Neuropeptide Y Research Articles

Development of Radiopharmaceuticals for NPY Receptor-5 (Y5) Nuclear Imaging in Tumors by Synthesis of Specific Agonists and Investigation of Their Binding Mode.

The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y1, Y2, Y4, and Y5. A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala31,Aib32,Gln34]hPP scaffold, further referred to as sY5ago, was modified with a DOTA chelator and radiolabeled with 68Ga and 111In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY5ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY5ago_scrambled). sY5ago and DOTA-sY5ago showed subnanomolar affinity toward the Y5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y5 was identified. [68Ga]Ga-DOTA-sY5ago and [111In]In-DOTA-sY5ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/106 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [68Ga]Ga-DOTA-sY5ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y5-mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [68Ga]Ga-DOTA-sY5ago showed 12-fold higher uptake than [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [111In]In-DOTA-sY5ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal.

Gβγ subunit signalling underlies neuropeptide Y-stimulated vasoconstriction in rat mesenteric and coronary arteries.

Raised serum concentrations of the sympathetic co-transmitter neuropeptide Y (NPY) are linked to cardiovascular diseases. However, the signalling mechanism for vascular smooth muscle (VSM) constriction to NPY is poorly understood. Therefore, the present study investigated the mechanisms of NPY-induced vasoconstriction in rat small mesenteric (RMA) and coronary (RCA) arteries. Third-order mesenteric or intra-septal arteries from male Wistar rats were assessed in wire myographs for isometric tension, VSM membrane potential and VSM intracellular Ca2+ events. NPY stimulated concentration-dependent vasoconstriction in both RMA and RCA, which was augmented by blocking NO synthase or endothelial denudation in RMA. NPY-mediated vasoconstriction was blocked by the selective Y1 receptor antagonist BIBO 3304 and Y1 receptor protein expression was detected in both the VSM and endothelial cells in RMA and RCA. The selective Gβγ subunit inhibitor gallein and the PLC inhibitor U-73122 attenuated NPY-induced vasoconstriction. Signalling via the Gβγ-PLC pathway stimulated VSM Ca2+ waves and whole-field synchronised Ca2+ flashes in RMA and increased the frequency of Ca2+ flashes in myogenically active RCA. Furthermore, in RMA, the Gβγ pathway linked NPY to VSM depolarization and generation of action potential-like spikes associated with intense vasoconstriction. This depolarization activated L-type voltage-gated Ca2+ channels, as nifedipine abolished NPY-mediated vasoconstriction. These data suggest that the Gβγ subunit, which dissociates upon Y1 receptor activation, initiates VSM membrane depolarization and Ca2+ mobilisation to cause vasoconstriction. This model may help explain the development of microvascular vasospasm during raised sympathetic nerve activity.

Circulating Neuropeptide Y May Be a Biomarker for Diagnosing Atrial Fibrillation

Introduction: Sympathetic nervous system disorder promotes atrial fibrillation (AF), and neuropeptide Y (NPY) is an important neurotransmitter. This study aimed to explore the predictive value of plasma NPY in patients with AF. Methods: Five hundred seventy-six patients were divided into AF (including paroxysmal and long-standing persistent AF; 360) and sinus rhythm (SR) groups (216). NPY level was detected using enzyme-linked immunosorbent assay, and NPY mRNA expression level was detected using quantitative polymerase chain reaction. Logistic regression was used to analyse the risk factors for AF; the correlations between blood NPY level and age, body mass index (BMI), left ventricular ejection fraction, left atrial diameter (LAD), and European Heart rate Association (EHRA) score in patients with AF were determined. The receiver operating characteristic (ROC) curve was utilised to predict AF. Results: Plasma NPY levels were found to be higher in patients with AF than in patients with SR and in patients with long-standing persistent AF than in patients with paroxysmal AF; blood NPY mRNA levels were higher in the paroxysmal and long-standing persistent AF groups compared to the SR group (p < 0.05). Increased age {odds ratio (OR) = 1.201 (95% confidence interval [CI]: 1.01, 1.427)} and high NPY [OR = 1.239 (95% CI: 1.022, 1.501)] were factors found to affect AF detrimentally. NPY was associated with BMI (r = 0.5856, p < 0.05), LAD (r = 0.4023, p < 0.05), and EHRA score (r = 0.898, p < 0.05). The ROC curve for the predictive value of plasma NPY levels for AF showed an area under the curve (AUC) value of 0.919 (p < 0.05), while that for long-standing persistent AF showed an AUC of 0.784 (p < 0.05). Conclusion: Circulating NPY may be a promising molecular biomarker of AF.

