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Dysfunction of group 2 innate lymphoid cells (ILC2s) plays an important role in the development of type 2 inflammation- related diseases such as asthma and pulmonary fibrosis. Notably, neural signals are increasingly recognized as pivotal regulators of ILC2s. However, how ILC2s intrinsically modulate their responsiveness to these neural signals is still largely unknown. Here, using single-cell RNA-Seq, we found that the immune-regulatory molecule phosphatase of activated cells 1 (PAC1) selectively promoted the signaling of the neuropeptide calcitonin gene-related peptide (CGRP) in ILC2s in a cell-intrinsic manner. Genetic ablation of PAC1 in ILC2s substantially impaired the inhibitory effect of CGRP on proliferation and IL-13 secretion. PAC1 deficiency significantly exacerbated allergic airway inflammation induced by Alternaria alternata or papain in mice. Moreover, in human circulating ILC2s, the expression level of PAC1 was also significantly negatively correlated with the number of ILC2s and their expression level of IL13. Mechanistically, PAC1 was necessary for ensuring the expression of CGRP response genes by influencing chromatin accessibility. In summary, our study demonstrated that PAC1 is an important regulator of ILC2 responses, and we propose that PAC1 is a potential target for therapeutic interventions in type 2 inflammation-related diseases., Introduction Type 2 inflammation is characterized by the secretion of type 2 cytokines (e.g., IL-4, IL-5, and IL-13) and the recruitment of eosinophils (1) and plays a core role in [...]

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH., Introduction The liver is the principal organ involved in lipid metabolism. Dyslipidemia leads to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), which has become an increasing global public [...]

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and [PAX2.sup.+] progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans., Introduction Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder caused by defective development or functioning of hypothalamic gonadotrophin-releasing hormone-secreting (GnRH-secreting) neurons, leading to deficiency of GnRH, the master hormone [...]

Neuropeptide Y (NPY) plays a mediatory role in cerebral insulin function by maintaining energy balance. The current study was designed to determine the role of insulin in food intake and its interaction with NPY receptors in 8 experiments using broiler cockerels (4 treatment groups per experiment, except for experiment 8). Chicks received control solution or 2.5, 5, or 10 ng of insulin in experiment 1 and control solution or 1.25, 2.5, or 5 pg of receptor antagonists B5063, SF22, or SML0891 in experiments 2, 3, and 4 through intracerebroventricular (ICV) injection, respectively. In experiments 5, 6, and 7, chicks received ICV injection of B5063, SF22, SML0891, or co-injection of an antagonist + insulin, control solution, and insulin. In experiment 8, blood glucose was measured. Insulin, B5063, and SML0891 decreased food intake, while SF22 led to an increase in food intake. The hypophagic effect of insulin was also reinforced by injection of B560, but ICV injection of SF22 destroyed this hypophagic effect of insulin and increased food intake (p < 0.05). However, SML0891 had no effect on decreased food intake induced by insulin (p > 0.05). At 30 min postinjection, blood sugar in the control group was higher than that in the insulin group (p < 0.05). Therefore, the [NPY.sub.1] and [NPY.sub.2] receptors mediate the hypophagic effect of insulin in broiler cockerels.Key words: hypophagic effects, insulin, broiler cockerels, NPY receptors, ICV injection.Le neuropeptide Y (NPY) joue un role de mediateur dans la fonction cerebrale de l'insuline en preservant l'equilibre energetique. La presente etude a ete con^ue en vue d'etablir le role de l'insuline dans la consommation de nourriture et ses interactions avec les recepteurs NPY dans 8 experiences sur des coquelets a rotir (chacune avec 4 groupes de traitement a l'exception de l'experience 8). Les poulets ont re^u par injection intracerebroventriculaire (ICV) une solution temoin ou 2,5,5 ou 10 ng d'insuline dans l'experience 1, et une solution temoin ou 1,25, 2,5 ou 5 pg de B5063, de SF22 ou de SML0891 dans les experiences 2, 3 et 4, respectivement. Dans les experiences 5, 6 et 7, les poulets ont re^u des injections ICV de B5063, de SF22 et de SML0891, l'injection de chacun de ces produits avec de l'insuline, une solution temoin et de l'insuline. Dans l'experience 8, nous avons mesure la glycemie. L'administration d'insuline, de B5063 et de SML0891 a entraine une diminution de la consommation de nourriture, alors l'administration de SF22 menait a une augmentation de la consommation de nourriture. De plus, l'effet hypophagique de l'insuline etait renforce avec l'injection de B560, mais l'injection ICV de SF22 aneantissait l'effet hypophagique de l'insuline avec une augmentation de la consommation de nourriture (p < 0,05). Cependant, le SML0891 n'avait aucun effet sur la diminution de la consommation de nourriture engendree par l'insuline (p > 0,05). Trente minutes apres l'injection, la glycemie etait plus elevee dans le groupe temoin qu'avec l'insuline (p < 0,05). Par consequent, les recepteurs [NPY.sub.1] et [NPY.sub.2] agissent comme mediateurs dans l'effet hypophagique de l'insuline chez les coquelets a rotir. [Traduit par la Redaction]Mots-cles: effets hypophagiques, insuline, coquelets a rotir, recepteurs NPY, injection ICV., IntroductionThe central regulation of food intake is modulated in different parts of the brain, including the corpus striatum, nucleus tractus solitarius, amygdala, hypothalamus, and arcuate nucleus (Hamidi and Yousefvand 2017). [...]

