Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity

Abstract

Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.

FIG. 1.

Effects of dexamethasone (Dex) in different hypothalamic nuclei on various aspects of glucose metabolism. A: Plasma glucose concentrations at the end of the equilibration state (basal) and at the end of the 90-min dexamethasone or vehicle administration. B: EGP at the end of equilibration state (basal vehicle state), at the end of the 90-min dexamethasone or vehicle administration, and at the end of the hyperinsulinemic–euglycemic clamp. C: Percentage suppression of EGP by hyperinsulinemia at the end of the clamp. D: R_d at the end of the euglycemic–hyperinsulinemic clamp. E: Plasma corticosterone concentration at the end of equilibration state (basal vehicle state), at the end of the 90-min dexamethasone or vehicle administration, and at the end of the hyperinsulinemic–euglycemic clamp. A–D: #P < 0.05 vs. basal vehicle state; ^P < 0.05 vs. dexamethasone state; *P < 0.05 vs. other five groups during clamp. E: #P < 0.05 vs. basal vehicle state ZT4–5; *P < 0.05 vs. dexamethasone or vehicle ZT7–8. MC, misplacement control; Veh-ARC, vehicle-ARC; Veh-MC, vehicle-MC; Veh-PVN, vehicle-PVN.

FIG. 2.

Intracerebroventricular infusion of the NPY1R antagonist BIBP3226 blocks Dex-ARC–induced hepatic insulin resistance. A: Plasma glucose concentrations at the end of the basal state and at the end of the 90-min Dex-ARC or vehicle (veh) in combination with intracerebroventricular BIBP3226 or vehicle infusion. B: EGP at the end of basal vehicle state, at the end of the 90-min Dex-ARC/BIBP state, and at the end of the hyperinsulinemic–euglycemic clamp. C: Percentage suppression of EGP by hyperinsulinemia at the end of the clamp. D: R_d at the end of the euglycemic–hyperinsulinemic clamp. E: NPY mRNA expression in hypothalamic cells after dexamethasone (Dex) treatment. F: NPY protein expression level in hypothalamic cells after dexamethasone treatment. G: Western blotting for NPY in comparison with housekeeping protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH). #P < 0.05 vs. basal vehicle state; ^P < 0.05 vs. dexamethasone or vehicle state; *P < 0.05 vs. the other three groups in B and C; *P < 0.05 vs. control in E and F. Dia, dialysis.

FIG. 3.

Hepatic sympathetic denervation eliminates hepatic insulin resistance induced by Dex-ARC. A: Plasma glucose concentrations at the end of the basal state and at the end of the 90-min Dex-ARC within the different denervation groups. B: EGP at the end of basal vehicle state, at the end of the 90-min Dex-ARC state, and at the end of the hyperinsulinemic–euglycemic clamp. C: Percentage suppression of EGP by hyperinsulinemia at the end of the clamp. D: R_d at the end of the euglycemic–hyperinsulinemic clamp. HSX, hepatic sympathetic denervation; HPX, hepatic parasympathetic denervation; ShamX, sham denervation. #P < 0.05 vs. basal vehicle state; ^P < 0.05 vs. dexamethasone (Dex) state; *P < 0.05 vs. HPX and ShamX.