Obesity wars: hypothalamic sEVs a new hope.

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

Emesis to trichothecene deoxynivalenol and its congeners correspond to secretion of peptide YY and 5-HT.

The type B trichothecenes pollute food crops and have been associated to alimentary toxicosis resulted in emetic reaction in human and animal. This group of mycotoxins consists deoxynivalenol (DON) and four structurally related congeners: 3-acetyl-deoxynivalenol (3-ADON), 15-acetyl deoxynivalenol (15-ADON), nivalenol (NIV) and 4-acetyl-nivalenol (fusarenon X, FX). While emesis induced by intraperitoneally dosed to DON in the mink has been related to plasma up-grading of 5-hydroxytryptamine (5-HT) and neurotransmitters peptide YY (PYY), the impact of oral dosing with DON or its four congeners on secretion of these chemical substances have not been established. The aim of this work was to contraste emetic influence to type B trichothecene mycotoxins by orally dosing and involve these influence to PYY and 5-HT. All five toxins attracted marked emetic reaction that are relevant to elevated PYY and 5-HT. The reduction in vomiting induced by the five toxins and PYY was due to blocking of the neuropeptide Y2 receptor. The inhibition of the induced vomiting response by 5-HT and all five toxins is regulated by the 5-HT3 receptor inhibitor granisetron. In a word, our results indicate that PYY and 5-HT take a key role in the emetic reaction evoked by type B trichothecenes.

Dynamics of the Second Extracellular Loop Control Transducer Coupling of Peptide-Activated GPCRs.

Many peptide-activated rhodopsin-like GPCRs share a β-hairpin folding motif in the extracellular loop 2 (ECL2), which interacts with the peptide ligand while at the same time being connected to transmembrane helix 3 (TM3) via a highly conserved disulfide bond. Currently, it remains unknown whether the coupling of the specifically shaped ECL2 to TM3 influences the activation of peptide-activated GPCRs. We investigated this possibility in a selection of peptide GPCRs with known structures. Most of the receptors with cysteine to alanine mutations folded like the respective wild-type and resided in the cell membrane, challenging pure folding stabilization by the disulfide bridge. G-protein signaling of the disulfide mutants was retained to a greater extent in secretin-like GPCRs than in rhodopsin-like GPCRs, while recruitment of arrestin was completely abolished in both groups, which may be linked to alterations in ligand residence time. We found a correlation between receptor activity of the neuropeptide Y2 receptor and alterations in ECL2 dynamics using engineered disulfide bridges or site-directed spin labeling and EPR spectroscopy. These data highlight the functional importance of the TM3-ECL2 link for the activation of specific signaling pathways in peptide-activated GPCRs, which might have implications for future drug discovery.

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling.

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling

Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here, we investigate the role of interneurons that continue to express NPY (NPY-INs) in the adult mouse spinal cord. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen-evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY-IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch.

