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

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 hyperinsulinemiceuglycemic 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 Ϯ 8 vs. 49 Ϯ 6 vs. 55 Ϯ 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 Ϯ 9 vs. 55 Ϯ 6% for NPY/sham vs. vehicle/sham, respectively, P ϭ 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 Ϯ 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 Ϯ 7%).CONCLUSIONS-Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.

A free-choice high-fat high-sugar diet induces glucose intolerance and insulin unresponsiveness to a glucose load not explained by obesity

“…The pancreas is innervated by the ANS and it has been shown that the hypothalamus may regulate this sensitivity via this ANS innervation. [25][26][27][28] The latter hypothesis is supported by our recent finding that centrally, neuropeptide Y and proopiomelanocortin mRNA expression in the arcuate nucleus were altered in HFHS-choice diet rats in such a direction that it promotes glucose intolerance and insulin resistance. 15 Neuropeptide Y-and proopiomelanocortinexpressing neurons in the arcuate nucleus affect glucose metabolism via their projections to (pre-autonomic) hypothalamic neurons that control the autonomic nervous input to various peripheral organs, such as the pancreas.…”

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

“…Intracerebroventricular infusion of NPY influences glucose metabolism and sensitivity to insulin in fasted rats (12,36,63,64); therefore, we determined whether CNS NPY signaling via either the Y1 or Y2 receptor alters glucoregulatory hormones. The Y2 receptor agonist increased plasma glucose levels by 13% (P Ͻ 0.05; Table 2), whereas neither the NPY nor Y1 receptor agonist had any effect on glucose concentration (P ϭ NS; Table 2).…”

Brain-liver connections: role of the preautonomic PVN neurons

“…NPY neurons send dense projections to the PVN, and it has been demonstrated that hepatic sympathectomy abolishes the NPY/insulin effect on liver glucose production, suggesting that the hypothalamic insulin effect may depend on modulation of presympathetic PVN neurons (65). On the other hand, Pocai et al (39) revealed that the parasympathetic outflow to the liver is involved in the inhibitory effect of hypothalamic insulin on hepatic glucose production.…”