The Hypothalamic Neuropeptides' Role in Metabolic Diseases and Immunoregulation

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 27700

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Guest Editor
Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Caserta, Italy
Interests: pediatric neurology; pediatric rehabilitation; pediatric sleep disorders; pediatric polysomnography; pediatric headaches; pediatric epilepsy; pediatric EEG; autism spectrum disorders; intellectual disability; neurogenetic disorders; pediatric movement disorders; neurodevelopmental disorders
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Special Issue Information

Dear Colleagues,

Interdisciplinary studies in the research fields of endocrinology and immunology show that obesity-associated overnutrition leads to neuroinflammatory molecular changes, particularly in the hypothalamus, chronically causing various disorders known as elements of metabolic syndrome. In this process, neural or hypothalamic inflammation impairs the neuroendocrine and autonomic regulation of the brain in relation to blood pressure, glucose homeostasis, and insulin secretion, and elevated sympathetic activation is appreciated as a critical mediator.

Hypothalamic inflammation is an important factor in the pathogenesis of diabetes and hypertension. Indeed, an overnutrition and aging leads to hypothalamic inflammation. This inflammation can stem from, in part, the activation of IKKβ/NF-κB cascade in association with functional changes of intracellular organelles such as RNA stress responses, endoplasmic reticulum, and oxidative stresses, and, more chronically, autophagic defects. Such hypothalamic inflammation affects not only neuroendocrine signaling but also the connections between the hypothalamus and the autonomic nervous system, leading to increased sympathetic outflow. Consequently, the autonomic control over peripheral organs, including the liver, skeletal muscle, pancreas, and cardiovascular system, is perturbed, resulting in glucose disorder, insulin resistance, insulin secretion impairment, and increased blood pressure, which are predicted to chronically contribute to the development of diabetes and hypertension. It is well known that there is an important and intricate relationship between the immune system and the nervous system. These systems are communicate through the production of molecules such as cytokines, hormones, and peptides from the CNS and through the activation of afferent and efferent neurological pathways in lymphoid organs, with both immuno-suppressive and immuno-stimulating effects. On the other hand, the cytokines are able to communicate with the CNS and ensure the passage of specific signals and information from the periphery to the brain.

Moreover, these pathways’ activation may be relevant in many chronic diseases such as neurodevelopmental disorders (i.e., autism spectrum disorders, Rett disease, X-Fragile) with relevant neurovegetative dysregulation.

Having a comprehensive and extensive understanding of the mechanisms underlying the interaction between the CNS and immune systems may be important for understanding the modulation of certain brain functions as a possible clinic therapeutic approach for immune-mediated diseases. In this context, many cytokines and neuropeptides, for example, orexin-A, adiponectin, leptin, and other neuropeptides, may represent key factors linking the immune system, metabolism, and CNS functions. Recent reports have shown that caloric restriction can significantly increase overall survival in several experimental animal models of autoimmune diseases. More specifically, CR has anti-inflammatory, antioxidant, and neuroprotective effects that could be instrumental in the improvement of clinical outcomes in many autoimmune diseases such as multiple sclerosis, or reumatoid arthritis, since this regimen is able to impair pathological proliferation of autoreactive cells and pro-inflammatory cytokine production. We have summarized the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. For these reasons, it is important understand that molecular pathways and biological mechanisms undergo a strong interaction between the central nervous system, the immune system, and metabolic functions to use new, more targeted, and specific therapeutic approaches in metabolic and immune diseases.

Prof. Dr. Giovanni Messina
Prof. Dr. Marco Carotenuto
Guest Editors

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Keywords

  • Central nervous system
  • Nueropeptides
  • Sleep regulation
  • Metabolic disorders
  • Cardiovascular diseases
  • Autoimmune diseases
  • Neurodevelopmental disorders
  • Rett disorder
  • Cognitive disabilities
  • Autism spectrum disorders

Published Papers (6 papers)

