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Luque EM, Díaz-Luján CM, Paira DA, de Loredo N, Torres PJ, Cantarelli VI, Fretes R, Motrich RD, Martini AC. Ghrelin misbalance affects mice embryo implantation and pregnancy success by uterine immune dysregulation and nitrosative stress. Front Endocrinol (Lausanne) 2023; 14:1288779. [PMID: 38107518 PMCID: PMC10722256 DOI: 10.3389/fendo.2023.1288779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/09/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction In a previous study we found that ghrelin (Ghrl) misbalance during the peri-implantation period significantly impaired fetus development. In this study we aimed to evaluate the putative mechanisms underlying these effects, including embryo implantation success, uterine nitric oxide synthase (NOS) activity, nitric oxide synthesis and the inflammatory/immune uterine profile. Methods Ghrelin misbalance was induced by injecting 4nmol/animal/day of Ghrl (hyperghrelinemia) or 6nmol/animal/day of a Ghrl antagonist (Ant: (D-Lys3)GHRP-6) from day 3 to 8 of pregnancy. Control animals (C) were injected with de vehicle. Females were euthanized at pregnancy day 8 and their uteri excised in order to evaluate: the percentage of reabsorbed embryos (microscopically), eNOS, iNOS and nytrotirosine expression (by immunohistochemistry), nitrite synthesis (by Griess technique), VEGF, IL-10, IL-17, IL-6, MMP9 and GM-CSF expression (by qPCR) and leukocyte infiltration by flow cytometry (evaluating T cells, NK cells, granulocytes, dendritic cells and macrophages). Results Ant-treatment significantly increased the percentage of reabsorbed embryos and the uterine expression of eNOS, iNOS and nytrotirosine. (D-Lys3)GHRP-6-treatment increased also the expression of the inflammatory cytokines IL-6, IL-17 and MMP9, and decreased that of IL-10 (anti-inflammatory). Moreover, Ant-treatment increased also the NK cells population and that of CD11b+ dendritic cells; and decreased T cells percentages. Similarly, hyperghrelinemia showed a significant increase vs. C on eNOS, iNOS and nytrotirosineuterine expression and a decrease in T cells percentages. Conclusion Ghrl misbalance during the peri-implantation period induces pro-inflammatory changes and nitrosative stress in the gravid uterus, impairing significantly embryo implantation and/or development.
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Affiliation(s)
- Eugenia Mercedes Luque
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Cintia María Díaz-Luján
- Instituto de Biología Celular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Daniela Andrea Paira
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Nicolás de Loredo
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Pedro Javier Torres
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Verónica Inés Cantarelli
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Ricardo Fretes
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
- Instituto de Biología Celular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Rubén Darío Motrich
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
| | - Ana Carolina Martini
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/Universidad Nacional de Córdoba (UNC), Córdoba, Argentina
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Correa‐da‐Silva F, Fliers E, Swaab DF, Yi C. Hypothalamic neuropeptides and neurocircuitries in Prader Willi syndrome. J Neuroendocrinol 2021; 33:e12994. [PMID: 34156126 PMCID: PMC8365683 DOI: 10.1111/jne.12994] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have abnormal neurocircuitry engaged in the hedonic and physiological control of feeding behavior. This is translated into diminished production of hypothalamic effector peptides which are responsible for the coordination of energy homeostasis and satiety. So far, studies with animal models for PWS and with human post-mortem hypothalamic specimens demonstrated changes particularly in the infundibular and the paraventricular nuclei of the hypothalamus, both in orexigenic and anorexigenic neural populations. Moreover, many PWS patients have a severe endocrine dysfunction, e.g. central hypogonadism and/or growth hormone deficiency, which may contribute to the development of increased fat mass, especially if left untreated. Additionally, the role of non-neuronal cells, such as astrocytes and microglia in the hypothalamic dysregulation in PWS is yet to be determined. Notably, microglial activation is persistently present in non-genetic obesity. To what extent microglia, and other glial cells, are affected in PWS is poorly understood. The elucidation of the hypothalamic dysfunction in PWS could prove to be a key feature of rational therapeutic management in this syndrome. This review aims to examine the evidence for hypothalamic dysfunction, both at the neuropeptidergic and circuitry levels, and its correlation with the pathophysiology of PWS.
