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Purpose Sleep restriction is increasingly common and associated with the development of health problems. We investigated how the neuroendocrine stress systems respond to prolonged sleep restriction and subsequent recovery sleep in healthy young men. Methods After two baseline (BL) nights of 8 h time in bed (TIB), TIB was restricted to 4 h per night for five nights (sleep restriction, SR, n = 15), followed by three recovery nights (REC) of 8 h TIB, representing a busy workweek and a recovery weekend. The control group (n = 8) had 8 h TIB throughout the experiment. A variety of autonomic cardiovascular parameters, together with salivary neuropeptide Y (NPY) and cortisol levels, were assessed. Results In the control group, none of the parameters changed. In the experimental group, heart rate increased from 60 +/- 1.8 beats per minute (bpm) at BL, to 63 +/- 1.1 bpm after SR and further to 65 +/- 1.8 bpm after REC. In addition, whole day low-frequency to-high frequency (LF/HF) power ratio of heart rate variability increased from 4.6 +/- 0.4 at BL to 6.0 +/- 0.6 after SR. Other parameters, including salivary NPY and cortisol levels, remained unaffected. Conclusions Increased heart rate and LF/HF power ratio are early signs of an increased sympathetic activity after prolonged sleep restriction. To reliably interpret the clinical significance of these early signs of physiological stress, a follow-up study would be needed to evaluate if the stress responses escalate and lead to more unfavourable reactions, such as elevated blood pressure and a subsequent elevated risk for cardiovascular health problems.

The cross-linked pentapeptides (2R, 7R)-diaminooctanedioyl- bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2R, 7R)BVD- 74D, (2R, 7R)-1) and octanedioyl-bis(Tyr-Arg-Leu-ArgTyr- amide) (2) as well as the pentapeptide Ac-Tyr-Arg-LeuArg- Tyr-amide (3) were previously described as neuropeptide Y Y-4 receptor (Y4R) partial agonists. Here, we report on a series of analogues of (2R, 7R)-1 and 2 in which Arg(2), Leu(3), or Arg(4) were replaced by the respective aza-amino acids. The replacement of Arg(2) in 3 with a carbamoylated arginine building block and the extension of the N-terminus by an additional arginine led to the high-affinity hexapeptide Ac-Arg-Tyr-N-omega-[(4-aminobutyl) aminocarbonyl] Arg-Leu-Arg-Tyr-amide (35), which was used as a precursor for a D-amino acid scan. The target compounds were investigated for Y4R functional activity in assays with complementary readouts: aequorin Ca2+ and beta-arrestin 1 or beta-arrestin 2 assays. In contrast to the parent compounds, which are Y4R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y4R antagonists.

Ladrón de Guevara-Miranda, David et al., Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety andmemory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while othermice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocainewithdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal., This research was funded by the Spanish Ministerio de Economía y Competitividad and the European Commission Regional Development Fund (UE-ERDF) (PSI2015- 73156-JIN to E.C-O, SAF12-36853 to M.A.-D and PSI2013-44901-P to L.J.S.), Junta de Andalucıa (CTS-2563 to M.A.-D) and Red de Trastornos Adictivos (RD12/ ́ 0028/0001 to F.R.F.). Authors received funds from the National System of Health Instituto de Salud Carlos III (Sara Borrell CD12/00455 to E.C-O; Miguel Servet CP14/00173 to A.S. and CP14/00212 to F.J.P.), from the Spanish Ministerio de Educación, Cultura y Deporte (FPU13/04819 to D.L.d.G.-M.) and from the University of Málaga (Plan Propio grant to C.M. and C.R.-V.).