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron-specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding., Introduction Hypothalamic pro-opiomelanocortin (POMC) neurons critically mediate leptin signaling and regulate feeding behavior and systemic metabolic homeostasis via the secretion of several bioactive neuropeptides derived from the POMC protein precursor [...]

Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-[alpha] (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics., Author(s): Yifeng Zhang [1]; Jiankun Xu [1]; Ye Chun Ruan [2]; Mei Kuen Yu [2]; Micheal O'Laughlin [1]; Helen Wise [3]; Di Chen [4]; Li Tian [1]; Dufang Shi [1]; [...]

BACKGROUND/OBJECTIVES: Neuropeptide Y (NpY) is an important factor in neuropeptide signalling, and significantly change in the blood and cerebrospinal fluid (CSF) during chronic kidney disease (CKD) progression. However, the role of NpY remains unclear. We aimed to investigate the associations between NpY levels, nutritional status and cardiovascular disease (CVD) in patients with CKD. SUBJECTS/METHODS: In this cohort study, we performed Pearson's correlation analysis and multiple linear regressions to assess the relationship between CSF and serum NpY levels, as well as nutritional indices. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of CSF NpY levels. As NpY affects the cardiovascular system, Kaplan- Meier analysis was used to investigate the relationship between serum NpY levels and CVD. RESULTS: CSF NpY levels and nutritional indices were related during CKD progression (energy intake: β = 0.236, P < 0.001; mid-arm muscle circumference: β = 0.953, P = 0.014; prealbumin: β = 0.067, P < 0.001), and had high specificity (79.9%). High serum NpY levels may be a risk factor associated with CVD (relative risk =1.8015, 95% confidence interval: 1.0509-3.0881). CONCLUSIONS: Our results suggested a relationship between CSF NpY levels and nutritional indices in CKD patients. High serum NpY concentrations may be a risk factor associated with CVD. European Journal of Clinical Nutrition (2015) 69, 717-721; doi: 10.1038/ejcn.2015.67; published online 29 April 2015, INTRODUCTION Patients with chronic kidney disease (CKD), especially those with end-stage renal disease, suffer from cachexia, potentially along with protein energy wasting (PEW). (1) Nutritional status is both affected by [...]

