title: 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.
abstract: 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<0.05) glucose uptake by ∼47%, glucose oxidation by ∼32%, and phospho-Akt by ∼238%. Insulin also increased (P<0.05) phospho-p38, but only after 2h in incubation. Muscle incubated with β2 agonist alone exhibited ∼20% less (P<0.05) glucose uptake but ∼32% greater (P<0.05) glucose oxidation than unstimulated muscle. Moreover, co-incubation with insulin+β2 agonist increased (P<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<0.05) glucose oxidation by ∼23% and ∼33%, respectively, in the absence of insulin. This coincided with increased (P<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<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.
authors.affiliation: Department of Animal Science, University of Nebraska-Lincoln, Lincoln NE 68583, United States.
authors.forename: Caitlin N
authors.initials: CN
authors.lastname: Cadaret
authors.affiliation: Department of Animal Science, University of Nebraska-Lincoln, Lincoln NE 68583, United States.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Beede
authors.affiliation: Department of Animal Science, University of Nebraska-Lincoln, Lincoln NE 68583, United States.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Riley
authors.affiliation: Department of Animal Science, University of Nebraska-Lincoln, Lincoln NE 68583, United States. Electronic address: dustin.yates@unl.edu.
authors.forename: Dustin T
authors.initials: DT
authors.lastname: Yates
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008660:Metabolism / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014297:Trimethylsilyl Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018663:Adrenergic Agents; D007328:Insulin; D015850:Interleukin-6; D010627:Phenethylamines; D014297:Trimethylsilyl Compounds; D014409:Tumor Necrosis Factor-alpha; C475840:Zilpaterol; C060897:ractopamine; D005947:Glucose
keywords: Glucose oxidation; IL-6; Metabolic regulation; TNFα; β2 adrenergic agonist