The hypothalamus contains catecholaminergic neurons marked by the expression of tyrosine hydroxylase (TH). As multiple chemical messengers coexist in each neuron, we determined if hypothalamic TH-immunoreactive (ir) neurons express glutamate or GABA. We used Cre/loxP recombination to express enhanced GFP fluorescence (EGFP) in neurons that express the vesicular glutamate (vGLUT2) or GABA transporter (vGAT), then determined TH immunoreactivity in glutamatergic or GABAergic neurons, respectively. EGFP-positive vGLUT2 neurons were not TH-ir. However, discrete TH-ir signals colocalized with EGFP-positive vGAT neurons, which we validated by in situ hybridization for Vgat mRNA. In order to contextualize the observed pattern of TH+EGFP colocalization in vGAT neurons, we first performed Nissl-based parcellation and plane-of-section analysis, and then mapped the distribution of TH-ir vGAT neurons onto atlas templates from the Allen Reference Atlas (ARA) of the mouse brain. TH-ir vGAT neurons were distributed throughout the rostrocaudal extent of the hypothalamus. Within the ARA ontology of gray matter regions, TH-ir neurons localized primarily to the periventricular hypothalamic zone, periventricular hypothalamic region, and lateral hypothalamic zone. There was a very strong presence of EGFP fluorescence in TH-ir neurons across all brain regions, but the most striking colocalization was found in the zona incerta (ZI) – a region assigned to the hypothalamus in the ARA – where every TH-ir neuron was EGFP-positive. Neurochemical characterization of these ZI neurons revealed that they display immunoreactivity for dopamine but not dopamine β-hydroxylase. In aggregate, these findings indicate the existence of a novel hypothalamic population in the mouse that may signal through the release of GABA and/or dopamine.

Feeding is a complex behaviour comprised of satiety control, foraging, ingestion and subsequent digestion. Cichlids from the East African Great Lakes are renowned for their diverse trophic specializations, largely predicated on highly variable jaw morphologies. Thus, most research has focused on dissecting the genetic, morphological and regulatory basis of jaw and teeth development in these species. Here for the first time we explore another aspect of feeding, the regulation of appetite related genes that are expressed in the brain and control satiety in cichlid fishes. Using qPCR analysis, we first validate stably expressed reference genes in the brain of six haplochromine cichlid species at the end of larval development prior to foraging. We next evaluate the expression of 16 appetite related genes in herbivorous and carnivorous species from the parallel radiations of Lake Tanganyika, Malawi and Victoria. Interestingly, we find increased expression of two anorexigenic genes, cart and npy2r, in the brain of carnivorous species in all the lakes. This supports the notion that herbivory compared to carnivory requires stronger appetite stimulation in order to feed larger quantity of food and to compensate for the relatively poorer nutritional quality of a plant- and algae-based diet. Our study contributes to the limited body of knowledge on the neurological circuitry that controls feeding transitions and adaptations and in cichlids and other teleosts.

PURPOSE. The purpose of this study was to study the status and association among tear-soluble factors, corneal dendritic cell density, vitamin D, and signs and symptoms in dry eye disease (DED).METHODS. A total of 33 control subjects and 47 evaporative dry eye patients were included in the study. DED diagnosis and classification was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). DED workup, including tear film break-up time (TBUT), Schirmer's test I (STI), corneal and conjunctival staining, ocular surface disease index (OSDI) scoring, and in vivo confocal microscopy (to assess corneal dendritic cell density [cDCD] and subbasal nerve plexus [SBNP] features) was performed in the study subjects. Tear fluid using Schirmer's strip and serum were collected from the subjects. Multiplex ELISA or single analyte ELISA was performed to measure 34 tear-soluble factors levels including vitamin D.RESULTS. Significantly higher OSDI discomfort score, lower TBUT, and lower STI were observed in DED patients. cDCD was significantly higher in DED patients. No significant difference was observed in SBNP features. Tear fluid IL-1 beta, IL-17A, MMP9, MMP10, MMP9/TIMP ratio, and VEGF-B were significantly higher in DED patients. Significantly lower tear fluid IL-2, IP-10, NPY, VEGF-A, and vitamin D was observed in DED patients. These dysregulated tear factors showed significant associations with DED signs and symptoms.CONCLUSIONS. Altered tear fluid soluble factors with potential to modulate nociception exhibited a distinct association with ocular surface discomfort status, TBUT, STI, and cDCD. This implies a functional relationship between the various tear-soluble factors and dry eye pathogenesis, indicating new molecular targets for designing targeted therapies.