Inflammatory profile of keratoconic corneal epithelium

BackgroundRecent studies have presented inflammatory features on keratoconus (KC) and many inflammatory markers are described in the tears of patients with this disease. The KC pathogenesis is still unknown just like the correlation with inflammatory patterns. However, environmental and genetic issues may be part of the progress of KC. In addition, some systemic features, such as allergy and obesity, seem to be related to the progression of KC. Our purpose was to evaluate the neuropeptides vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), chemokines ligand 2 (CCL-2) and 5 (CCL-5), and interleukins 6 (IL-6) and 8 (IL-8) on corneal epithelial cells and blood of patients with KC and in healthy controls. In addition, the neutrophil-to-lymphocyte ratio (NLR) was evaluated to predict inflammation.MethodsThis including prospective observational study included 32 KC patients who underwent corneal crosslinking (CXL) and 32 control patients who underwent photorefractive keratectomy (PRK). Patients’ corneal epithelial cells were removed surgically, and blood (buffy coat) was analyzed. Samples in triplicate were evaluated on rt-PCR for neuropeptides (VIP e NPY), interleukins (IL-6 e IL-8), and chemokines (CCL-2 and CCL-5).ResultsOur study showed statistically higher CCL-5 and IL-8 on corneal epithelial cells in patients with KC. Blood cells were statistically higher in VIP and NPY in the KC group. Interleukin-8 on blood cells was statistically significant in KC’S group; for CCL-2 and CCL-5 they were statistically lower in patients with KC compared with controls. NLR showed no difference between the groups.ConclusionsOur data support the findings of other studies that suggested altering KC status, such as inflammatory corneal disease. The presence of IL-8 in the cornea and blood samples of KC’s group suggested systemic disease with a possible local or repercussion action. Further studies are warranted to elucidate KC pathogenesis and its correlation to systemic disease.

Potential for NPY receptor-related therapies for polycystic ovary syndrome: an updated review.

Polycystic ovary syndrome (PCOS) is a complex endocrine disease that can cause female infertility and bring economic burden to families and to society. The clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, and polycystic ovarian changes, often accompanied by insulin resistance and obesity. Although its pathogenesis is unclear, PCOS involves the abnormal regulation of the hypothalamic-pituitary-ovarian axis and the abnormal activation of GnRH neurons. Neuropeptide Y (NPY) is widely distributed in the arcuate nucleus of the hypothalamus and functions as the physiological integrator of two neuroendocrine systems, one governing feeding and the other controlling reproduction. In recent years, an increasing number of studies have focused on the improvement of the reproductive and metabolic status of PCOS through the therapeutic application of NPY and its receptors.In this review, we summarize the central and peripheral regulation of NPY and its receptors in the development of PCOS and discuss the potential for NPY receptor-related therapies for PCOS.

Dry heat whole Sorghum BRS 305 flour modulate satiety and improves antioxidant response in brain of Wistar rats fed with high-fat high-fructose diet

Sorghum BRS 305 (Sorghum bicolor L. Moench) is a cereal with high tannins and anthocyanins content and keep better the resistant starch when submitted to dry heat treatment. Our objective was to investigate the effects of BRS 305 dry heat treatment whole sorghum flour on satiety and antioxidant response in brain and adipose tissue of Wistar rats fed with a high fat high fructose diet (HFHF). Male Wistar rats were divided in two groups: control (n = 8) and HFHF (n = 16) for eight weeks. After, animals of HFHF group were divided: HFHF (n = 8) and HFHF + BRS 305 sorghum whole flour (n = 8), for 10 weeks. Sorghum consumption reduced gene expression of leptin, resistin, and endocannabinoid receptor 1 type (CB1) in adipose and brain tissues compared to HFHF group. In brain, sorghum consumption also promotes reduction in neuropeptide Y (NPY) gene expression. BRS305 sorghum consumption improved gene expression of sirtuin-1 (SIRT1) in adipose tissue, and in the brain increased heat shock protein 72 (HSP72), erythroid-derived nuclear factor 2 (NRF2), peroxisome proliferator-activated receptor alpha (PPARα), superoxide dismutase (SOD) and catalase activity compared to HFHF. In silicoanalysis showed interaction with PPARα, CB1, and leptin receptors. Advanced glycation end products (AGEs) concentrations in group HFHF + sorghum did not differ from HFHF group. Advanced glycation end products receptors (RAGEs) concentrations did not differ among experimental groups. Then, BRS 305 sorghum submitted to dry treatment was able to modulate gene expression of markers related to satiety and improve antioxidant capacity of rats fed with HFHF diet.

