The role of neuropeptide Y in the pathogenesis of the metabolic syndrome : A study of liver metabolism in transgenic mice overexpressing neuropeptide Y in noradrenergic neurons

The metabolic syndrome (MetS) is a set of symptoms related to obesity, predisposing patients to cardiovascular diseases, and recently hepatosteatosis has been shown to play a major role in its pathogenesis. Neuropeptide Y (NPY) is a neurotransmitter found abundantly in the brain, promoting food intake and energy storage, but also the increased NPY levels in the periphery cause fat accumulation and are associated with impaired glucose tolerance. The main aim of this study was to evaluate the influence of excess NPY on the hepatic metabolism of fatty acids, glucose and cholesterol as a cause of the MetS. The study was performed with genetically obese mice overexpressing NPY in central noradrenergic neurons and the peripheral sympathetic nervous system (OE-NPYDβH), which display obesity, impaired glucose tolerance and insulin resistance as they age. This study revealed that obese OE-NPYDβH mice exhibited also hepatic accumulation of triglycerides and glycogen, as well as hypercholesterolemia preceded by decreased hepatic fatty acid oxidation and increased synthesis of glycogen and cholesterol. Due to this phenotype, these mice are more prone to type 2 diabetes. Furthermore, hepatic glycogen metabolism could be inhibited by the anti-hyperglycemic agent, metformin, which suggests that changes in glycogen metabolism may associate with the prediabetes encountered in obese OE-NPYDβH mice. The mechanism of action of NPY inducing the hepatic pathologies seems to involve decreased sympathetic activity in the liver of OE-NPYDβH mice, similar to that previously detected in adipose tissue. However, there seems to be less involvement of NPY directly on the liver via peripheral Y-receptors. Instead, Y2-receptors appear to mediate the obesogenic effects of NPY, and they could be a potential drug target for obesity induced by consuming an unhealthy diet combined with excess NPY

The role of neuropeptide Y in the pathogenesis of the metabolic syndrome : A study of liver metabolism in transgenic mice overexpressing neuropeptide Y in noradrenergic neurons

The metabolic syndrome (MetS) is a set of symptoms related to obesity, predisposing patients to cardiovascular diseases, and recently hepatosteatosis has been shown to play a major role in its pathogenesis. Neuropeptide Y (NPY) is a neurotransmitter found abundantly in the brain, promoting food intake and energy storage, but also the increased NPY levels in the periphery cause fat accumulation and are associated with impaired glucose tolerance. The main aim of this study was to evaluate the influence of excess NPY on the hepatic metabolism of fatty acids, glucose and cholesterol as a cause of the MetS. The study was performed with genetically obese mice overexpressing NPY in central noradrenergic neurons and the peripheral sympathetic nervous system (OE-NPYDβH), which display obesity, impaired glucose tolerance and insulin resistance as they age. This study revealed that obese OE-NPYDβH mice exhibited also hepatic accumulation of triglycerides and glycogen, as well as hypercholesterolemia preceded by decreased hepatic fatty acid oxidation and increased synthesis of glycogen and cholesterol. Due to this phenotype, these mice are more prone to type 2 diabetes. Furthermore, hepatic glycogen metabolism could be inhibited by the anti-hyperglycemic agent, metformin, which suggests that changes in glycogen metabolism may associate with the prediabetes encountered in obese OE-NPYDβH mice. The mechanism of action of NPY inducing the hepatic pathologies seems to involve decreased sympathetic activity in the liver of OE-NPYDβH mice, similar to that previously detected in adipose tissue. However, there seems to be less involvement of NPY directly on the liver via peripheral Y-receptors. Instead, Y2-receptors appear to mediate the obesogenic effects of NPY, and they could be a potential drug target for obesity induced by consuming an unhealthy diet combined with excess NPY

