Function and dysfunction of fatty acid mobilization: a review

Western populations have a growing obesity epidemic due in part to excessive nutrient intake from high-fat diets, which are increasingly common. Overindulgence of nutrients is associated with a greater incidence of metabolic dysfunction and a greater risk for obesity, diabetes, hypertension, and other metabolic disorders that lower quality of life. Research in humans and animal models has improved our understanding of how excess circulating free fatty acids negatively impact the ability of muscle and other tissues to regulate nutrient uptake and utilization. It is generally accepted by the scientific community that excess circulating fatty acids lead to insulin resistance, but there is little clarity regarding the underlying mechanisms. In the present review, we will outline the current understanding of the characteristics associated with fatty acid mobilization and fatty acid utilization within specific tissues. We will also discuss the potential mechanistic role of hyperlipidemia on metabolic dysfunction associated with type 2 diabetes

Inflammatory Mediation of Heat Stress-Induced Growth Deficits in Livestock and Its Potential Role as a Target for Nutritional Interventions: A Review

Heat stress is detrimental to well-being and growth performance in livestock, and systemic inflammation arising during chronic heat stress contributes to these poor outcomes. Sustained exposure of muscle and other tissues to inflammation can impair the cellular processes that facilitate muscle growth and intramuscular fat deposition, thus reducing carcass quality and yield. Climate change is expected to produce more frequent extreme heat events, increasing the potential impact of heat stress on sustainable livestock production. Feedlot animals are at particularly high risk for heat stress, as confinement limits their ability to seek cooling from the shade, water, or breeze. Economically practical options to circumvent heat stress in feedlot animals are limited, but understanding the mechanistic role of inflammation in heat stress outcomes may provide the basis for treatment strategies to improve well-being and performance. Feedlot animals receive formulated diets daily, which provides an opportunity to administer oral nutraceuticals and other bioactive products to mitigate heat stress-induced inflammation. In this review, we examine the complex associations between heat stress, systemic inflammation, and dysregulated muscle growth in meat animals. We also present evidence for potential nutraceutical and dietary moderators of inflammation and how they might improve the unique pathophysiology of heat stress

The Price of Surviving on Adrenaline: Developmental Programming Responses to Chronic Fetal Hypercatecholaminemia Contribute to Poor Muscle Growth Capacity and Metabolic Dysfunction in IUGR-Born Offspring

Maternofetal stress induces fetal programming that restricts skeletal muscle growth capacity and metabolic function, resulting in intrauterine growth restriction (IUGR) of the fetus. This thrifty phenotype aids fetal survival but also yields reduced muscle mass and metabolic dysfunction after birth. Consequently, IUGR-born individuals are at greater lifelong risk for metabolic disorders that reduce quality of life. In livestock, IUGR-born animals exhibit poor growth efficiency and body composition, making these animals more costly and less valuable. Specifically, IUGR-associated programming causes a greater propensity for fat deposition and a reduced capacity for muscle accretion. This, combined with metabolic inefficiency, means that these animals produce less lean meat from greater feed input, require more time on feed to reach market weight, and produce carcasses that are of less quality. Despite the health and economic implications of IUGR pathologies in humans and food animals, knowledge regarding their specific underlying mechanisms is lacking. However, recent data indicate that adaptive programing of adrenergic sensitivity in multiple tissues is a contributing factor in a number of IUGR pathologies including reduced muscle mass, peripheral insulin resistance, and impaired glucose metabolism. This review highlights the findings that support the role for adrenergic programming and how it relates to the lifelong consequences of IUGR, as well as how dysfunctional adrenergic signaling pathways might be effective targets for improving outcomes in IUGR-born offspring

Going Up Inflame: Reviewing the Underexplored Role of Inflammatory Programming in Stress-Induced Intrauterine Growth Restricted Livestock

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 and decrease value. Ultimately, this reduces the amount of meat produced by each animal and threatens the economic sustainability of livestock industries. Intrauterine growth restriction is most commonly the result of fetal programming responses to placental insufficiency, but the exact mechanisms by which this occurs are not well-understood. In uncompromised pregnancies, inflammatory cytokines are produced at modest rates by placental and fetal tissues and play an important role in fetal development. However, unfavorable intrauterine conditions can cause cytokine activity to be excessive during critical windows of fetal development. Our recent evidence indicates that this impacts developmental programming of muscle growth and metabolism and contributes to the IUGR phenotype. In this review, we outline the role of inflammatory cytokine activity in the development of normal and IUGR phenotypes. We also highlight the contributions of sheep and other animal models in identifying mechanisms for IUGR pathologies

Function and dysfunction of fatty acid mobilization: a review.