The enteric nervous system (ENS) is required for peristalsis of the gut and is derived from Enteric Neural Crest Cells (ENCCs). During ENS development, the RET receptor tyrosine kinase plays a critical role in the proliferation and survival of ENCCs, their migration along the developing gut, and differentiation into enteric neurons. Mutations in RET and its ligand GDNF cause Hirschsprung disease (HSCR), a complex genetic disorder in which ENCCs fail to colonize variable lengths of the distal bowel. To identify key regulators of ENCCs and the pathways underlying RET signaling, gene expression profiles of untreated and GDNF-treated ENCCs from E14.5 mouse embryos were generated. ENCCs express genes that are involved in both early and late neuronal development, whereas GDNF treatment induced neuronal maturation. Predicted regulators of gene expression in ENCCs include the known HSCR genes Ret and Sox10, as well as Bdnf, App and Mapk10. The regulatory overlap and functional interactions between these genes were used to construct a regulatory network that is underlying ENS development and connects to known HSCR genes. In addition, the adenosine receptor Ala (Adora2a) and neuropeptide Y receptor Y2 (Npy2r) were identified as possible regulators of terminal neuronal differentiation in GDNF-treated ENCCs. The human orthologue of Npy2r maps to the HSCR susceptibility locus 4q31.3-q32.3, suggesting a role for NPY2R both in ENS development and in HSCR. (C) 2016 Elsevier Inc. All rights reserved.

Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin's metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.

Aims To investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans. Materials and methods In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells). Results Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. Conclusions Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin-(CR), calbindin-(CB), cholecystokinin-(CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II–III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR-and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.

Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2(-/-) mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2(-/-) mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2(-/-) mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

Objective Neuropeptide Y (NPY) is one of the most potent orexigenic peptides. The hypothalamic paraventricular nucleus (PVN) is a major locus where NPY exerts its effects on energy homeostasis. We investigated how NPY exerts its effect within the PVN. Methods Patch clamp electrophysiology and Ca2+ imaging were used to understand the involvement of Ca2+ signaling and retrograde transmitter systems in the mediation of NPY induced effects in the PVN. Immuno-electron microscopy were performed to elucidate the subcellular localization of the elements of nitric oxide (NO) system in the parvocellular PVN. In vivo metabolic profiling was performed to understand the role of the endocannabinoid and NO systems of the PVN in the mediation of NPY induced changes of energy homeostasis. Results We demonstrated that NPY inhibits synaptic inputs of parvocellular neurons in the PVN by activating endocannabinoid and NO retrograde transmitter systems via mobilization of Ca2+ from the endoplasmic reticulum, suggesting that NPY gates the synaptic inputs of parvocellular neurons in the PVN to prevent the influence of non-feeding-related inputs. While intraPVN administered NPY regulates food intake and locomotor activity via NO signaling, the endocannabinoid system of the PVN selectively mediates NPY-induced decrease in energy expenditure. Conclusion Thus, within the PVN, NPY stimulates the release of endocannabinoids and NO via Ca2+-influx from the endoplasmic reticulum. Both transmitter systems appear to have unique roles in the mediation of the NPY-induced regulation of energy homeostasis, suggesting that NPY regulates food intake, energy expenditure, and locomotor activity through different neuronal networks of this nucleus., Graphical abstract Image 1, Highlights • NPY increases the intracellular Ca2+ level of PVN neurons by mobilizing the Ca2+ from ER. • NPY inhibits the input of these neurons by endocannabinoids and NO. • IntraPVN administered NPY regulates food intake and locomotor activity via NO signaling. • IntraPVN administered NPY regulates energy expenditure via the endocannabinoid system. • NPY regulates the energy expenditure and food intake via different neuronal networks of the PVN.

