Genetics and Genomics Commons^™

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

Department of Animal Science: Faculty Publications

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.

Daily Injection Of The Β2 Adrenergic Agonist Clenbuterol Improved Poor Muscle Growth And Body Composition In Lambs Following Heat Stress-Induced Intrauterine Growth Restriction, Rachel L. Gibbs, Rebecca M. Swanson, Joslyn K. Beard, Zena M. Hicks, Micah S. Most, Haley Beer, Pablo C. Grijalva, Shawna M. Clement, Eileen Marks-Nelson, Ty B. Schmidt, Jessica Lynn Petersen, Dustin T. Yates

Department of Animal Science: Faculty Publications

Background: Intrauterine growth restriction (IUGR) is associated with reduced β2 adrenergic sensitivity, which contributes to poor postnatal muscle growth. The objective of this study was to determine if stimulating β2 adrenergic activity postnatal would rescue deficits in muscle growth, body composition, and indicators of metabolic homeostasis in IUGR offspring.

Methods: Time-mated ewes were housed at 40°C from day 40 to 95 of gestation to produce IUGR lambs. From birth, IUGR lambs received daily IM injections of 0.8 μg/kg clenbuterol HCl (IUGR+CLEN; n = 11) or saline placebo (IUGR; n = …

Dousing The Flame: Reviewing The Mechanisms Of Inflammatory Programming During Stress-Induced Intrauterine Growth Restriction And The Potential For Ω-3 Polyunsaturated Fatty Acid Intervention, Melanie White, Dustin T. Yates

Department of Animal Science: Faculty Publications

Intrauterine growth restriction (IUGR) arises when maternal stressors coincide with peak placental development, leading to placental insufficiency. When the expanding nutrient demands of the growing fetus subsequently exceed the capacity of the stunted placenta, fetal hypoxemia and hypoglycemia result. Poor fetal nutrient status stimulates greater release of inflammatory cytokines and catecholamines, which in turn lead to thrifty growth and metabolic programming that benefits fetal survival but is maladaptive after birth. Specifically, some IUGR fetal tissues develop enriched expression of inflammatory cytokine receptors and other signaling cascade components, which increases inflammatory sensitivity even when circulating inflammatory cytokines are no longer elevated …

Primary Myoblasts From Intrauterine Growth-Restricted Fetal Sheep Exhibit Intrinsic Dysfunction Of Proliferation And Differentiation That Coincides With Enrichment Of Inflammatory Cytokine Signaling Pathways, Robert J. Posont, Micah S. Most, Caitlin Cadaret, Eileen Marks-Nelson, Kiristen A. Beede, Sean W. Limesand, Ty B. Schmidt, Jessica L. Petersen, Dustin T. Yates

Department of Animal Science: Faculty Publications

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their …

Going Up Inflame: Reviewing The Underexplored Role Of Inflammatory Programming In Stress-Induced Intrauterine Growth Restricted Livestock, Zena M. Hicks, Dustin T. Yates

Department of Animal Science: Faculty Publications

The impact of intrauterine growth restriction (IUGR) on health in humans is well-recognized. It is the second leading cause of perinatal mortality worldwide, and it is associated with deficits in metabolism and muscle growth that increase lifelong risk for hypertension, obesity, hyperlipidemia, and type 2 diabetes. Comparatively, the barrier that IUGR imposes on livestock production is less recognized by the industry. Meat animals born with low birthweight due to IUGR are beset with greater early death loss, inefficient growth, and reduced carcass merit. These animals exhibit poor feed-to-gain ratios, less lean mass, and greater fat deposition, which increase production costs …

Postnatal Nutrient Repartitioning Due To Adaptive Developmental Programming, Robert J. Posont, Dustin T. Yates

Department of Animal Science: Faculty Publications

The consequences of prenatal stress on lifelong metabolic function and health was first proposed by David Barker and Nicholas Hales with the publication of their Thrifty Phenotype Hypothesis in the early 1990s.1,2 Subsequent studies in humans and animals have further demonstrated that stress-induced adaptive fetal programming leads to tissue-specific changes in metabolic function and growth capacity.3,4 Developmental adaptations to the intrauterine nutrient restriction that accompanies most maternofetal stressors target regulatory pathways for nutrient utilization in non-essential tissues such as skeletal muscle.4-6 This aids intrauterine survival by re-appropriating nutrients to support neural, cardiac, and endocrine tissue function but reduces metabolic efficiency …