Intracerebroventricular Neuropeptide Y Infusion Precludes Inhibition of Glucose and VLDL Production by Insulin

Abstract

Recent evidence demonstrates that hypothalamic insulin signaling is required for inhibition of endogenous glucose production. The downstream mechanisms that are responsible for the effects of hypothalamic insulin receptor activation on hepatic fuel flux remain to be determined. To establish whether downregulation of neuropeptide Y (NPY) release by insulin is mandatory for its capacity to suppress glucose production, we examined the effects of a continuous intracerebroventricular (ICV) infusion of NPY (10 g/h for 3-5 h) on glucose flux during a hyperinsulinemic-euglycemic clamp in mice. We also evaluated the effects of ICV NPY administration on free fatty acid and glycerol flux and VLDL production in this experimental context. In basal conditions, none of the metabolic parameters was affected by NPY infusion. In hyperinsulinemic conditions, peripheral glucose disposal was not different between vehicle-and NPY-infused animals. In contrast, hyperinsulinemia suppressed endogenous glucose production by ϳ8% vs. 30% in NPY-vs. vehicle-infused mice, respectively (P < 0.05). Also, VLDL production was significantly higher during hyperinsulinemia in NPYcompared with vehicle-infused mice (97.5 ؎ 18.0 vs. 54.7 ؎ 14.9 mol ⅐ kg ؊1 ⅐ h ؊1 ; P < 0.01). These data suggest that the neurophysiological action of insulin to downregulate hypothalamic NPY release is a prerequisite for its ability to suppress hepatic fuel production, whereas it is not mandatory for its capacity to modulate glucose disposal or lipolysis. Diabetes 53:2529 -2534, 2004 I nsulin resistance is an important characteristic of obesity and type 2 diabetes (1,2). It hampers proper suppression of endogenous glucose and VLDL production in response to food intake. Accordingly, the metabolic features of obesity and type 2 diabetes include hyperglycemia and hypertriglyceridemia.It was shown recently that hypothalamic insulin signaling is required for inhibition of endogenous glucose production (EGP) (3). Indeed, intracerebroventricular (ICV) infusion of insulin can suppress glucose production (by 40%) in the presence of basal circulating insulin concentrations, whereas antagonism of insulin signaling or downregulation of insulin receptor expression in hypothalamic nuclei considerably impairs the ability of circulating insulin to inhibit EGP (3,4).The downstream mechanisms that are responsible for the apparent impact of hypothalamic insulin receptor activation on hepatic fuel flux remain to be established. The arcuate nucleus of the hypothalamus is a major target of insulin in the brain. This nucleus contains two insulinsensitive populations of neurons that exert powerful, opposing effects on fuel flux: pro-opiomelanocortin (POMC) neurons (stimulated by insulin), guiding a catabolic adaptive response to environmental cues, and NPY neurons (inhibited by insulin) that primarily promote anabolic adaptations (5). ICV infusion of a melanocortin antagonist (SHU9119) does not affect the ability of hyperinsulinemia to inhibit EGP, which suggests that the POMC pathway is not inv...

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

“…In contrast, selective destruction of parasympathetic nerves innervating the liver does not modify the impact of NPY on hepatic insulin sensitivity. These data corroborate previous findings in rats and mice, demonstrating that intracerebroventricular administration of NPY hampers insulin action to inhibit glucose and VLDL production (6,20). The present results suggest that NPY neurons modulate this inhibitory effect of insulin on glucose production via efferent sympathetic nerves innervating the liver.…”

“…Insulin inhibits neuropeptide Y (NPY)-producing neurons in the arcuate nucleus of the hypothalamus (5). Intracerebroventricular administration of NPY hampers the capacity of insulin to suppress EGP (6), suggesting that silencing of arcuate NPY neurons may contribute to the inhibitory effect of intracerebroventricular insulin administration on EGP.…”

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

“…An increase in NPY expression in the arcuate and dorsomedial nuclei is characteristic of several models of insulin resistance, for example Lep ob/ob and agouti (A y ) mice, Otsuka Long-Evans Tokushima fatty rats, and tubby mice (Guan et al, 1998;Beck, 2006). Moreover, similar to the effect of intracerebroventricular resistin in the current study, central administration of NPY during a hyperinsulinemic clamp increased glucose production without altering peripheral glucose uptake (Marks and Waite, 1997;van den Hoek et al, 2004). Furthermore, deletion of Y1, Y2, and Y4 receptors in NPY overexpressing mice reversed hyperinsulinemia (Lin et al, 2006).…”

“…A previous study has shown that infusion of NPY intracerebroventricularly impairs insulin sensitivity and increases endogenous glucose production (Marks and Waite, 1997;van den Hoek et al, 2004). We administered resistin intracerebroventricularly in NPY deficient C57BL/6J mice (npyϪ/Ϫ) (Patel et al, 2006) and performed a hyperinsulinemic-euglycemic clamp and tracer kinetics.…”

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

“…We observed that within the arcuate nucleus of the hypothalamus, the expression of neuropeptide Y increased and that of proopiomelanocortin decreased when rats were fed a free-choice HFHS diet. 15 Because neuropeptide Y and proopiomelanocortin are known to regulate glucose metabolism, 16,17 we hypothesized that the HFHS diet would result in glucose intolerance. Interestingly, rats on a free-choice highfat (HF) diet or on a free-choice high-sugar (HS) diet also developed obesity.…”