Background: Recently, intra-articular botulinum toxin A (IA BoNT A) has been shown to reduce joint pain in osteoarthritic dogs. Similar results have been reported in human patients with arthritis. However, the mechanism of the antinociceptive action of IA BoNT A is currently not known. The aim of this study was to explore this mechanism of action by investigating the effect of IA BoNT A on synovial fluid (SF) and serum substance P (SP), prostaglandin E-2 (PGE(2)), and tumor necrosis factor alpha (TNF-alpha) in osteoarthritic dogs. Additionally, the aim was to compare SF SP and PGE(2) between osteoarthritic and non-osteoarthritic joints, and investigate associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs. Thirty-five dogs with chronic naturally occurring osteoarthritis and 13 non-osteoarthritic control dogs were included in the study. Osteoarthritic dogs received either IA BoNT A (n = 19) or IA placebo (n = 16). Serum and SF samples were collected and osteoarthritic pain was evaluated before (baseline) and 2 and 8 weeks after treatment. Osteoarthritic pain was assessed with force platform, Helsinki Chronic Pain Index, and joint palpation. Synovial fluid samples were obtained from control dogs after euthanasia. The change from baseline in SP and PGE(2) concentration was compared between the IA BoNT A and placebo groups. The synovial fluid SP and PGE(2) concentration was compared between osteoarthritic and control joints. Associations between SP, PGE(2), osteoarthritic pain, and the signalment of dogs were evaluated. Results: There was no significant change from baseline in SP or PGE(2) after IA BoNT A. Synovial fluid PGE(2) was significantly higher in osteoarthritic compared to control joints. Synovial fluid PGE(2) correlated with osteoarthritic pain. No associations were found between SP or PGE2 and the signalment of dogs. The concentration of TNF-alpha remained under the detection limit of the assay in all samples. Conclusions: The results suggest that the antinociceptive effect of IA BoNT A in the joint might not be related to the inhibition of SP nor PGE(2). Synovial fluid PGE(2,) but not SP, could be a marker for chronic osteoarthritis and pain in dogs.

Cortical GABAergic dysfunctions have been documented by clinical studies in major depression. We used here an animal model for depression and investigated whether long-term stress exposure can affect the number of GABAergic neurons in the orbitofrontal cortex (OFC). Adult male rats were subjected to 7-weeks of daily stress exposure and behaviorally phenotyped as anhedonic or stress-resilient animals. GABAergic interneurons were identified by immunohistochemistry and systematically quantified. We analyzed calbindin-(CB), calretinin-(CR), cholecystokinin-(CCK), parvalbumin-(PV), neuropeptide Y-(NPY) and somatostatin-positive (SST+) neurons in the following specific subareas of the OFC: medial orbital (MO), ventral orbital (VO), lateral orbital (LO) and dorsolateral orbital (DLO) cortex. For comparison, we also analyzed the primary motor cortex (M1) as a non-limbic cortical area. Stress had a pronounced effect on CB+ neurons and reduced their densities by 40-50% in the MO, VO and DLO. Stress had no effect on CCK+, CR+, PV+, NPY+ and SST+ neurons in any cortical areas. None of the investigated GABAergic neurons were affected by stress in the primary motor cortex. Interestingly, in the stress-resilient animals, we observed a significantly increased density of CCK+ neurons in the VO. NPY+ neuron densities were also significantly different between the anhedonic and stress-resilient rats, but only in the LO. Our present data demonstrate that chronic stress can specifically reduce the density of calbindin-positive GABAergic neurons in the orbitofrontal cortex and suggest that NPY and CCK expression in the OFC may relate to the stress resilience of the animals. (C) 2016 Elsevier B.V. All rights reserved.