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Affiliation(s)
- Felipe Correa‐da‐Silva
- Department of Endocrinology and MetabolismAmsterdam Gastroenterology Endocrinology and MetabolismAmsterdam University Medical Center (UMC)University of AmsterdamAmsterdamThe Netherlands
- Laboratory of EndocrinologyAmsterdam University Medical Center (UMC)University of AmsterdamAmsterdamThe Netherlands
- Department of Neuropsychiatric DisordersNetherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamThe Netherlands
| | - Eric Fliers
- Department of Endocrinology and MetabolismAmsterdam Gastroenterology Endocrinology and MetabolismAmsterdam University Medical Center (UMC)University of AmsterdamAmsterdamThe Netherlands
| | - Dick F. Swaab
- Department of Neuropsychiatric DisordersNetherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamThe Netherlands
| | - Chun‐Xia Yi
- Department of Endocrinology and MetabolismAmsterdam Gastroenterology Endocrinology and MetabolismAmsterdam University Medical Center (UMC)University of AmsterdamAmsterdamThe Netherlands
- Laboratory of EndocrinologyAmsterdam University Medical Center (UMC)University of AmsterdamAmsterdamThe Netherlands
- Department of Neuropsychiatric DisordersNetherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamThe Netherlands
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Bruni V, Dei M. Eating Disorders in Adolescence. GOOD PRACTICE IN PEDIATRIC AND ADOLESCENT GYNECOLOGY 2018:131-141. [DOI: 10.1007/978-3-319-57162-1_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nammi D, Yarla NS, Chubarev VN, Tarasov VV, Barreto GE, Pasupulati AMC, Aliev G, Neelapu NRR. A Systematic In-silico Analysis of Helicobacter pylori Pathogenic Islands for Identification of Novel Drug Target Candidates. Curr Genomics 2017; 18:450-465. [PMID: 29081700 PMCID: PMC5635650 DOI: 10.2174/1389202918666170705160615] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Revised: 01/22/2016] [Accepted: 01/25/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Helicobacter pylori is associated with inflammation of different areas, such as the duodenum and stomach, causing gastritis and gastric ulcers leading to lymphoma and cancer. Pathogenic islands are a type of clustered mobile elements ranging from 10-200 Kb contributing to the virulence of the respective pathogen coding for one or more virulence factors. Virulence factors are molecules expressed and secreted by pathogen and are responsible for causing disease in the host. Bacterial genes/virulence factors of the pathogenic islands represent a promising source for identifying novel drug targets. OBJECTIVE The study aimed at identifying novel drug targets from pathogenic islands in H. pylori. MATERIAL & METHODS The genome of 23 H. pylori strains were screened for pathogenic islands and bacterial genes/virulence factors to identify drug targets. Protein-protein interactions of drug targets were predicted for identifying interacting partners. Further, host-pathogen interactions of interacting partners were predicted to identify important molecules which are closely associated with gastric cancer. RESULTS Screening the genome of 23 H. pylori strains revealed 642 bacterial genes/virulence factors in 31 pathogenic islands. Further analysis identified 101 genes which were non-homologous to human and essential for the survival of the pathogen, among them 31 are potential drug targets. Protein-protein interactions for 31 drug targets predicted 609 interacting partners. Predicted interacting partners were further subjected to host-pathogen interactions leading to identification of important molecules like TNF receptor associated factor 6, (TRAF6) and MAPKKK7 which are closely associated with gastric cancer. CONCLUSION These provocative studies enabled us to identify important molecules in H. pylori and their counter interacting molecules in the host leading to gastric cancer and also a pool of novel drug targets for therapeutic intervention of gastric cancer.
