neuropeptide-y and Syndrome

Topics: Agouti-Related Protein; Diagnosis, Differential; Energy Metabolism; Feeding Behavior; Ganglia, Autonomic; Humans; Hypothalamic Area, Lateral; Hypothalamic Diseases; Intercellular Signaling Peptides and Proteins; Leptin; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Proteins; Syndrome; Ventromedial Hypothalamic Nucleus

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life.

Topics: Adipose Tissue; Agouti Signaling Protein; Anorexia; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Appetite Stimulants; Cachexia; Cytokines; Energy Metabolism; Gastrointestinal Agents; Glucocorticoids; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Neoplasms; Neuropeptide Y; Patient Care Team; Progesterone; Signal Transduction; Starvation; Syndrome

Concepts related to the pathophysiology of reflex sympathetic dystrophy syndrome (RSDS) are changing. Although sympathetic influences are still viewed as the most likely mechanism underlying the development and/or perpetuation of RSDS, these influences are no longer ascribed to an increase in sympathetic tone. Rather, the most likely mechanism may be increased sensitivity to catecholamines due to sympathetic denervation with an increase in the number and/or sensitivity of peripheral axonal adrenoceptors. Several other pathophysiological mechanisms have been suggested, including neurogenic inflammation with the release of neuropeptides by primary nociceptive afferents and sympathetic efferents. These neuromediators, particularly substance P, calcitonin gene-related peptide, and neuropeptide Y (NPY), may play a pivotal role in the genesis of pain in RSDS. They induce an inflammatory response (cutaneous erythema and edema) and lower the pain threshold. Neurogenic inflammation at the site of the lesion with neuromediator accumulation or depletion probably contributes to the pathophysiology of RSDS. However, no single neuromediator has been proved responsible, and other hypotheses continue to arouse interest.

Topics: Calcitonin Gene-Related Peptide; Humans; Neurogenic Inflammation; Neuropeptide Y; Neuropeptides; Pain; Reflex Sympathetic Dystrophy; Substance P; Sympathetic Nervous System; Syndrome

Anorexia and body weight loss are characteristic of many diseases, including cancer and AIDS. Recent studies indicate that inflammatory cytokines, such as interleukin 1, the interleukin 6 subfamily and tumor necrosis factor, induce anorexia and cachexia by inhibiting the normal adaptive feeding response to energy deficits. Here, I discuss the evidence for and against a central role for neuropeptide Y and leptin in anorexia and cachexia.

Topics: Animals; Anorexia; Appetite; Cachexia; Cytokines; Humans; Hypothalamus; Neuropeptide Y; Syndrome; Wasting Syndrome

Neuropeptide Y (NPY), a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project mainly to the paraventricular nucleus (PVN), an important site of NPY release. NPY synthesis in the ARC is thought to be regulated by several factors, notably insulin, which may exert an inhibitory action. The effects of NPY injected into the PVN and other sites include hyperphagia, reduced energy expenditure and enhanced weight gain, insulin secretion, and stimulation of corticotropin and corticosterone release. The ARC-PVN projection appears to be overactive in insulin-deficient diabetic rats, and could contribute to the compensatory hyperphagia and reduced energy expenditure, and pituitary dysfunction found in these animals; overactivity of these NPY neurons may be due to reduction of insulin's normal inhibitory effect. The ARC-PVN projection is also stimulated in rat models of obesity +/- non-insulin diabetes, possibly because the hypothalamus is resistant to inhibition by insulin; in these animals, enhanced activity of ARC NPY neurons could cause hyperphagia, reduced energy expenditure, and obesity, and perhaps contribute to hyperinsulinemia and altered pituitary secretion. Overall, these findings suggest that NPY released in the hypothalamuss, especially from the ARC-PVN projection, plays a key role in the hypothalamic regulation of energy balance and metabolism. NPY is also found in the human hypothalamus. Its roles (if any) in human homeostasis and glucoregulation remain enigmatic, but the animal studies have identified it as a potential target for new drugs to treat obesity and perhaps NIDDM.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Homeostasis; Humans; Mice; Neural Pathways; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Syndrome

The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus.