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Research

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11 pages, 1618 KiB  
Article
Leptin Modulates the Expression of miRNAs-Targeting POMC mRNA by the JAK2-STAT3 and PI3K-Akt Pathways
by Adel Derghal, Julien Astier, Flavie Sicard, Charlène Couturier, Jean-François Landrier and Lourdes Mounien
J. Clin. Med. 2019, 8(12), 2213; https://doi.org/10.3390/jcm8122213 - 14 Dec 2019
Cited by 16 | Viewed by 5017
Abstract
The central control of energy balance involves a strongly regulated neuronal network within the hypothalamus and the brainstem. In these structures, pro-opiomelanocortin (POMC) neurons are known to decrease food intake and to increase energy expenditure. Thus, leptin, a peripheral signal that relays information [...] Read more.
The central control of energy balance involves a strongly regulated neuronal network within the hypothalamus and the brainstem. In these structures, pro-opiomelanocortin (POMC) neurons are known to decrease food intake and to increase energy expenditure. Thus, leptin, a peripheral signal that relays information regarding body fat content, modulates the activity of POMC neurons. MicroRNAs (miRNAs) are short non-coding RNAs of 22–26 nucleotides that post-transcriptionally interfere with target gene expression by binding to their mRNAs. It has been demonstrated that leptin is able to modulate the expression of miRNAs (miR-383, miR-384-3p, and miR-488) that potentially target POMC mRNA. However, no study has identified the transduction pathways involved in this effect of leptin on miRNA expression. In addition, miRNAs targeting POMC mRNAs are not clearly identified. In this work, using in vitro models, we have identified and confirmed that miR-383, miR-384-3p, and miR-488 physically binds to the 3′ untranslated (3′UTR) regions of POMC mRNA. Importantly, we show that leptin inhibits these miRNAs expression by different transduction pathways. Taken together, these results allowed us to highlight the miRNA involvement in the regulation of POMC expression downstream of the leptin signaling and satiety signal integration. Full article
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11 pages, 978 KiB  
Article
Hsa-miR-34a-5p and hsa-miR-375 as Biomarkers for Monitoring the Effects of Drug Treatment for Migraine Pain in Children and Adolescents: A Pilot Study
by Luca Gallelli, Erika Cione, Fancesco Peltrone, Serena Siviglia, Antonio Verano, Domenico Chirchiglia, Stefania Zampogna, Vincenzo Guidetti, Luca Sammartino, Angelo Montana, Maria Cristina Caroleo, Giovambattista De Sarro and Giulio Di Mizio
J. Clin. Med. 2019, 8(7), 928; https://doi.org/10.3390/jcm8070928 (registering DOI) - 27 Jun 2019
Cited by 29 | Viewed by 4416
Abstract
MicroRNAs (miRs) have emerged as biomarkers of migraine disease in both adults and children. In this study we evaluated the expression of hsa-miR-34a-5p and hsa-miR-375 in serum and saliva of young subjects (age 11 ± 3.467 years) with migraine without aura (MWA), while [...] Read more.
MicroRNAs (miRs) have emerged as biomarkers of migraine disease in both adults and children. In this study we evaluated the expression of hsa-miR-34a-5p and hsa-miR-375 in serum and saliva of young subjects (age 11 ± 3.467 years) with migraine without aura (MWA), while some underwent pharmacological treatment, and healthy young subjects were used as controls. miRs were determined using the qRT-PCR method, and gene targets of hsa-miR-34a-5p and hsa-miR-375 linked to pain-migraine were found by in silico analysis. qRT-PCR revealed comparable levels of hsa-miRs in both blood and saliva. Higher expression of hsa-miR-34a-5p and hsa-miR-375 was detected in saliva of untreated MWAs compared to healthy subjects (hsa-miR-34a-5p: p < 0.05; hsa-miR-375 p < 0.01). Furthermore, in MWA treated subjects, a significant decrease of hsa-miR-34a-5p and of hsa-miR-375 was documented in saliva and blood compared to MWA untreated ones. Altogether, these findings suggested thathsa-miR-34a-5p and hsa-miR-375 are expressed equally in blood and saliva and that they could be a useful biomarker of disease and of drug efficacy in patients with MWA. Full article
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10 pages, 863 KiB  
Article
25-Hydroxy Vitamin D Detection Using Different Analytic Methods in Patients with Migraine
by Luca Gallelli, Andzelika Michniewicz, Erika Cione, Aida Squillace, Manuela Colosimo, Corrado Pelaia, Alessia Fazio, Stefania Zampogna, Francesco Peltrone, Rosario Iannacchero, Giovambattista De Sarro, G&SP Working Group, Monica Salerno and Giulio Di Mizio
J. Clin. Med. 2019, 8(6), 895; https://doi.org/10.3390/jcm8060895 - 22 Jun 2019
Cited by 18 | Viewed by 3508
Abstract
Objectives: The aim of this study was to evaluate the performance of different analytic methods, such as liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography-ultraviolet (HPLC-UV), enzyme-linked immunosorbent assay (EIA), and chemiluminescence immunoassays (CLIA), in order to highlight whether or [...] Read more.
Objectives: The aim of this study was to evaluate the performance of different analytic methods, such as liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography-ultraviolet (HPLC-UV), enzyme-linked immunosorbent assay (EIA), and chemiluminescence immunoassays (CLIA), in order to highlight whether or not there is relative superiority amongst the assays. We analyzed two groups of subjects suffering from headache and two groups of healthy subjects. Design and Methods: We performed a prospective, single-blind single-center control-group study on 220 subjects with migraine. Subjects of both sexes >10 years old and with 12 months’ history of migraine were eligible for the study. As a control group, 120 healthy subjects were chosen by their family physician. Results: LC-MS/MS evaluation documented that in all enrolled subjects (migraine and control groups), the serum vitamin D3 levels were lower with respect to the normal range (30–100 ng/mL), with a mean value of 15.4 ng/mL, without difference between sex. The mean values measured using HPLC-UV, EIA, and CLIA tests such as Liaison® and Architect® did not show significant differences compared to the values obtained using LC-MS/MS. Conclusions: In conclusion, the population generally has low values of the vitamin D3 hormone, and the suggested range should probably be revised. HPLC-UV and CLIA were found to have appropriate analytical values compared to the reference method (LC-MS/MS), so it is possible to suggest their routine use to optimize care. Full article
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10 pages, 2765 KiB  
Article
Effects of Feeding-Related Peptides on Neuronal Oscillation in the Ventromedial Hypothalamus
by Kamon Iigaya, Yoshino Minoura, Hiroshi Onimaru, Sayumi Kotani and Masahiko Izumizaki
J. Clin. Med. 2019, 8(3), 292; https://doi.org/10.3390/jcm8030292 - 1 Mar 2019
Cited by 7 | Viewed by 3300
Abstract
The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic [...] Read more.
The ventromedial hypothalamus (VMH) plays an important role in feeding behavior, obesity, and thermoregulation. The VMH contains glucose-sensing neurons, the firing of which depends on the level of extracellular glucose and which are involved in maintaining the blood glucose level via the sympathetic nervous system. The VMH also expresses various receptors of the peptides related to feeding. However, it is not well-understood whether the action of feeding-related peptides mediates the activity of glucose-sensing neurons in the VMH. In the present study, we examined the effects of feeding-related peptides on the burst-generating property of the VMH. Superfusion with insulin, pituitary adenylate cyclase-activating polypeptide, corticotropin-releasing factor, and orexin increased the frequency of the VMH oscillation. In contrast, superfusion with leptin, cholecystokinin, cocaine- and amphetamine-regulated transcript, galanin, ghrelin, and neuropeptide Y decreased the frequency of the oscillation. Our findings indicated that the frequency changes of VMH oscillation in response to the application of feeding-related peptides showed a tendency similar to changes of sympathetic nerve activity in response to the application of these substances to the brain. Full article
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Review