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Affiliation(s)
- Deepthi Nammi
- Department of Biochemistry and Bioinformatics, GITAM Institute of Science, GITAM University, Rushikonda, Visakhapatnam – 534005 (AP), India
| | - Nagendra S. Yarla
- Department of Biochemistry and Bioinformatics, GITAM Institute of Science, GITAM University, Rushikonda, Visakhapatnam – 534005 (AP), India
| | - Vladimir N. Chubarev
- Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 19991Moscow, Russia
| | - Vadim V. Tarasov
- Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 19991Moscow, Russia
| | - George E. Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriama, BogotáD.C., Colombia
| | - Amita Martin Corolina Pasupulati
- Department of Biochemistry and Bioinformatics, GITAM Institute of Science, GITAM University, Rushikonda, Visakhapatnam – 534005 (AP), India
| | - Gjumrakch Aliev
- Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, 19991Moscow, Russia
- Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia
| | - Nageswara Rao Reddy Neelapu
- Department of Biochemistry and Bioinformatics, GITAM Institute of Science, GITAM University, Rushikonda, Visakhapatnam – 534005 (AP), India
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Sominsky L, Hodgson DM, McLaughlin EA, Smith R, Wall HM, Spencer SJ. Linking Stress and Infertility: A Novel Role for Ghrelin. Endocr Rev 2017; 38:432-467. [PMID: 28938425 DOI: 10.1210/er.2016-1133] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 07/24/2017] [Indexed: 12/23/2022]
Abstract
Infertility affects a remarkable one in four couples in developing countries. Psychological stress is a ubiquitous facet of life, and although stress affects us all at some point, prolonged or unmanageable stress may become harmful for some individuals, negatively impacting on their health, including fertility. For instance, women who struggle to conceive are twice as likely to suffer from emotional distress than fertile women. Assisted reproductive technology treatments place an additional physical, emotional, and financial burden of stress, particularly on women, who are often exposed to invasive techniques associated with treatment. Stress-reduction interventions can reduce negative affect and in some cases to improve in vitro fertilization outcomes. Although it has been well-established that stress negatively affects fertility in animal models, human research remains inconsistent due to individual differences and methodological flaws. Attempts to isolate single causal links between stress and infertility have not yet been successful due to their multifaceted etiologies. In this review, we will discuss the current literature in the field of stress-induced reproductive dysfunction based on animal and human models, and introduce a recently unexplored link between stress and infertility, the gut-derived hormone, ghrelin. We also present evidence from recent seminal studies demonstrating that ghrelin has a principal role in the stress response and reward processing, as well as in regulating reproductive function, and that these roles are tightly interlinked. Collectively, these data support the hypothesis that stress may negatively impact upon fertility at least in part by stimulating a dysregulation in ghrelin signaling.
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Affiliation(s)
- Luba Sominsky
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
| | - Deborah M Hodgson
- School of Psychology, Faculty of Science and IT, The University of Newcastle, New South Wales 2308, Australia
| | - Eileen A McLaughlin
- School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland 1010, New Zealand.,School of Environmental & Life Sciences, Faculty of Science and IT, The University of Newcastle, New South Wales 2308, Australia
| | - Roger Smith
- Mothers and Babies Research Centre, Hunter Medical Research Institute, Lookout Road, New Lambton Heights, New South Wales 2305, Australia.,Priority Research Centre in Reproductive Science, The University of Newcastle, New South Wales 2308, Australia
| | - Hannah M Wall
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
| | - Sarah J Spencer
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria 3083, Australia