Topics: Abnormalities, Multiple; Adolescent; Animals; Chromosome Disorders; Chromosomes, Human, Pair 5; Female; Gene Deletion; Humans; Hypoglycemia; Hypothalamus; Hypothermia; Male; MEF2 Transcription Factors; Methyl-CpG-Binding Protein 2; Mice; Neuropeptide Y; Phenotype; Syndrome

Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved.. All experiments were performed in CCl₄-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α₁-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries.. NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries.. NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.

Topics: Animals; Blotting, Western; Hypertension, Portal; Infusions, Intravenous; Liver Cirrhosis, Experimental; Male; Neuropeptide Y; Nitric Oxide Synthase; Perfusion; Portal Pressure; Rats; Rats, Sprague-Dawley; rhoA GTP-Binding Protein; Splanchnic Circulation; Syndrome; Treatment Outcome; Vasoconstriction; Vasodilation

Fibromyalgia (FM) is thought to occur because of the combination of interactions among neurotransmitters, such as neuropeptide Y (NPY), stressors, hormones, cytokines, and both the immune and sympathetic nervous systems. The aim of this study was to evaluate serum concentrations of cytokines, antipolymer antibodies (APA), and NPY in 51 patients with FM, 25 with tension-type headache (TTH), and 15 healthy controls. Serum concentrations of eight different cytokines, APA and NPY, were measured. Interleukin (IL)-1RA, IL-6, IL-10, and tumor necrosis factor-alpha were higher in serum of FM patients compared with TTH patients and a significant correlation between IL-10 and Fibromyalgia Impact Questionnaire score was observed. There was a significant difference between FM and TTH versus controls in NPY levels, but not in APA levels. Cytokines and NPY take part in pain modulation and even if they are altered in FM they cannot be considered as measurable biomarkers of disease.

Topics: Adult; Aged; Antibodies; Case-Control Studies; Cytokines; Female; Fibromyalgia; Humans; Interviews as Topic; Male; Middle Aged; Neuropeptide Y; Pain; Surveys and Questionnaires; Syndrome; Tension-Type Headache

To observe the difference in fatty degree, glucose-lipid disorder and adipose-hormones between diet induced obesity (DIO) rats and diet induced obesity resistance (DIO-R) rats, and to explore the effect and acting mechanism of Chinese drugs for strengthening Pi (CD-SP) and those for both strengthening Pi and dissolving phlegm (CD-SPDP) in inhibiting obesity.. Excepting eight rats allocated in the blank control group, the other 54 rats were fed with high-lipid forage for 12 weeks to establish models of obesity. Finally, 30 DIO rats and 8 DIO-R rats (shown by their body weight) were obtained. The DIO rats were divided into three groups, which were given gastric perfusion, respectively, with normal saline (Group A), CD-SP (Group B), and CD-SPDP (Group C). Fourteen weeks later, the animals' body weight (BW), length (BL), blood levels of fasting insulin (FIn), fasting glucose (FBG), triglyceride (TG), cholesterol (TC), leptin (LP), neuropeptide Y (NPY), C-reactive protein (CRP), tumor necrosis factor-alpha(TNF-alpha), adiponectin (AN), and resistin (RS) were measured; insulin resistance index (IRI) was calculated, and the degree of obesity and lipid content in abdominal cavity of rats were estimated. Moreover, the levels of LP, CRP, TNF-alpha, AN and RS in homogenate of rats' adipose tissues (ATH) were determined.. After 12 weeks of high-lipid diet, the BW of DIO rats was higher than that of normal or DIO-R rats. After a 14-week continuous high-lipid diet feeding, in DIO rats, BW, lipid coefficient (LC), and IRI were significantly increased (P<0.01); serum levels of TNF-alpha, LP and AN were lower, NPY was higher, while the ATH levels of LP and AN were lower and TNF-alpha was higher in DIO rats than in DIO-R rats (P<0.05 or P<0.01); blood levels of FBG and lipids in DIO rats showed an increasing trend but was statistically insignificant (P>0.05); no significant difference was found in serum levels of CRP and RS due to the overly high data dispersion. Comparisons of the 3 DIO groups showed that BW, body weight index (BWI), LC and IRI were significantly lowered after treatment (P<0.01) in Group C, while these indexes were not significantly different between Group A and B; the serum levels of TNF-alpha, LP, and AN increased, NPY decreased in Group B and C, ATH levels of LP and AN increased, and TNF-alpha decreased in the two groups; but NPY, LP, and AN in blood and ATH were higher in Group C than those in Group B (P<0.05 or P<0.01).. CD-SPDP could inhibit DIO and IR, showing that the effect is better than that of CD-SP, and its mechanism is related to promotion of LP and AN secretion and elevation of serum NPY.