Like all heterotrophic organisms, insects require a strict control of food intake and efficient digestion of food into nutrients to maintain homeostasis and to fulfill physiological tasks. Feeding and digestion are steered by both external and internal signals that are transduced by a multitude of regulatory factors, delivered either by neurons innervating the gut or mouthparts, or by midgut endocrine cells. The present review gives an overview of peptide regulators known to control feeding and digestion in insects. We describe the discovery and functional role in these processes for insect allatoregulatory peptides, diuretic hormones, FMRFamide-related peptides, (short) neuropeptide F, proctolin, saliva production stimulating peptides, kinins, and tachykinins. These peptides control either gut myoactivity, food intake, and (or) release of digestive enzymes. Some peptides exert their action at multiple levels, possibly having a biological function that depends on their site of delivery. Many regulatory peptides have been physically extracted from different insect species. However, multiple peptidomics, proteomics, transcriptomics, and genome sequencing projects have led to increased discovery and prediction of peptide (precursor) and receptor sequences. In combination with physiological experiments, these large-scale projects have already led to important steps forward in unraveling the physiology of feeding and digestion in insects. Key words: insect, midgut, digestion, neuropeptides, stomatogastric nervous system. Comme tous les organismes heterotrophes, les insectes requierent un controle strict de leur ingestion de nourriture et la digestion de leur nourriture en nutriments afin de maintenir leur homeostasie et de completer leurs taches physiologiques. L'alimentation et la digestion sont gouvernees par des signaux tant externes qu'internes qui sont transmis par un multitude de facteurs regulateurs, livres ou bien par les neurones qui innervent le tube digestif ou les pieces buccales ou alors par les cellules endocrines du tube digestif moyen. Notre revue fournit une synthese des regulateurs peptidiques connus pour controler l'alimentation et la digestion chez les insectes. Nous decrivons la decouverte et le role fonctionnel de ces processus dans le cas des peptides allatoregulateurs, des hormones diuretiques, des peptides apparentes aux amides FMRF, du neuropeptide F (court), de la proctoline, des peptides stimulateurs de la production de salive, des kinines et des tachykinines des insectes. Ces peptides controlent la myoactivite du tube digestif, l'ingestion de nourriture et(ou) la liberation des enzymes digestives. Certains peptides agissent a de multiples niveaux, possedant une fonction biologique qui depend de leur site d'action. Plusieurs peptides regulateurs ont ete extraits physiquement de differentes especes d'insectes. Cependant, plusieurs projets de peptidomique, de proteomique, de transcriptomique et de genomique ont mene a de nombreuses decouvertes supplementaires et des predictions de sequences de peptides (precurseurs) et de recepteurs. En combinaison avec les experiences physiologiques, ces projets a grande echelle ont deja mene a des progres importants dans l'elucidation de la physiologie de l'alimentation et de la digestion chez les insectes. Mots-cles: insecte, tube digestif moyen, digestion, neuropeptides, systeme nerveux stomogastrique. [Traduit par la Redaction], Introduction Eumetazoa are heterotrophs that acquire organic compounds through feeding. Therefore, strict control of food intake and efficient digestion of food into nutrients are indispensible for these organisms to maintain [...]

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein--coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8-22 (BAM 822), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8-22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets. inflammation | neuropeptides | sensory neurons | Mrgpr doi/ 10.1073/pnas.1011221107

Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE + 2% CL; HE + 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC + HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL + HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15-30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL + HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL + HE and SC + HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release. fatty acid; intestinal absorption; cholesterol 7[alpha]-hydroxylase; glucagon-like peptide-1 doi:10.1152/ajpgi.00362.2009.