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17 pages, 518 KiB  
Review
Hypothalamic Neuropeptide Brain Protection: Focus on Oxytocin
by Maria Antonietta Panaro, Tarek Benameur and Chiara Porro
J. Clin. Med. 2020, 9(5), 1534; https://doi.org/10.3390/jcm9051534 - 19 May 2020
Cited by 30 | Viewed by 5909
Abstract
Oxytocin (OXT) is hypothalamic neuropeptide synthetized in the brain by magnocellular and parvo cellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory nuclei (AN) of the hypothalamus. OXT acts in the central and peripheral nervous systems via G-protein-coupled receptors. The classical physiological [...] Read more.
Oxytocin (OXT) is hypothalamic neuropeptide synthetized in the brain by magnocellular and parvo cellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory nuclei (AN) of the hypothalamus. OXT acts in the central and peripheral nervous systems via G-protein-coupled receptors. The classical physiological functions of OXT are uterine contractions, the milk ejection reflex during lactation, penile erection and sexual arousal, but recent studies have demonstrated that OXT may have anti-inflammatory and anti-oxidant properties and regulate immune and anti-inflammatory responses. In the pathogenesis of various neurodegenerative diseases, microglia are present in an active form and release high levels of pro-inflammatory cytokines and chemokines that are implicated in the process of neural injury. A promising treatment for neurodegenerative diseases involves new therapeutic approaches targeting activated microglia. Recent studies have reported that OXT exerts neuroprotective effects through the inhibition of production of pro-inflammatory mediators, and in the development of correct neural circuitry. The focus of this review is to attribute a new important role of OXT in neuroprotection through the microglia–OXT interaction of immature and adult brains. In addition, we analyzed the strategies that could enhance the delivery of OXT in the brain and amplify its positive effects. Full article
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9 pages, 244 KiB  
Review
Vasopressin in the Amelioration of Social Functioning in Autism Spectrum Disorder
by Mohamed A. Hendaus, Fatima A. Jomha and Ahmed H. Alhammadi
J. Clin. Med. 2019, 8(7), 1061; https://doi.org/10.3390/jcm8071061 - 19 Jul 2019
Cited by 11 | Viewed by 4677
Abstract
Autism spectrum disorder (ASD) is a developmental disability described by diagnostic criteria that comprise deficits in social communication and the existence of repetitive, restricted patterns of behavior, interests, or activities that can last throughout life. Many preclinical studies show the importance of arginine [...] Read more.
Autism spectrum disorder (ASD) is a developmental disability described by diagnostic criteria that comprise deficits in social communication and the existence of repetitive, restricted patterns of behavior, interests, or activities that can last throughout life. Many preclinical studies show the importance of arginine vasopressin (AVP) physiology in social functioning in several mammalian species. Currently, there is a trend to investigate more specific pharmacological agents to improve social functioning in patients with ASD. Neurobiological systems that are crucial for social functioning are the most encouraging conceivable signaling pathways for ASD therapeutic discovery. The AVP signaling pathway is one of the most promising. The purpose of this commentary is to detail the evidence on the use of AVP as an agent that can improve social functioning. The pharmacologic aspects of the drug as well as its potential to ameliorate social functioning characteristics in human and animal studies are described in this manuscript. AVP, especially in its inhaled form, seems to be safe and beneficial in improving social functioning including in children with autism. Larger randomized studies are required to implement a long awaited safe and feasible treatment in people with a deficiency in social functioning. Full article
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