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Gómez-Díaz RA, Gómez-Medina MP, Ramírez-Soriano E, López-Robles L, Aguilar-Salinas CA, Saucedo R, Zarate A, Valladares-Salgado A, Wacher NH. Lower Plasma Ghrelin Levels are Found in Women with Diabetes-Complicated Pregnancies. J Clin Res Pediatr Endocrinol 2016; 8:425-431. [PMID: 27476441 PMCID: PMC5198001 DOI: 10.4274/jcrpe.2504] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To evaluate the associations of glycemic control and gestational age with ghrelin and proinsulin levels in cord blood and mothers' peripheral blood during pregnancy. METHODS This is a cross-sectional comparative study of twenty-four pregnant women with gestational diabetes (GD), 18 with type 2 diabetes mellitus (T2DM), and 36 without diabetes, as well as their neonates. Levels of proinsulin, ghrelin, and glycated hemoglobin A1c (HbA1c) were measured from maternal blood during the last week before caesarian delivery and in neonatal umbilical cord blood samples. RESULTS Mothers with GD and T2DM had significantly lower ghrelin levels compared to the healthy mothers (p<0.001). Maternal proinsulin was lower in women with GD than in women without diabetes (p<0.001). Proinsulin was significantly elevated in the neonates of women with GD and in women with HbA1c ≥6.5% (p<0.001). However, maternal ghrelin levels were higher (p=0.031) and neonate proinsulin levels lower in the pre-term offspring of mothers with GD (p=0.033). There was a negative correlation between HbA1c levels and birth weight (r=-0.407, p<0.001). CONCLUSION Ghrelin levels were lower in pregnant women with diabetes, although pre-term birth appeared to reverse this trend in GD. Proinsulin levels were also low in pregnant women with diabetes and even lower in pre-term vs. at-term births. Both ghrelin and proinsulin levels were lower in pregnant women with diabetes and HbA1c of <6.5%. Thus, ghrelin participates in the adaptation to the caloric imbalance of diabetic pregnancy and may play a similar role in pregnancy-related complications, since high ghrelin concentrations may be necessary for normal fetal development.
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Affiliation(s)
- Rita Angélica Gómez-Díaz
- National Medical Center "Siglo XXI", Mexican Social Security Institute, UMAE Hospital of Specialties, Unit of Medical Research in Clinical Epidemiology, Mexico City, Mexico Phone: +52-55-5627-6900 ext. 21481, 21507 E-mail:
| | | | - Eleazar Ramírez-Soriano
- National Medical Center “La Raza”, Hospital of Gynecology Pediatrics 3A, Mexico City, Mexico
| | - Lucio López-Robles
- UMAE Hospital of Specialties, Clinic of Obstetrics Gynecology, Mexico City, Mexico
| | - Carlos A. Aguilar-Salinas
- National Institute of Medical Sciences and Nutrition, Department of Endocrinology and Metabolism, Mexico City, Mexico
| | - Renata Saucedo
- National Medical Center “Siglo XXI”, Mexican Social Security Institute, UMAE Hospital of Specialties, Unit of Medical Research in Endocrine Diseases, Mexico City, Mexico
| | - Arturo Zarate
- National Medical Center “Siglo XXI”, Mexican Social Security Institute, UMAE Hospital of Specialties, Unit of Medical Research in Endocrine Diseases, Mexico City, Mexico
| | - Adan Valladares-Salgado
- National Medical Center “Siglo XXI”, Mexican Social Security Institute, UMAE Hospital of Specialties, Unit of Biochemistry, Mexico City, Mexico
| | - Niels H. Wacher
- National Medical Center “Siglo XXI”, Mexican Social Security Institute, UMAE Hospital of Specialties, Unit of Medical Research in Clinical Epidemiology, Mexico City, Mexico
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Ristic N, Stevanovic D, Nesic D, Ajdzanovic V, Rakocevic R, Jaric I, Milosevic V. Diet-Induced Obesity and Ghrelin Effects on Pituitary Gonadotrophs: Immunohistomorphometric Study in Male Rats. CELL JOURNAL 2016; 17:711-9. [PMID: 26862530 PMCID: PMC4746421 DOI: 10.22074/cellj.2016.3843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 02/24/2015] [Indexed: 11/12/2022]
Abstract
Objective The close relationship between energy metabolism, nutritional state, and
reproductive physiology suggests that nutritional and metabolic disorders can disrupt
normal reproductive function and fertility. Considering the importance of leptin and
ghrelin effects in regulation of the hypothalamic-pituitary-gonadal axis, the objective
of this study was to investigate the influence of obesity and centrally applied ghrelin
on immunohistochemical appearance and quantitative morphology of the pituitary
follicle-stimulating hormone (FSH) and luteinizing hormone (LH) producing cells in
adult male rats. Materials and Methods In this experimental study, animals were given two differ-
ent diets: normal-fat (NF) and high-fat (HF), for 4 weeks, corresponding to normal
and positive energy balance (n=2×14), respectively. Each group was subsequently
divided into two subgroups (n=7) receiving intracerebroventricular (ICV) injections of
either ghrelin [G, 1 µg/5 µL phosphate buffered saline (PBS)] or vehicle (5 µL PBS,
control group) every 24 hours for five consecutive days.