To investigate the role of the central neuromedin U (NMU) signaling system in body weight and energy balance regulation, we examined the effects of long-term intracerebroventricular (icy) infusion of NMU in C57B1/6 mice and in mice lacking the gene encoding NMU receptor 2. In diet-induced obese male and female C57BL/6 mice, icy infusion of NMU (8 [micro]g x [day.sup.-1] x [mouse.sup.-1]) for 7 days decreased body weight and total energy intake compared with vehicle treatment. However, these parameters were unaffected by NMU treatment in lean male and female C57BL/6 mice fed a standard diet. In addition, female (but not male) NMUR2-null mice had increased body weight and body fat mass when fed a high-fat diet but lacked a clear body weight phenotype when fed a standard diet compared with wild-type littermates. Furthermore, female (but not male) NMUR2-null mice fed a high-fat diet were protected from central NMU-induced body weight loss compared with littermate wild-type mice. Thus, we provide the first evidence that long-term central NMU treatment reduces body weight, food intake, and adiposity and that central NMUR2 signaling is required for these effects in female but not male mice. neuromedin U; appetite; anorexic; energy expenditure; obesity; food intake; neuromedin U receptor 2; FM4; GRP66

Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A[beta]). We have hypothesized that the intrinsic A[beta] calcium channel activity of the oligomeric A[beta] polymer may be responsible for the neurotoxic properties of A[beta], and that A[beta] channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A[beta] channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A[beta] channel and protect neurons from A[beta] toxicity. Both block the A[beta] channel with similar potency ([approximately equal to] 500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery. brain | neurodegeneration | rational drug design | drug | toxicity

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein ([MOG.sub.35-55])-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNF[alpha], IL-6, IFN-[gamma] IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1[alpha]/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-[beta]) in the spinal cord. Moreover, the abundance of CD[4.sup.+]CD[25.sup.+][FoxP3.sup.+] Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-[beta] secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation. autoimmunity | regulatory T cell | inflammation | knock-out | multiple sclerosis

Treatment of neuropathic pain is a major clinical problem. This study shows expression of phospholipase [beta]3 (PLC[beta]3) in mouse and human DRG neurons, mainly in small ones and mostly with a nonpeptidergic phenotype. After spared nerve injury, the pain threshold was strongly reduced, and systemic treatment of such animals with the unselective PLC inhibitor U73122 caused a rapid and long-lasting (48-h) increase in pain threshold. Thus, inhibition of PLC may provide a way to treat neuropathic pain. galanin receptor 2 | nerve injury | neuropeptide | pain treatment | sensory neuron

Agouti-related peptide (AgRP), the endogenous antagonist to the melanocortin 3 and 4 receptors, elicits robust hyperphagia and weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause weight gain in rodents partially depends on the activity level of the melanocortin agonist-producing proopiomelanocortin neurons. Both proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as leptin and insulin. Another modulator of AgRP activity includes the cell surface molecule syndecan-3. Because leptin and insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days (P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of hyperphagia (P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure ([Vo.sub.2]) following AgRP compared with male rats (P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in [Vo.sub.2] exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats. AgRP; melanocortin; energy expenditure; sex; food intake

A neuropeptide, calcitonin gene-related peptide (CGRP), is widely distributed in neuronal systems and exhibits numerous biological activities. Using CGRP-knockout mice ([CGRP.sup.-/-]), we examined whether or not endogenous CGRP facilitates angiogenesis indispensable to tumor growth. CGRP increased tube formation by endothelial cells in vitro and enhanced sponge-induced angiogenesis in vivo. Tumor growth and tumor-associated angiogenesis in [CGRP.sup.-/-] implanted with Lewis lung carcinoma (LLC) cells were significantly reduced compared with those in wild-type (WT) mice. A CGRP antagonist, CGRP8-37 or denervation of sciatic nerves ([L.sub.1-5]) suppressed LLC growth in the sites of denervation compared with vehicle infusion or sham operation. CGRP precursor mRNA levels in the dorsal root ganglion in LLC-bearing WT were increased compared with those in non-LLC-bearing mice. This increase was abolished by denervation. The expression of VEGF in tumor stroma was down-regulated in [CGRP.sup.-/-]. These results indicate that endogenous CGRP facilitates tumor-associated angiogenesis and tumor growth and suggest that relevant CGRP may be derived from neuronal systems including primary sensory neurons and may become a therapeutic target for cancers. knockout mice | neuropeptide | CGRP antagonist | sensory nerve

