The Wnt signaling pathway has implicated in numerous physiological and pathophysiological activities. In addition, recent clinical and in vitro studies reveal that aberrant Wnt signaling is thought to play an important role in the onset of diabetes. Our previous studies also mentioned that insulin plays a role in central blood pressure regulation in the nucleus tractus solitarii (NTS), located at the dorsal part of the brainstem. Nevertheless, the relationship between Wnt signaling and insulin pathway and related modulation of blood pressure in the central nervous system has not been established. In the present study, we postulated that Wnt signaling pathway may improve neuronal insulin resistance and that neuronal insulin resistance is a core mechanism involved in triggering hypertension. Intracerebroventricular administration of Wnt3a (0.9 pmol/per day) produced depressor in both spontaneously hypertensive rats (SHRs) and fructose-fed rats (FFRs). Pretreatment with a low density lipoprotein receptor-related protein (LRP) antagonist, Dickkopf-1 (DKK-1) (1 μg/per day) significantly attenuated the depressor effect and nitric oxide (NO) production evoked by Wnt3a. Additionally, immunoblotting and pharmacological studies further showed that inhibition of LRP6 activity by DKK-1 significantly abolished Wnt3a-induced glycogen synthase kinase 3beta (GSK-3beta)S9, extracellular signal-regulated kinases 1/2 (ERK1/2)T202/Y204, ribosomal protein S6 kinase (RSK)T359/S363, AktS473, insulin receptor substrate (IRS)Y612 phosphorylation and increased IRS1S332 phosphorylation. GSK-3beta was also found to direct bind to IRS1 and induced Ser332 phosphorylation in the NTS. Likewise, administration of GSK-3beta inhibitor (TWS119, 0.173 μg/per day) into the brain decreased blood pressure of SHRs and FFRs through enhancing IRS1 activity. Taken together, these results suggest that the Wnt-LRP6-GSK3beta signaling may as a key regulator of insulin pathway and a potential therapeutic target for essential hypertension.