Western populations have a growing obesity epidemic due in part to excessive nutrient intake from high-fat diets, which are increasingly common. Overindulgence of nutrients is associated with a greater incidence of metabolic dysfunction and a greater risk for obesity, diabetes, hypertension, and other metabolic disorders that lower quality of life. Research in humans and animal models has improved our understanding of how excess circulating free fatty acids negatively impact the ability of muscle and other tissues to regulate nutrient uptake and utilization. It is generally accepted by the scientific community that excess circulating fatty acids lead to insulin resistance, but there is little clarity regarding the underlying mechanisms. In the present review, we will outline the current understanding of the characteristics associated with fatty acid mobilization and fatty acid utilization within specific tissues. We will also discuss the potential mechanistic role of hyperlipidemia on metabolic dysfunction associated with type 2 diabetes

Maternal inflammation at midgestation impairs subsequent fetal myoblast function and skeletal muscle growth in rats, resulting in intrauterine growth restriction at term

Maternal inflammation induces intrauterine growth restriction (MI-IUGR) of the fetus, which compromises metabolic health in human offspring and reduces value in livestock. The objective of this study was to determine the effect of maternal inflammation at midgestation on fetal skeletal muscle growth and myoblast profiles at term. Pregnant Sprague-Dawley rats were injected daily with bacterial endotoxin (MI-IUGR) or saline (controls) from the 9th to the 11th day of gestational age (dGA; term = 21 dGA). At necropsy on dGA 20, average fetal mass and upper hindlimb cross-sectional areas were reduced (P \u3c 0.05) in MI-IUGR fetuses compared with controls. MyoD+ and myf5+ myoblasts were less abundant (P \u3c 0.05), and myogenin+ myoblasts were more abundant (P \u3c 0.05) in MI-IUGR hindlimb skeletal muscle compared with controls, indicating precocious myoblast differentiation. Type I and Type II hindlimb muscle fibers were smaller (P \u3c 0.05) in MI-IUGR fetuses than in controls, but fiber type proportions did not differ between experimental groups. Fetal blood plasma TNFα concentrations were below detectable amounts in both experimental groups, but skeletal muscle gene expression for the cytokine receptors TNFR1, IL6R, and FN14 was greater (P \u3c 0.05) in MI-IUGR fetuses than controls, perhaps indicating enhanced sensitivity to these cytokines. Maternal blood glucose concentrations at term did not differ between experimental groups, but MI-IUGR fetal blood contained less (P \u3c 0.05) glucose, cholesterol, and triglycerides. Fetal-to-maternal blood glucose ratios were also reduced (P \u3c 0.05), which is indicative of placental insufficiency. Indicators of protein catabolism, including blood plasma urea nitrogen and creatine kinase, were greater (P \u3c 0.05) in MI-IUGR fetuses than in controls. From these findings, we conclude that maternal inflammation at midgestation causes muscle-centric fetal programming that impairs myoblast function, increases protein catabolism, and reduces skeletal muscle growth near term. Fetal muscle sensitivity to inflammatory cytokines appeared to be enhanced after maternal inflammation, which may represent a mechanistic target for improving these outcomes in MI-IUGR fetuses

Real supermodels wear wool: summarizing the impact of the pregnant sheep as an animal model for adaptive fetal programming

• Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals. • Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans (and other animals). • Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction. • Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring

Acute exposure of primary rat soleus muscle to zilpaterol HCl (β2 adrenergic agonist), TNFα, or IL-6 in culture increases glucose oxidation rates independent of the impact on insulin signaling or glucose uptake