Neuropeptides are a diverse class of intercellular signalling molecules that mediate neuronal regulation of many physiological and behavioural processes. Recent advances in genome/transcriptome sequencing are enabling identification of neuropeptide precursor proteins in species from a growing variety of animal taxa, providing new insights into the evolution of neuropeptide signalling. Here, detailed analysis of transcriptome sequence data from three brittle star species, Ophionotus victoriae , Amphiura filiformis and Ophiopsila aranea , has enabled the first comprehensive identification of neuropeptide precursors in the class Ophiuroidea of the phylum Echinodermata. Representatives of over 30 bilaterian neuropeptide precursor families were identified, some of which occur as paralogues. Furthermore, homologues of endothelin/CCHamide, eclosion hormone, neuropeptide-F/Y and nucleobinin/nesfatin were discovered here in a deuterostome/echinoderm for the first time. The majority of ophiuroid neuropeptide precursors contain a single copy of a neuropeptide, but several precursors comprise multiple copies of identical or non-identical, but structurally related, neuropeptides. Here, we performed an unprecedented investigation of the evolution of neuropeptide copy number over a period of approximately 270 Myr by analysing sequence data from over 50 ophiuroid species, with reference to a robust phylogeny. Our analysis indicates that the composition of neuropeptide ‘cocktails’ is functionally important, but with plasticity over long evolutionary time scales.

Context: The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY3–36 and GLP-17–36 amide, on glucose homeostasis are unknown. Objective: This study sought to investigate the acute effects of PYY3–36 and GLP-17–36 amide, individually and in combination, on insulin secretion and sensitivity. Setting and Design: Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY3–36 alone, GLP-17–36 amide alone, and a combination of PYY3–36 and GLP-17–36 amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility. Results: PYY3–36 alone caused a small but nonsignificant increase in AIRg. GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide did increase AIRg significantly. No significant differences in SI were observed with any intervention. Conclusions: PYY3–36 lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-17–36 amide alone and the combination of PYY3–36 and GLP-17–36 amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY3–36 and GLP-17–36 amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Background Heterogeneity is increasingly recognized in clinical presentation of neuropathic pain (NP), but less often recognized in animal models. Neurochemical dysregulation in rodent dorsal root ganglia (DRG) is associated with peripheral nerve trauma, but poorly studied in non‐traumatic NP conditions. Methods This study aimed to investigate the temporal expressions of activating transcription factor‐3 (ATF‐3), growth‐associated protein‐43 (GAP‐43), neuropeptide Y (NPY) and galanin in traumatic and non‐traumatic rat models of neuropathies associated with NP. Expressions of these markers were examined in the DRG at different time points following tibial nerve transection (TNT) injury and antiretroviral drug stavudine (d4T) administration using immunohistochemistry. The development of sensory gain following these insults was assessed by measuring limb withdrawal to a punctate mechanical stimulus. Results Both TNT‐injured and d4T‐treated rats developed hindpaw mechanical hypersensitivity. Robust expressions of ATF‐3, GAP‐43, NPY and galanin in both small‐ and large‐sized L5 DRG neurons were observed in the DRG from TNT‐injured rats. In contrast, d4T‐treated rats did not exhibit any significant neurochemical changes in the DRG. Conclusions Taken together, the results suggest that ATF‐3, GAP‐43, NPY and galanin are likely indicators of nerve trauma‐associated processes and not generic markers for NP. These experiments also demonstrate distinct expression patterns of neurochemical markers in the DRG and emphasize the mechanistic difference between nerve trauma and antiretroviral drug‐associated NP.

Parasitic infections are often followed by changes in host behaviour. Numerous and exquisite examples of such behavioural alterations are known, covering a broad spectrum of parasites and hosts. Most descriptions of such parasite-induced changes in host behaviour are observational reports, while experimentally confirmed examples of parasite genes inducing these changes are limited. In this study, we review changes in invertebrate host behaviour observed upon infection by parasites and discuss such changes in an evolutionary context. We then explore possible mechanisms involved in parasite-induced changes in host behaviour. Genes and pathways known to play a role in invertebrate behaviour are reviewed, and we hypothesize how parasites (may) affect these pathways. This review provides the state of the art in this exciting, interdisciplinary field by exploring possible pathways triggered in hosts, suggesting methodologies to unravel the molecular mechanisms that lead to changes in host behaviour.

