title: Glucocorticoids attenuate the central sympathoexcitatory actions of insulin.
abstract: Insulin acts within the central nervous system to regulate food intake and sympathetic nerve activity (SNA). Strong evidence indicates that glucocorticoids impair insulin-mediated glucose uptake and food intake. However, few data are available regarding whether glucocorticoids also modulate the sympathoexcitatory response to insulin. Therefore, the present study first confirmed that chronic administration of glucocorticoids attenuated insulin-induced increases in SNA and then investigated whether these effects were attributed to deficits in central insulin-mediated responses. Male Sprague-Dawley rats were given access to water or a drinking solution of the glucocorticoid agonist dexamethasone (0.3 μg/ml) for 7 days. A hyperinsulinemic-euglycemic clamp significantly increased lumbar SNA in control rats. This response was significantly attenuated in rats given access to dexamethasone for 7, but not 1, days. Similarly, injection of insulin into the lateral ventricle or locally within the arcuate nucleus (ARC) significantly increased lumbar SNA in control rats but this response was absent in rats given access to dexamethasone. The lack of a sympathetic response to insulin cannot be attributed to a generalized depression of sympathetic function or inactivation of ARC neurons as electrical activation of sciatic afferents or ARC injection of gabazine, respectively, produced similar increases in SNA between control and dexamethasone-treated rats. Western blot analysis indicates insulin produced similar activation of Akt Ser(473) and rpS6 Ser(240/244) in the ventral hypothalamus of control and dexamethasone-treated rats. Collectively, these findings suggest that dexamethasone attenuates the sympathoexcitatory actions of insulin through a disruption of ARC neuronal function downstream of Akt or mammalian target of rapamycin (mTOR) signaling.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Steiner
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania;
authors.forename: Megan E
authors.initials: ME
authors.lastname: Bardgett
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania;
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wolfgang
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania;
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State College of Medicine, Hershey, Pennsylvania; Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania sstocker@hmc.psu.edu.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Stocker
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D008159:Lumbar Vertebrae; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D005938:Glucocorticoids; D007328:Insulin; D046912:Multiprotein Complexes; D011724:Pyridazines; D003907:Dexamethasone; C049853:gabazine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Akt; arcuate nucleus; dexamethasone; mTOR; sympathetic nerve activity