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1

Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1. Pain sensitivity was assessed behaviorally by using mechanical and heat stimuli. Effect on the discharge rate of rostral ventromedial medullary (RVM) pain control neurons was studied in lightly anesthetized animals. Netrin-1, in a dose-related fashion, induced mechanical hypersensitivity that lasted up to three weeks. Netrin-1 had no effect on heat nociception. Mechanical hypersensitivity induced by netrin-1 was attenuated by TRPA1 antagonist Chembridge-5861528 and by the control analgesic compound pregabalin both during the early (first two days) and late (third week) phase of hypersensitivity. TRPC4/C5 antagonist ML-204 had a weak antihypersensitivity effect that was only in the early phase, whereas TRPC4/C5 antagonist HC-070 had no effect on hypersensitivity induced by netrin-1. The discharge rate in pronociceptive ON-like RVM neurons was increased by netrin-1 during the late but not acute phase, whereas netrin-1 had no effect on the discharge rate of antinociceptive RVM OFF-like neurons. The results suggest that spinal TRPA1 receptors and pronociceptive RVM ON-like neurons are involved in the maintenance of submodality-selective pronociceptive actions induced by netrin-1 in the spinal cord

Spinal TRPA1 Contributes to the Mechanical Hypersensitivity Effect Induced by Netrin-1

Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1. Pain sensitivity was assessed behaviorally by using mechanical and heat stimuli. Effect on the discharge rate of rostral ventromedial medullary (RVM) pain control neurons was studied in lightly anesthetized animals. Netrin-1, in a dose-related fashion, induced mechanical hypersensitivity that lasted up to three weeks. Netrin-1 had no effect on heat nociception. Mechanical hypersensitivity induced by netrin-1 was attenuated by TRPA1 antagonist Chembridge-5861528 and by the control analgesic compound pregabalin both during the early (first two days) and late (third week) phase of hypersensitivity. TRPC4/C5 antagonist ML-204 had a weak antihypersensitivity effect that was only in the early phase, whereas TRPC4/C5 antagonist HC-070 had no effect on hypersensitivity induced by netrin-1. The discharge rate in pronociceptive ON-like RVM neurons was increased by netrin-1 during the late but not acute phase, whereas netrin-1 had no effect on the discharge rate of antinociceptive RVM OFF-like neurons. The results suggest that spinal TRPA1 receptors and pronociceptive RVM ON-like neurons are involved in the maintenance of submodality-selective pronociceptive actions induced by netrin-1 in the spinal cord.Peer reviewe

The Effects of Neuropeptide Y Overexpression on the Mouse Model of Doxorubicin-Induced Cardiotoxicity

Doxorubicin is a potent anticancer drug with cardiotoxicity hampering its use. Neuropeptide Y (NPY) is the most abundant neuropeptide in the heart and a co-transmitter of the sympathetic nervous system that plays a role in cardiac diseases. The aim of this work was to study the impact of NPY on doxorubicin-induced cardiotoxicity. Transgenic mice overexpressing NPY in noradrenergic neurons (NPY-OEDβH) and wild-type mice were treated with a single dose of doxorubicin. Doxorubicin caused cardiotoxicity in both genotypes as demonstrated by decreased weight gain, tendency to reduced ejection fraction, and changes in the expression of several genes relevant to cardiac pathology. Doxorubicin resulted in a tendency to lower ejection fraction in NPY-OEDβH mice more than in wild-type mice. In addition, gain in the whole body lean mass gain was decreased only in NPY-OEDβH mice, suggesting a more severe impact of doxorubicin in this genotype. The effects of doxorubicin on genes expressed in the heart were similar between NPY-OEDβH and wild-type mice. The results demonstrate that doxorubicin at a relatively low dose caused significant cardiotoxicity. There were differences between NPY-OEDβH and wild-type mice in their responses to doxorubicin that suggest NPY to increase susceptibility to cardiotoxicity. This may point to the therapeutic implications as suggested for NPY system in other cardiovascular diseases.</p

Peripherally Administered Y-2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice

Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y-2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y-2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y-2-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPYD beta H) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y-2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYD beta H and WT mice feeding on chow or Western diet. Treatment with Y-2-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y-2-receptors induced obesity in WT mice, whereas OE-NPYD beta H mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y-2-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y-2-receptor antagonism has beneficial effects on metabolic status

Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice

Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y2-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPYDβH) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYDβH and WT mice feeding on chow or Western diet. Treatment with Y2-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y2-receptors induced obesity in WT mice, whereas OE-NPYDβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y2-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y2-receptor antagonism has beneficial effects on metabolic status