OBJECTIVE-We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The down stream 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 parasympa- thetically (hepatic parasympathectomy) denervated. RESULTS Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroven- tricular 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 intrace- rebroventricular 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-Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver. © 2008 by the American Diabetes Association.