Neuropeptide Y: Direct vasoconstrictor and facilitatory effects on P2X1 receptor-dependent vasoconstriction in human small abdominal arteries

Neuropeptide Y (NPY) is co-released with norepinephrine and ATP by sympathetic nerves innervating arteries. Circulating NPY is elevated during exercise and cardiovascular disease, though information regarding the vasomotor function of NPY in human blood vessels is limited. Wire myography revealed NPY directly stimulated vasoconstriction (EC50 10.3 ± 0.4 nM; N = 5) in human small abdominal arteries. Maximum vasoconstriction was antagonised by both BIBO03304 (60.7 ± 6%; N = 6) and BIIE0246 (54.6 ± 5%; N = 6), suggesting contributions of both Y1 and Y2 receptor activation, respectively. Y1 and Y2 receptor expression in arterial smooth muscle cells was confirmed by immunocytochemistry, and western blotting of artery lysates. α,β-meATP evoked vasoconstrictions (EC50 282 ± 32 nM; N = 6) were abolished by suramin (IC50 825 ± 45 nM; N = 5) and NF449 (IC50 24 ± 5 nM; N = 5), suggesting P2X1 mediates vasoconstriction in these arteries. P2X1, P2X4 and P2X7 were detectable by RT-PCR. Significant facilitation (1.6-fold) of α,β-meATP-evoked vasoconstrictions was observed when submaximal NPY (10 nM) was applied between α,β-meATP applications. Facilitation was antagonised by either BIBO03304 or BIIE0246. These data reveal NPY causes direct vasoconstriction in human arteries which is dependent upon both Y1 and Y2 receptor activation. NPY also acts as a modulator, facilitating P2X1-dependent vasoconstriction. Though in contrast to the direct vasoconstrictor effects of NPY, there is redundancy between Y1 and Y2 receptor activation to achieve the facilitatory effect.

Efficacy and safety of high-voltage pulsed radiofrequency combined with pregabalin on severe thoracic postherpetic neuralgia

Objective: To investigate the efficacy and safety of high-voltage pulse radiofrequency combined with pregabalin on severe thoracic postherpetic neuralgia (PHN). Methods: A total of 103 patients with PHN who were admitted to the Department of Pain Medicine of Henan Provincial People's Hospital from May 2020 to May 2022 were retrospectively selected, including 50 males and 53 females, and aged 40 to 79 (65.4±9.2) years. The patients were divided into two groups according to the treatment methods they received: the control group (n=51) and the study group (n=52). The patients in the control group were treated with oral pregabalin, and the patients in the study group received pregabalin plus high-voltage pulse radiofrequency therapy. The pain intensity and efficacy of the two groups were evaluated before treatment and 4 weeks after treatment. The pain intensity, the sleep quality and the efficacy of treatment was evaluated by visual analogue scale (VAS) score, Pittsburgh Sleep Quality Index (PSQI) score and nimodipine method, respectively. The levels of pain factors including serum neuropeptide Y (NPY), prostaglandin E2 (PGE2), substance P (SP) and β-Endorphin were measured. The differences of the above indicators and the incidence of adverse reactions were compared between the two groups. Results: The VAS scores and PSQI scores of the study group and the control group before treatment were (7.94±0.76), (8.20±0.81), (16.84±3.90) and (16.29±3.84), respectively, with no statistically significant difference (both P>0.05). After 4 weeks of treatment, the VAS scores and PSQI scores of the two groups were (2.84±0.80), (3.35±0.87), (6.78±1.90) and (7.98±2.40), respectively, and the VAS score and PSQI score in the study group were lower than those in the control group (both P<0.05). Serum levels of NPY, PGE2, SP and β-Endorphin were (298.5±31.0) ng/L, (92.3±11.0) μg/L, (156.8±21.4) ng/L, and (8.6±1.6) ng/L in the study group and (304.2±28.6) ng/L, (94.4±12.9) μg/L, (152.7±23.8) ng/L and (8.2±1.8) ng/L in the control group, with no significant differences (all P>0.05). After 4 weeks of treatment, levels of NPY, PGE2, SP and β-Endorphin were (240.7±26.8) ng/L, (74.4±8.6) μg/L, (108.9±15.7) ng/L and (4.4±0.9) ng/L, which were lower than those in the control group [(268.1±29.4) ng/L, (79.7±8.3) μg/L, (115.2±16.2) ng/L, (5.2±1.3) ng/L, respectively], with statistically significant differences (all P<0.05). After treatment, 29 cases were cured, 16 cases were markedly effective and 6 cases were effective in the study group, while 16 cases, 24 cases and 8 cases were cured, markedly effective and effective in the control group. The overall efficacy of patients in the study group was better than that in the control group (Z=-2.32, P=0.018). The incidence of adverse reactions in the study group and control group was 11.5% (6/52) and 7.8% (4/51), respectively, with no statistically significant difference (χ2=0.40, P=0.527). Conclusion: High-voltage pulse radiofrequency combined with pregabalin can significantly improve the pain and sleep quality of patients with severe thoracic PHN and reduce the level of pain factors, with a high safety profile.

Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide Is Co-Expressed with Parvalbumin, Neuropeptide Y and Somatostatin in the Claustrum of the Chinchilla.

Although for many years, researchers have been working on understanding the function of the cocaine- and amphetamine-regulated transcript (CART) peptide at the central- and peripheral-nervous-system level, data describing the presence of CART in the claustrum are still missing. Therefore, the aim of the present study was to immunohistochemically investigate the CART expression in the claustrum neurons in chinchillas as well as the CART co-localization with somatostatin (SOM), parvalbumin (PV), and neuropeptide Y (NPY) using double-immunohistochemical staining. The claustrum is divided into two main parts: the dorsal segment (CL), which is located above the rhinal fissure, and the ventral segment (EN), located below the rhinal fissure. The presence of HU C/D-IR CART-IR-positive neurons was detected in both the insular claustrum (CL) and the endopiriform nucleus (EN). The vast majority of CART-IR neurons were predominantly small and medium in size and were evenly scattered throughout the claustrum. CART co-localization with selected neurotransmitters/neuromodulators (SOM, NPY, and PV) showed the presence of a CART-IR reaction only in the neurons, while the nerve fibers were, in all cases, devoid of the CART-IR response. Our research supplements missing knowledge about the distribution and co-localization pattern of CART with SOM, NPY, and PV in the chinchilla claustrum, and also provides a better understanding of the similarities and differences compared to other species of rodents and other mammals.

Poria cocos compounds targeting neuropeptide Y1 receptor (Y1R) for weight management: A computational ligand- and structure-based study with molecular dynamics simulations identified beta-amyrin acetate as a putative Y1R inhibitor.

Poria cocos (PC) is a medicinal herb frequently used in weight-loss clinical trials, however the mechanisms by which its compounds target orexigenic receptors including the neuropeptide Y1 receptor (Y1R) remain largely unknown. This study aimed to screen PC compounds for favourable pharmacokinetics profiles and examine their molecular mechanisms targeting Y1R. Forty-three PC compounds were systematically sought from pharmacological databases and docked with Y1R (PDB: 5ZBQ). By comparing the relative binding affinities, pharmacokinetics and toxicity profiles, we hypothesised that compounds designated PC1 3,4-Dihydroxybenzoic acid, PC8 Vanillic acid, PC40 1-(alpha-L-Ribofuranosyl)uracil, could be potential antagonists as they contact major residues Asn283 and Asp287, similar to various potent Y1R antagonists. In addition, PC21 Poricoic acid B, PC22 Poricoic acid G and PC43 16alpha,25-Dihydroxy-24-methylene-3,4-secolanosta-4(28),7,9(11)-triene-3,21-dioic acid, contacting Asn299, Asp104 and Asp200 proximal to the extracellular surface could also interfere with agonist binding by stabilising the extracellular loop (ECL) 2 of Y1R in a closed position. Owing to their selective interaction with Phe302, an important residue in binding of selective Y1R antagonists, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were proposed as putative antagonists. Following the consensus approach, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were identified as candidate compounds due to their high affinities (-12.2, -11.0 and -10.8 kcal, respectively), high drug-likeness and low toxicity profiles. Trajectory analyses and energy contributions of PC12-Y1R complex further confirmed their structural stability and favourable binding free energies, highlighting the feasibility and possible development of PC12 beta-Amyrin acetate as a future Y1R inhibitor.