Results Morphometric analyses showed that in HF control group, the percentage of
FSH cells per unit volume of total pituitary gland tissue (in μm3), i.e. volume density
(Vvc), was increased (P<0.05) by 9.1% in comparison with the NF controls. After
ICV treatment with ghrelin, volume (Vc) and volume density (Vvc) of FSH cells in
ghrelin+NF (GNF) and ghrelin+HF (GHF) groups remained unchanged in comparison
with NF and HF controls. Volume of LH cells in HF control group was increased by
17% (P<0.05), but their Vvc was decreased by 8.3% (P<0.05) in comparison with
NF controls. In GNF group, the volume of LH cells increased by 7% (P<0.05), in
comparison with the NF controls, but in GHF group, the same parameter remained
unchanged when compared with HF controls. The central application of ghrelin de-
creased the Vvc of LH cells only in GNF group by 38.9% (P<0.05) in comparison with
the NF control animals.
Conclusion The present study has shown that obesity and repetitive ICV administra-
tion of low doses of ghrelin, in NF and HF rats, modulated the immunohistomorphometric
features of gonadotrophs, indicating the importance of obesity and ghrelin in regulation of
the reproductive function.
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Affiliation(s)
- Natasa Ristic
- Institute for Biological Research Sinisa Stankovic, University of Belgrade, Belgrade, Serbia
| | - Darko Stevanovic
- Institute of Medical Physiology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dejan Nesic
- Institute of Medical Physiology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir Ajdzanovic
- Institute for Biological Research Sinisa Stankovic, University of Belgrade, Belgrade, Serbia
| | - Rastko Rakocevic
- Institute of Medical Physiology, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ivana Jaric
- Institute for Biological Research Sinisa Stankovic, University of Belgrade, Belgrade, Serbia
| | - Verica Milosevic
- Institute for Biological Research Sinisa Stankovic, University of Belgrade, Belgrade, Serbia
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Ghrelin Actions on Somatotropic and Gonadotropic Function in Humans. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 138:3-25. [PMID: 26940384 DOI: 10.1016/bs.pmbts.2015.11.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ghrelin, a 28 amino-acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor (GHS-R1a). It was thus considered as a natural GHS additional to GHRH, although later on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing action of ghrelin takes place both directly on pituitary cells and through modulation of GHRH from the hypothalamus; some functional antisomatostatin action has also been shown. However, ghrelin is much more than a natural GH secretagogue. In fact, it also modulates lactotroph and corticotroph secretion in humans as well as in animals and plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function. Several studies have indicated that ghrelin plays an inhibitory effect on gonadotropin pulsatility, is involved in the regulation of puberty onset in animals, and may regulate spermatogenesis, follicular development and ovarian cell functions in humans. In this chapter ghrelin actions on the GH/IGF-I and the gonadal axes will be revised. The potential therapeutic role of ghrelin as a treatment of catabolic conditions will also be discussed.