Prokineticin 2 (PK2) is a neuropeptide that acts as a signaling molecule regulating circadian rhythms in mammals. We have previously reported PK2 actions on subfornical organ (SFO) neurons, identifying this circumventficular organ as a target at which PK2 acts to influence autonomic control (Cottrell GT, and Ferguson AV. J. Neurosci. 24: 2375-2379, 2004). In this study, we have examined the cellular mechanisms by which PK2 increases the excitability of SFO neurons. Whole cell patch recordings from dissociated rat SFO neurons demonstrated that the mitogen-activated protein (MAP) kinase inhibitor PD-98059 prevented PK2-induced depolarization and decreases in delayed rectifier [K.sup.+] current. PK2 also increased intracellular [Ca.sup.2+] concentration ([[Ca.sup.2+]]i) in 39% of dissociated SFO neurons (mean increase = 20.8 [+ or -] 5.5%), effects that were maintained in the presence of thapsigargin but abolished by both nifedipine, or the absence of extracellular [Ca.sup.2+], suggesting that PK2-induced [[Ca.sup.2+]]i transients resulted from [Ca.sup.2+] entry through voltage-gated [Ca.sup.2+] channels. Voltage-clamp recordings showed that PK2 was without effects on [Ca.sup.2+] currents evoked by voltage ramps, suggesting that PK2-induced [Ca.sup.2+] influx was secondary to PK2-induced increases in action potential frequency, an hypothesis supported by data showing that tetrodotoxin abolished effects of PK2 on [[Ca.sup.2+]]i. These observations suggested PK2 modulation of voltage-gated [Na.sup.+] currents, a possibility confirmed by voltage-clamp experiments showing that PK2 increased the amplitude of both transient and persistent [Na.sup.+] currents in 29% of SFO neurons (by 34 and 38%, respectively). These data indicate that PK2 influences SFO neurons through the activation of a MAP kinase cascade, which, in turn, modulates [Na.sup.+] and [K.sup.+] conductances. circumventricular organs; neuropeptides; potassium current; sodium current; mitogen-activated protein kinase; intracellular [Ca.sup.2+]

Melanin-concentrating hormone (MCH) is expressed primarily in the hypothalamus and has a positive impact on feeding behavior and energy balance. Although MCH is expressed in the gastrointestinal tract, its role in this system remains elusive. We demonstrate that, compared to wild type, mice genetically deficient in MCH had substantially reduced local inflammatory responses in a mouse model of experimental colitis induced by intracolonic administration of 2,4,6 trinitrobenzene sulfonic acid (TNBS). Likewise, mice receiving treatments with an anti-MCH antibody, either prophylactically or after the establishment of colitis, developed attenuated TNBS-associated colonic inflammation and survived longer. Consistent with a potential role of MCH in intestinal pathology, we detected increased colonic expression of MCH and its receptor in patients with inflammatory bowel disease. Moreover, we found that human colonic epithelial cells express functional MCH receptors, the activation of which induces IL-8 expression. Taken together, these results clearly implicate MCH in inflammatory processes in the intestine and perhaps elsewhere. experimental colitis | IL-8 | inflammatory bowel disease | neuropeptides | MCH deficient mice

Background: Denervation substantially impairs healing of the medial collateral ligament (MCL). Because normal ligaments are sparsely innervated, we hypothesized that neuropeptide-containing neurons would sprout or proliferate after ligament transection, followed [...]