Morphological study of neuropeptide Y expression in human and mouse anterior insular cortex: Overexpression in the insular cortex and nucleus accumbens in obese mice on a long-term obesogenic diet

BackgroundThe anterior lobe of the insular cortex (aINS) is a cortical region that has reciprocal connections with limbic centers such as the anterior cingulate cortex, prefrontal cortex, amygdala and nucleus accumbens (NAc). In fact, the aINS has been involved in the integration of autonomic information for emotional and motivational functions. The compulsive consumption of drugs or high-fat foods induces alterations at both behavioural and brain levels. Brain reward circuits are altered in response to continued intake, in particular the dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The aINS has multiple connections with the components of this system. In recent years, efforts have been made to better understand the fundamental role of the aINS in addiction, making it one of the key centres of interest for research into new treatments for addiction. ObjectivesThe present work focuses on studying 1.- whether the human aINS expresses orexigenic peptides such as neuropeptide Y (NPY), a peptide known to induce hyperphagia, and which has been implicated in the onset and development of obesity, 2.- the long-term effect of an obesogenic diet on NPY expression in the aINS and NAc of C57BL/6 mice. MethodsA total of 17 female C57BL/6 J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were seven female mice on the SD and ten on the HFD. The duration of the experiment was 180 days. We also studied 3 human adult brains (1 male and 2 females, mean age 55.7 ± 5.2 years). The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of NPY neurons of the aINS and NAc of humans and mice. ResultsOur morphological analysis demonstrates for the first time the basal expression of NPY in different layers of the human cortex (II, III, IV, V/VI), in a pattern similar to previous studies in other species. Furthermore, we observed an increase in the number of NPY-positive cells and their intracytoplasmic signal in the aINS and NAc of the obese mice subjected to a long-term obesogenic diet. ConclusionsTo our knowledge, this is the first study to show the distribution and expression of NPY in the human INS and how its expression is altered after prolonged treatment with an obesogenic diet in obese mice. Our findings may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions related to the reward system and associated with uncontrolled intake of high-fat foods, thus facilitating the identification of novel therapeutic targets.

Effects of Various LED Light Spectra on Growth, Gonadal Development, and Growth-/Reproduction-Related Hormones in the Juvenile Red Spotted Grouper, Epinephelus akaara.

The light spectrum is a key environmental cue involved in growth and reproduction in teleosts. This study investigated the effects of exposure on juvenile red spotted grouper exposed to white (control), red (590 nm), blue (480 nm), and green (520 nm) light-emitting diodes (LEDs) (12 h light:12 h dark) for two months. The body weight (BW), total length (TL), condition factor (CF), weight gain rate (WGR), gonadosomatic index (GSI), and hepatosomatic index (HSI) were assessed. Gonadal development was observed. The gene expression of growth-related hormones, such as growth hormone (GH), pre-pro-somatostatin-I (PSS-I), neuropeptide Y (NPY), and CCK, and of reproduction-related hormones, such as Kiss1, Kiss2, GPR54, sbGnRH, FSHβ, and LHβ, was analyzed. The results showed that the fish in the white LED group exhibited the best BW, TL, CF, WGR, and HSI after one or two months. The fish exposed to white LEDs showed the best growth after two months, but no significant differences in GH levels were detected. Contrarily, the expression levels of the PSS-I significantly increased (p < 0.05) in fish from the white group, suggesting the complex regulation of GH production and the limited effects of PSS-I on the inhibition of GH synthesis and somatic growth. The significantly increased NPY levels in the four LED groups (p < 0.05) indicated that these four LED spectra were effective in stimulating food intake and energy homeostasis. After two months, the gonads developed from chromatin nucleolar-stage oocytes to perinucleolar-stage oocytes in the four LED groups. The gene expression of Kiss2 and GPR54 in the four LED groups and of sbGnRH in the white and blue LED groups significantly increased when compared to that in the initial group (p < 0.05), while there were no significant differences in FSHβ and LHβ expression in the four LED groups. These results suggest that FSH and LH may not play important roles in gonadal development in juvenile red spotted grouper that are exposed to these four LED spectra.

