Intracerebroventricular Administration of Neuropeptide Y Induces Hepatic Insulin Resistance via Sympathetic Innervation

Intracerebroventricular Administration of Neuropeptide Y Induces Hepatic Insulin Resistance via Sympathetic Innervation Anita M. van den Hoek 1 , Caroline van Heijningen 2 , Janny P. Schröder-van der Elst 3 , D. Margriet Ouwens 4 , Louis M. Havekes 1 3 5 6 , Johannes A. Romijn 3 , Andries Kalsbeek 2 and Hanno Pijl 3 1 TNO-Quality of Life, Gaubius Laboratory, Leiden, the Netherlands 2 Netherlands Institute for Neuroscience, Amsterdam, the Netherlands 3 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands 4 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands 5 Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands 6 Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands Corresponding author: Anita van den Hoek, a.vandenhoek{at}tno.nl Abstract OBJECTIVE— We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The downstream mechanisms responsible for these effects of NPY remain to be elucidated. Therefore, the aim of this study was to establish whether intracerebroventricular NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation. RESEARCH DESIGN AND METHODS— The effects of a continuous intracerebroventricular infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemic-euglycemic clamp. Either rats were sham operated, or the liver was sympathetically (hepatic sympathectomy) or parasympathetically (hepatic parasympathectomy) denervated. RESULTS— Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroventricular vehicle–infused animals (50 ± 8 vs. 49 ± 6 vs. 55 ± 6%, in hepatic sympathectomy vs. hepatic parasympathectomy vs. sham, respectively). Intracerebroventricular infusion of NPY significantly hampered the suppression of EGP by insulin in sham-denervated animals (29 ± 9 vs. 55 ± 6% for NPY/sham vs. vehicle/sham, respectively, P = 0.038). Selective sympathetic denervation of the liver completely blocked the effect of intracerebroventricular NPY administration on insulin action to suppress EGP (NPY/hepatic sympathectomy, 57 ± 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 ± 7%). CONCLUSIONS— Intrace