Recent studies show that adrenergic agonists and inflammatory cytokines can stimulate skeletal muscle glucose uptake, but it is unclear if glucose oxidation is similarly increased. Thus, the objective of this study was to determine the effects of ractopamine HCl (β1 agonist), zilpaterol HCl (β2 agonist), TNFα, and IL-6 on glucose uptake and oxidation rates in unstimulated and insulin-stimulated soleus muscle strips from adult Sprague-Dawley rats. Effects on phosphorylation of Akt (phospho-Akt), p38 MAPK (phospho-p38), and p44/42 MAPK (phospho-p44/42) was also determined. Incubation with insulin increased (P \u3c 0.05) glucose uptake by ~47%, glucose oxidation by ~32%, and phospho-Akt by ~238%. Insulin also increased (P \u3c 0.05) phospho-p38, but only after 2 hours in incubation. Muscle incubated with β2 agonist alone exhibited ~20% less (P \u3c 0.05) glucose uptake but ~32% greater (P \u3c 0.05) glucose oxidation than unstimulated muscle. Moreover, co-incubation with insulin + β2 agonist increased (P \u3c 0.05) glucose oxidation and phospho-Akt compared to insulin alone. Conversely, β1 agonist did not appear to affect basal or insulin-stimulated glucose metabolism, and neither β agonist affected phospho-p44/42. TNFα and IL-6 increased (P \u3c 0.05) glucose oxidation by ~23% and ~33%, respectively, in the absence of insulin. This coincided with increased (P \u3c 0.05) phospho-p38 and phospho-p44/42 but not phospho-Akt. Furthermore, co-incubation of muscle with insulin + either cytokine yielded glucose oxidation rates that were similar to insulin alone, despite lower (P \u3c 0.05) phospho-Akt. Importantly, cytokine-mediated increases in glucose oxidation rates were not concomitant with greater glucose uptake. These results show that acute β2 adrenergic stimulation, but not β1 stimulation, directly increases fractional glucose oxidation in the absence of insulin and synergistically increases glucose oxidation when combined with insulin. The cytokines, TNFα and IL-6, likewise directly increased glucose oxidation in the absence of insulin, but were not additive in combination with insulin and in fact appeared to disrupt Akt-mediated insulin signaling. Rather, cytokines appear to be acting through MAPKs to elicit effects on glucose oxidation. Regardless, stimulation of glucose oxidation by these key stress factors did not rely upon greater glucose uptake, which may promote metabolic efficiency during acute stress by increasing fractional glucose oxidation without increasing total glucose consumption by muscle

Changes in myoblast responsiveness to TNFα and IL-6 contribute to decreased skeletal muscle mass in intrauterine growth restricted fetal sheep

Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality (Alisi et al., 2011). Skeletal muscle growth is disproportionately reduced in IUGR fetuses and offspring (Padoan et al. 2004; Yates et al. 2014). These individuals present with reduced muscle mass and increased risk for metabolic disorders at all stages of life (Godfrey and Barker, 2000; Yates et al. 2016.). Muscle growth requires proliferation, differentiation, and fusion of myoblasts (muscle stem cells) to form muscle fibers early in gestation and to increase myonuclear content of existing fibers during late gestation and after birth (Yates et al., 2014). These processes can be disrupted by inflammation, which is a potential factor in impaired muscle development in the IUGR fetus (Yates et al., 2012; Cadaret et al., 2017). Tumor necrosis factor-alpha (TNFα) and interleukin 6 (IL-6) are potent multifunctional cytokines involved in inflammatory and noninflammatory skeletal muscle disorders (Tüzün et al., 2006). We recently found that changes in gene expression of these cytokines and muscle sensitivity to them differed between IUGR and control rats (Cadaret et al., 2017), and that maternal inflammation induced fetal leukocyte adaptations, increasing gene expression of TNFα and its receptor TNFR1, but decreasing gene expression of IL-6 receptor. Both cytokines also regulate myoblast proliferation and differentiation outside of inflammatory states (Al-Shanti et al., 2008). These findings indicate TNFα and IL-6 are essential factors in proper growth and development of muscle, and thus, we postulate that expression and sensitivity changes contribute to decreased muscle growth capacity in IUGR fetuses. The objective of this study was to determine the effects of cytokines on fetal myoblast function and to determine if altered responsiveness is intrinsic in IUGR myoblasts, which would represent a potential adaptive mechanism for reduced muscle mass in IUGR offspring

Ractopamine HCl improved cardiac hypertrophy but not poor growth, metabolic inefficiency, or greater white blood cells associated with heat stress in concentrate-fed lambs

Heat stress decreases livestock performance and well-being (Hahn, 1999; Nienaber and Hahn, 2007), causes metabolic dysfunction that decreases growth efficiency (O’Brien et al., 2010), and alters cardiovascular function (Crandall et al., 2008). Each year, heat stress costs the livestock industry up to $2.5 billion (St-Pierre et al., 2003). Ractopamine HCl acts as a nutrient repartitioning agent (Beermann, 2002); classified as a β adrenergic agonist (βAA), it shares pharmacological properties with adrenaline (Beermann, 2002). βAA increase muscle mass and decreases fat deposition through unknown mechanisms (Beermann, 2002). In feedlot cattle, they increase growth efficiency and improve carcass yield and merit (Scramlin et al., 2010; Buntyn et al., 2017), which increases profit and allows more meat to be produced from fewer animals. However, because βAA act via a stress system, it is unclear how the products affect animals under stress conditions. β1AA and β2AA can also cause tachycardia, heart palpitations, and arrhythmias (Sears, 2002). We hypothesize that β1AA combined with heat stress may overstimulate the adrenergic system, resulting is metabolic dysfunction and decreased performance. Sheep are a common model for cattle, and thus, the objective of this study was to determine the impact of ractopamine HCl on health and cardiovascular parameters, growth, and metabolic efficiency in feeder lambs