#3949 NPY GENE POLYMORPHISMS ARE STRONGLY LINKED TO CKD PROGRESSION: A MENDELIAN RANDOMIZATION STUDY

Abstract Background and Aims Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that regulates various physiological processes in both the central and peripheral nervous systems, including cardiovascular and metabolic control. We showed that high plasma NPY predicts CKD progression (NDT 2018;33:1805-1812) in a cohort of 735 patients with stage G2-5 CKD. Whether this association is causal in nature is undetermined. Method In the same cohort of the previous study, we tested the relationship between NPY gene variability, as assessed by six single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure which explained about 80% of gene variability, and the incidence rate of renal events (dialysis/transplantation/eGFR reduction &amp;gt;30%) over a median follow up of 36 months (inter-quartile range 35-37 months). Results Three variants [rs16131 (TT, n = 563; CT+CC, n = 172), rs16140 (CG+GG, n = 413; CC, n = 322), rs16148 (CT+CC, n = 456; TT, n = 279)] coherently associated to the incidence rate of renal events (HR ranging from 1.36 to 1.57, P≤0.029). A dose response relationship was found between the number of risk variants and renal events, the HR for this outcome being highest in patients with three risk genotypes (HR: 1.66, 95% 1.05-2.61). In a multivariate model adjusting for traditional risk factors (age, gender, smoking, diabetes, cholesterol, systolic BP and background cardiovascular comorbidities) and factors peculiar to CKD (haemoglobin, eGFR, albumin, phosphate, and C-reactive protein), the association remained highly significant (P for trend = 0.001). In a separate analysis including the three variants simultaneously, only the rs16131 variant maintained an independent association with the risk for renal events (HR: 1.58, 95% CI 1.11-2.24, P = 0.01). Conclusion This Mendelian randomization study based on three gene variants is fully in line with findings indicating that high plasma NPY predicts a high risk for renal events and lends support to the hypothesis that NPY is causally involved in CKD progression. Establishing the functional significance of the rs16131 variant is a clinical research priority. Drugs antagonizing circulating NPY or its receptors, indeed, might favourably impact on CKD progression.

A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss

Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

EPEN-05. TRANSCRIPTIONAL FACTOR-DIRECTED EPIGENETIC REGULATION IN CANCER NEUROSCIENCE OF ZFTA-RELA EPENDYMOMA

Abstract ZFTA-RELA (ZRFUS) ependymoma is a pediatric brain tumor with dismal 10-year progression free survival rates. Prior studies revealed low somatic mutation load in pediatric ependymoma compared to adult glioma, suggesting that developmental mechanisms play a key role during disease development. Using human tissues and mouse tumors generated from our autochthonous in utero electroporation (IUE) model, we identified a cohort of developmental transcription factors (TFs) linked to ZRFUS by investigating histone serotonylation changes with other epigenetic datasets. We further performed in vivo barcode-screening and identified the ETS variant transcription factor 5 (ETV5) is sufficient and required for disease progression. To further reveal the disease mechanism driven by ETV5, we applied transcriptomic, epigenetic, and proteomic analyses, and found ETV5 suppresses neuropeptide Y (NPY) expression in mouse ZRFUS tumors by binding with epigenetic modulator, chromobox 3 (CBX3). We further found NPY overexpression delays tumor progression and suppressed tumor-driven neuronal activity in mice. This study suggests developmental TF can shape tumor-promoting microenvironment during disease progression through epigenetic regulation.