlimb blood flow, muscle glucose oxidation, and intramuscular glycogen. Glucose-stimulated insulin secretion was partially recovered (p < 0.05) in clenbuterol-treated IUGR lambs, but circulating IGF-1 was not improved. Circulating triglycerides and HDL cholesterol were elevated (p < 0.05) in clenbuterol-treated IUGR lambs, despite being normal in untreated IUGR lambs. We conclude that deficient β2 adrenergic regulation is a primary mechanism for several components of metabolic dysfunction in IUGR-born offspring and thus represents a potential therapeutic target for improving metabolic outcomes. Moreover, benefits from the β2 agonist were likely complemented by its suppression of IUGR-associated inflammation.