Dietary intake changes during the course of aging. Normally an increase in food intake is observed around 55 years of age, which is followed by a reduction in food intake in individuals over 65 years of age. This reduction in dietary intake results in lowered levels of body fat and body weight, a phenomenon known as anorexia of aging. Anorexia of aging has a variety of consequences, including a decline in functional status, impaired muscle function, decreased bone mass, micronutrient deficiencies, reduced cognitive functions, increased hospital admission and even premature death. Several changes during lifetime have been implicated to play a role in the reduction in food intake and the development of anorexia of aging. These changes are both physiological, involving peripheral hormones, senses and central brain regulation and non-physiological, with differences in psychological and social factors. In the present review, we will focus on age-related changes in physiological and especially non-physiological factors, that play a role in the age-related changes in food intake and in the etiology of anorexia of aging. At the end we conclude with suggestions for future nutritional research to gain greater understanding of the development of anorexia of aging which could lead to earlier detection and better prevention. (c) 2012 Elsevier B.V. All rights reserved.

Type 2 Diabetes (T2D), a major public health issue reaching worldwide epidemic, has been correlated with lower olfactory abilities in humans. As olfaction represents a major component of feeding behavior, its alteration may have drastic consequences on feeding behaviors that may in turn aggravates T2D. In order to decipher the impact of T2D on the olfactory epithelium, we fed mice with a high fructose diet (HFruD) inducing early diabetic state in 4 to 8 weeks. After only 4 weeks of this diet, mice exhibited a dramatic decrease in olfactory behavioral capacities. Consistently, this decline in olfactory behavior was correlated to decreased electrophysiological responses of olfactory neurons recorded as a population and individually. Our results demonstrate that, in rodents, olfaction is modified by HFruD-induced diabetes. Functional, anatomical and behavioral changes occurred in the olfactory system at a very early stage of the disease.

International audience; The composition of gut microbiota has been associated with host metabolic phenotypes, but it is not known if gut bacteria may influence host appetite. Here we show that regular nutrient provision stabilizes exponential growth of E. coli, with the stationary phase occurring 20 min after nutrient supply accompanied by bacterial proteome changes, suggesting involvement of bacterial proteins in host satiety. Indeed, intestinal infusions of E. coli stationary phase proteins increased plasma PYY and their intraperitoneal injections suppressed acutely food intake and activated c-Fos in hypothalamic POMC neurons, while their repeated administrations reduced meal size. ClpB, a bacterial protein mimetic of alpha-MSH, was upregulated in the E. coli stationary phase, was detected in plasma proportional to ClpB DNA in feces, and stimulated firing rate of hypothalamic POMC neurons. Thus, these data show that bacterial proteins produced after nutrient-induced E. coli growth may signal meal termination. Furthermore, continuous exposure to E. coli proteins may influence long-term meal pattern.

The aim of this paper is twofold. First, it explores delayed effects of high endogenously evoked cortisol concentrations on visuo-spatial declarative memory. Subsequently, it applies multiple mediation (MM) analyses to reveal path processes between stress and cognitive performance in a sample of 24 male Special Forces (SF) candidates (mean age = 27.0 years, SD = 4.1). The SF candidates were randomly assigned to a control (n = 12) or an intense stress group (n = 12), and cortisol secretion for the intense stress condition was triggered by a brusque 60 min prisoner of war exercise. Stress exposure provoked robust increases in cortisol concentrations and a significant decline in immediate recall performance, measured with the Rey-Osterrieth Complex Figure (ROCF). The relative retrieval differences in regard to the ROCF persisted even after a recovery period of 24 h, as both groups showed similar levels of memory decline over 24 h. Next, the study applied a MM design that involved distribution-independent asymptotic and resampling strategies to extend traditional bivariate analyses. MM results showed that ROCF performance was mediated by increases in cortisol concentrations. Considering the studied variables, the current analysis was the first to provide statistical support for the generally accepted thesis that cortisol secretion in itself, rather than subjective strain or the experimental treatment, affects cognitive performance. The revelation of such path processes is important because it establishes process identification and may refine existing paradigms.