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylaseimmunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect. intrathecal; barodenervation; cholera toxin B; Sprague-Dawley

Secretoneurin (SN), a neuropeptide derived from secretogranin II, promotes neurite outgrowth of immature cerebellar granule cells. SN also aids in the growth and repair of neuronal tissue, although the precise mechanisms underlying the promotion of brain tissue neuroprotection and plasticity by SN are not understood. Here, in a rat model of stroke and in ischemic human brain tissue, SN was markedly upregulated in both neurons and endothelial cells. SN-mediated neuroprotection rescued primary cortical cell cultures from oxygen/glucose deprivation. SN also induced expression of the antiapoptotic proteins Bcl-2 and Bcl-xL through the Jak2/Stat3 pathway and inhibited apoptosis by blocking caspase-3 activation. In addition, rats with occluded right middle cerebral arteries showed less cerebral infarction, improved motor performance, and increased brain metabolic activity following i.v. administration of SN. Furthermore, SN injection enhanced stem cell targeting to the injured brain in mice and promoted the formation of new blood vessels to increase local cortical blood flow in the ischemic hemisphere. Both in vitro and in vivo, SN not only promoted neuroprotection, but also enhanced neurogenesis and angiogenesis. Our results demonstrate that SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway., Introduction Secretoneurin (SN) is a 33-amino acid neuropeptide produced by endoproteolytic processing of chromogranin/secretogranin family proteins, which are found in large dense-core vesicles in a wide variety of cell types [...]

Byline: Zafar Nazir (1), Rehan Masood (1), Resham Rehman (1) Keywords: Hypospadias; Wound healing; PGP 9.5; Calcitonin gene-related peptide (CGRP); Substance P (SP) Abstract: Sensory innervation of the skin influences wound healing through the release of neuropeptides from the nerve endings. The purpose of this study was to investigate the differences in the sensory innervation of the normal and the hypospadiac prepuce. The prepuce from 10 healthy children undergoing routine circumcision and 10 age-matched children undergoing hypospadias repair were submitted for immunohistochemistry, using antibodies against protein gene product (PGP) 9.5, calcitonin gene-related peptide (CGRP), and substance P (SP). The hypospadiac prepuce was found to be hypo-innervated for PGP 9.5 and CGRP positive nerves when compared with the normal prepuce (p&lt 0.05). The number of SP-positive nerves were increased in the hypospadiac prepuce, but not to statistical significance (p=0.06, confidence interval &gt 95%). There may be differences in the sensory innervation of the normal and hypospadiac prepuce. These differences in tissue environment may partly explain the postoperative edema, poor wound healing leading to urethrocutaneous fistula (UF), and increased analgesia requirements in patients undergoing hypospadias surgery. Author Affiliation: (1) Section of Pediatric Surgery, Department of Surgery, The Aga Khan University, Stadium Road, POB 3500, 74800, Karachi , Pakistan Article History: Registration Date: 05/07/2004 Accepted Date: 17/03/2004 Online Date: 29/07/2004

Brain functions are regulated by chemical messengers that include neurotransmitters and neuropeptides. Recent studies have shown that acupuncture or electrical stimulation in specific frequencies applied to certain body sites can facilitate the release of specific neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms. Investigation of the conditions controlling this neurobiological reaction could have theoretical and clinical implications

Galanin is a neuropeptide which inhibits sensory transmission and occurs in cells of the dorsal root ganglion and spinal chord interneurons. The effects of a galanin receptor antagonist, M-35, on flexor reflex excitability in intrathecally injected rats with intact and sectioned sciatic nerves was studied. The results showed that M-35 exerts a facilitatory effect on flexor reflex excitability by activating C-fibers. M-35 potentiated condition stimulation-induced reflex facilitation. Chronic infusion of M-35 resulted in enhanced autotomy behavior. The results suggest that galanin and galanin receptor agonists may be potential analgesic agents.

Amyloid-[beta] (A[beta]) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. A[beta] aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of A[beta]. Using in vivo microdialysis in mice, we found that the amount of ISF A[beta] correlated with wakefulness. The amount of ISF A[beta] also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, A[beta] plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease. 24 August 2009; accepted 11 September 2009 Published online 24 September 2009; 10.1126/science.1180962