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.

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

“…This observation confirms previous studies from several laboratories in which intravenous or intracerebroventricular administration of insulin does not alter ABP or produces a small pressor response (ϳ5 mmHg) in rodents (Bardgett et al 2010;Cassaglia et al 2011;Luckett et al 2013;Morgan et al 1993;Muntzel et al 1994;Pricher et al 2008;Rahmouni et al 2004;Steiner et al 2014;Ward et al 2011). However, it is noteworthy that chronic infusion of insulin has been reported to raise ABP in rodents (Brands et al 1996).…”

“…2. As previously reported in our laboratory (Bardgett et al 2010;Luckett et al 2013;Steiner et al 2014;Ward et al 2011), a hyperinsulinemic-euglycemic clamp significantly increased lumbar SNA without a change in renal SNA (Table 1), heart rate (Table 1), or mean ABP (Table 1). Infusion of isotonic saline did not alter any variable.…”

“…Baseline variables were recorded for 20 min, and then insulin (3.75 mU·kg Ϫ1 ·min Ϫ1 iv; Humulin R) and a 50% dextrose solution (0.25-2.0 ml/h iv) were infused for 150 -180 min as described previously (Bardgett et al 2010;Luckett et al 2013;Steiner et al 2014;Ward et al 2011). This dose of insulin has been reported previously in our laboratory to produce plasma insulin levels equivalent to those of rats fed a moderately high-fat diet for 13 wk or those of obese Zucker rats (Bardgett et al 2010).…”

“…Insulin receptors are highly expressed within the ARC (Grillo et al 2007;Marks et al 1990;Obici et al 2002;Werther et al 1987), and in vitro bath application of insulin alters the activity of proopiomelanocortin (POMC) and neuropeptide Y/agouti-related peptide (NPY/ AgRP) neurons in the ARC (Qiu et al 2014;Williams et al 2010). Direct microinjection of insulin into the ARC increases lumbar SNA and alters baroreflex function (Cassaglia et al 2011;Luckett et al 2013;Steiner et al 2014). Inhibition of ARC neurons or local injection of an anti-insulin affibody reverses/prevents the sympathoexcitatory response to central injection of insulin or a hyperinsulinemic-euglycemic clamp (Cassaglia et al 2011;Luckett et al 2013).…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…In close contact with the nucleus, which also produces ATP from the ADP-ribosyl residues after sudden extensive changes in chromatin [99] (perhaps the ones caused by the heterogeneous ribonucleoproteins (hnRNPs) identified in ALS) proteasome becomes especially important for maintaining cellular homeostasis through degradation of ubiquitinated factors like Drp1, which control mitochondria fusion and fission and the ubiquitinated misfolded ALS proteins [100]. In addition, reduced glucose uptake and metabolism consequent to increased glucocorticoid signaling pathways cannot be discarded [101][102][103].…”