The global obesity epidemic has resulted in significant morbidity and mortality. However, the medical treatment of obesity is limited. Gastric bypass is an effective surgical treatment but carries signifi cant perioperative risks. The gut hormones, peptide tyrosine tyrosine (PYY) and glucagon-like peptide 1 (GLP-1), are elevated following gastric bypass and have been shown to reduce food intake. They may provide new therapeutic targets. This review article provides an overview of the central control of food intake and the role of PYY and GLP-1 in appetite control. Key translational animal and human studies are reviewed. (Gut Liver 2012;6:10-20)

The present field experiment examined how multi-trial visuo-spatial learning and memory performance are impacted by excessive arousal, instigated by a potentially life-threatening event (i.e., a first parachute jump). Throughout a parachute training activity, subjective and neuroendocrine (i.e., cortisol) stress levels were assessed of 61 male military cadets who were randomly assigned to a control (n = 30) or a jump stress condition (n = 31). Post-stress learning and memory capacity was assessed with a 10-trial path-learning task that permitted emergence of learning curves. Pre-activity cortisol concentrations indicated a significant neuroendocrine anticipatory stress response in the stress group. Following parachuting, subjective stress levels and salivary cortisol reactivity differed significantly between groups. Visuo-spatial path-learning performance was impaired significantly after jump stress exposure, relative to the control group. Moreover, examination of the learning curves showed similar learning and memory performance at onset of the trials, with curves bifurcating as the task became more complex. These findings are in accordance with leading theories that acknowledge a moderating effect of task complexity. In sum, the present study extends knowledge concerning anticipatory stress effects, endogenously instigated cortisol reactivity, and the influence of extreme arousal on visuo-spatial path learning.

This study was designed to examine the effects of intracerebroventricular injection of DL-AP5 (N-methyl-D-aspartate (NMDA) receptor antagonist) and glutamate on ghrelin-induced feeding behavior in 3-h food-deprived (FD3) broiler cockerels. At first, guide cannula was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were intracerebroventricularly injected with 0, 2.5, 5, and 10 nmol of DL-AP5. In experiment 2, chickens received 5 nmol DL-AP5 prior to the injection of 0.6 nmol ghrelin. In experiment 3, birds were administered with 0.6 nmol ghrelin after 300 nmol glutamate, and the cumulative feed intake was determined at 3-h postinjection. The results of this study showed that the intracerebroventricular injection of DL-AP5 increased food consumption in FD3 broiler cockerels (P a parts per thousand currency signaEuro parts per thousand 0.05), and this increase occurs in a dose-dependent manner. Moreover, the decreased food intake induced with the intracerebroventricular injection of ghrelin was additively enhanced by pretreatment with glutamate, and this effect was attenuated by DL-AP5 administration(P a parts per thousand currency signaEuro parts per thousand 0.05).These results suggest that there is an interaction between ghrelin and glutamatergic system (through NMDA receptor) on food intake in broiler cockerels.

Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS. Pulmonary leptin expression was analyzed by immunohistochemistry and real-time PCR. Pulmonary inflammation upon 4 wk CS exposure was evaluated in bronchoalveolar lavage fluid (BALF) and lung tissue of WT, ob/ob, and db/db mice. Immunohistochemical analysis revealed leptin expression in bronchial epithelial cells, pneumocytes, alveolar macrophages, and bronchial/vascular smooth muscle cells. The 4 and 24 wk CS exposure increased leptin expression in bronchial epithelial cells and pneumocytes versus air-exposed WT mice (p < 0.05). The 4 wk CS exposure resulted in increased accumulation of neutrophils, dendritic cells, macrophages, and lymphocytes in BALF and lung tissue of WT, ob/ob, and db/db mice. CS-exposed ob/ob and db/db mice showed in general higher numbers of neutrophils and lower numbers of CD4+, CD8+, and dendritic cells versus CS-exposed WT mice. Consistently, CXCL1 levels were enhanced in BALF of CS-exposed ob/ob and db/db mice versus WT mice (p < 0.05). Exogenous leptin administration completely restored the skewed inflammatory profile in ob/ob mice. These data reveal an important role of leptin in modulating innate and adaptive immunity after CS inhalation in mice.