Topics: Adipokines; Animals; Blood Glucose; C-Reactive Protein; Diet, Atherogenic; Dietary Fats; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Leptin; Male; Neuropeptide Y; Obesity; Random Allocation; Rats; Rats, Wistar; Syndrome; Tumor Necrosis Factor-alpha

Using microarray analysis, in situ hybridization and immunocytochemistry, we found that the transcription factor TBX3 is produced in three discrete neuronal populations of the adult mouse brain, the arcuate nucleus (including in NPY but not dopaminergic neurons), the histaminergic tuberomammillary nucleus and in cholinergic neurons of the solitary tract nucleus. The immunoreactive protein had a nuclear location in these neurons, consistent with its function as a transcription factor. Although the function of tbx3 in these neurons is unknown, a review of the literature strongly suggests that these neuronal populations may be abnormal in Ulnar-Mammary syndrome patients with tbx3 mutations, explaining previously overlooked phenotypes in this syndrome, such as obesity, sexual dysfunction and possibly sleep abnormalities.

Topics: Acetylcholine; Animals; Arcuate Nucleus of Hypothalamus; Brain Mapping; Cell Nucleus; Gene Expression Regulation; Hypothalamic Area, Lateral; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Solitary Nucleus; Syndrome; T-Box Domain Proteins; Transcription Factors

Hemimegalencephaly (HMEG) is a malformation of cortical development characterized by unilateral enlargement of the cerebral hemisphere, severe architectural and cellular abnormalities and association with intractable epilepsy. HMEG may represent an isolated lesion of the central nervous system, but may also be associated with several neurocutaneous syndromes. In the present study we discuss the neuropathological findings of two autopsy cases of HMEG associated with linear naevus sebaceous syndrome. Both cases showed the presence of linear naevus sebaceous on extensive areas of the face. The neurochemical profile of the glial and neuronal components in the affected hemisphere was determined using immunocytochemical markers and was compared with the unaffected contralateral hemisphere and normal control tissue. The observed cytomegalic neurones expressed receptors for distinct neurotransmitters, neuropeptides and growth factors. Analysis of components of the phosphoinositide 3-kinase pathway revealed expression of phospho-S6 ribosomal protein in cytomegalic neurones. Autopsy findings confirm the complexity of the histologic phenotypic manifestations in HMEG and proved useful in determining the spectrum of cytoarchitectural and neurochemical abnormalities, underlying the molecular pathogenesis and epileptogenesis of this brain malformation.

Topics: Adolescent; Autopsy; Brain Chemistry; Cell Count; Cerebral Cortex; Functional Laterality; Humans; Immunohistochemistry; Infant, Newborn; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Nevus; Receptors, Glutamate; Seizures; Syndrome; Tissue Fixation; Vascular Endothelial Growth Factor A

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Topics: Animals; Hyperphagia; Hypogonadism; Insulin Resistance; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Syndrome

A 47 year old man, one of a sibship affected by amyotrophic choreo-acanthocytosis was studied neuropathologically after some years of clinical observation. Besides the classic optical findings (neuronal loss, astrocytic gliosis and "status spongiosus" in the basal ganglia, namely in the caudate nucleus) a few MEnk+ and NPY+ neurons were observed immunocytochemically in the striatum. In the spinal cord also, while no neuronal loss was perceivable, both mild demyelination and interfibrillary astrocytic hyperplasia of the long tracts were present. On the other hand, microscopic findings of muscle and peripheral nerve showed no differences from what was previously intra-vitam appreciated in the same patient. The neuropathological and immunocytochemical findings of this case are discussed in relation to the differential diagnosis between amyotrophic choreo-acanthocytosis and Huntington's disease.

Topics: Atrophy; Blood Cell Count; Brain; Caudate Nucleus; Enkephalin, Methionine; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Male; Middle Aged; Movement Disorders; Muscles; Neuromuscular Diseases; Neuropeptide Y; Peripheral Nerves; Reflex, Stretch; Spinal Cord; Syndrome