Many physiological and behavioral changes take place during pregnancy, including changes in taste and an increase in food intake. These changes are necessary to ensure growth and development of a healthy fetus. Both hyperphagia and taste changes during pregnancy may be induced by sex hormones estrogen and progesterone that are increased during pregnancy. Indeed, it has been shown that estrogen decreases food intake, while progesterone increases food intake. This is for instance apparent from the fact that food intake changes during the menstrual cycle with variation in sex hormones. This review will give a short overview of the effects of pregnancy and sex hormones on food intake and taste.

Huntington's Disease is a neurodegenerative condition caused by a polyglutamine expansion in the huntingtin (Htt) protein, which aggregates and also causes neuronal dysfunction. Pathogenic N-terminal htt fragments perturb axonal transport in vitro. To determine whether this occurs in vivo and to elucidate how transport is affected, we expressed htt exon 1 with either pathogenic (HttEx1Q93) or non-pathogenic (HttEx1Q20) polyglutamine tracts in Drosophila. We found that HttEx1Q93 expression causes axonal accumulation of GFP-tagged fast axonal transport vesicles in vivo and leads to aggregates within larval motor neuron axons. Time-lapse video microscopy, shows that vesicle velocity is unchanged in HttEx1Q93-axons compared to HttEx1Q20-axons, but vesicle stalling occurs to a greater extent. Whilst HttEx1Q93 expression did not affect locomotor behaviour, external heat stress unveiled a locomotion deficit in HttEx1Q93 larvae. Therefore vesicle transport abnormalities amidst axonal htt aggregation places a cumulative burden upon normal neuronal function under stressful conditions. © 2009 Elsevier Inc. All rights reserved.

Introduction: Excessive gestational body weight gain of mothers may predispose offspring towards obesity and metabolic derangements. It is difficult to discern the effects of maternal obesogenic factors-such as diet and/or thrifty genetic predisposition-from gestational weight gain per se.Methods: For this reason, genetically normal Wistar rats that were fed regular chow were rendered hypothalamically obese by chronic third-cerebral ventricular (i3vt) infusion during pregnancy and lactation with the melanocortin-3,4 receptor blocker SHU9119. This procedure caused significant increases in body weight gain during pregnancy and lactation compared with controls, and the effects thereof on offspring energy balance and fuel homeostasis were investigated.Results: At birth, litter weight and size, but not individual pup weight, of SHU9119-treated mothers were significantly smaller than controls. In litters culled to eight, pup weight gain during lactation was only transiently increased by treatment. After weaning, however, male offspring of SHU9119-treated mothers became increasingly heavier over time relative to controls until killing at 9 months. This effect was only transient in females. Increased body weights of males were not associated with disturbances in glucose homeostasis, but with increased energy expenditure instead. Multiple regression analysis revealed that gestational body weight gain, irrespective of the group, contributed positively to increased visceral fat deposition and carbohydrate oxidation in the male offspring. In contrast, the pre-pregnancy body weight of mothers contributed positively to male offspring daily energy expenditure, subcutaneous fat and eviscerated carcass as well as structural organ weights. In female offspring, gestational body weight gain, but not pre-gestational body weight, contributed both to aspects of weight gain as well as to the shift of fat oxidation toward carbohydrate oxidation.Conclusion: Gestational weight gain induced by low brain melanocortin receptor activity can lead to increased body weight gain in the offspring (particularly in males) independent of obesogenic dietary and/or thrifty genetic predisposition.