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Tasker JG, Chen C, Fisher MO, Fu X, Rainville JR, Weiss GL. Endocannabinoid Regulation of Neuroendocrine Systems. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 125:163-201. [PMID: 26638767 DOI: 10.1016/bs.irn.2015.09.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The hypothalamus is a part of the brain that is critical for sustaining life through its homeostatic control and integrative regulation of the autonomic nervous system and neuroendocrine systems. Neuroendocrine function in mammals is mediated mainly through the control of pituitary hormone secretion by diverse neuroendocrine cell groups in the hypothalamus. Cannabinoid receptors are expressed throughout the hypothalamus, and endocannabinoids have been found to exert pronounced regulatory effects on neuroendocrine function via modulation of the outputs of several neuroendocrine systems. Here, we review the physiological regulation of neuroendocrine function by endocannabinoids, focusing on the role of endocannabinoids in the neuroendocrine regulation of the stress response, food intake, fluid homeostasis, and reproductive function. Cannabis sativa (marijuana) has a long history of recreational and/or medicinal use dating back to ancient times. It was used as an analgesic, anesthetic, and antianxiety herb as early as 2600 B.C. The hedonic, anxiolytic, and mood-elevating properties of cannabis have also been cited in ancient records from different cultures. However, it was not until 1964 that the psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol, was isolated and its chemical structure determined (Gaoni & Mechoulam, 1964).
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Affiliation(s)
- Jeffrey G Tasker
- Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA; Neuroscience Program, Tulane University, New Orleans, Louisiana, USA.
| | - Chun Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA
| | - Marc O Fisher
- Neuroscience Program, Tulane University, New Orleans, Louisiana, USA
| | - Xin Fu
- Neuroscience Program, Tulane University, New Orleans, Louisiana, USA
| | - Jennifer R Rainville
- Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA
| | - Grant L Weiss
- Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA
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Cassar S, Teede HJ, Harrison CL, Joham AE, Moran LJ, Stepto NK. Biomarkers and insulin sensitivity in women with Polycystic Ovary Syndrome: Characteristics and predictive capacity. Clin Endocrinol (Oxf) 2015; 83:50-8. [PMID: 25262763 DOI: 10.1111/cen.12619] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 07/19/2014] [Accepted: 09/22/2014] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with metabolic complications. Metabolic biomarkers with roles in obesity, glycaemic control and lipid metabolism are potentially relevant in PCOS. The aim was to investigate metabolic biomarkers in lean and overweight women with and without PCOS and to determine whether any biomarker was able to predict insulin resistance in PCOS. DESIGN Cross-sectional study. PATIENTS Eighty-four women (22 overweight and 22 lean women with PCOS, 18 overweight and 22 lean women without PCOS) were recruited from the community and categorized based on PCOS and BMI status. MEASUREMENTS Primary outcomes were metabolic biomarkers [ghrelin, resistin, visfatin, glucagon-like peptide-1 (GLP-1), leptin, plasminogen activator inhibitor -1 (PAI-1), glucose-dependent insulinotropic polypeptide (GIP) and C-Peptide] measured using the Bio-Plex Pro Diabetes assay and insulin sensitivity as assessed by glucose infusion rate on euglycaemic-hyperinsulinaemic clamp. RESULTS The biomarkers C-peptide, leptin, ghrelin and visfatin were different between overweight and lean women, irrespective of PCOS status. The concentration of circulating biomarkers did not differ between women with PCOS diagnosed by the Rotterdam criteria or National Institute of Health criteria. PAI-1 was the only biomarker that significantly predicted insulin resistance in both control women (P = 0.04) and women with PCOS (P = 0.01). CONCLUSIONS Biomarkers associated with metabolic diseases appear more strongly associated with obesity rather than PCOS status. PAI-1 may also be a novel independent biomarker and predictor of insulin resistance in women with and without PCOS.
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Affiliation(s)
- Samantha Cassar
- Institute of Sport, Exercise and Active Living, Victoria University, Melbourne, Vic., Australia
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
| | - Helena J Teede
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
- Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Vic., Australia
| | - Cheryce L Harrison
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
| | - Anju E Joham
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
- Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Vic., Australia
| | - Lisa J Moran
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
- The Robinson Research Institute, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, SA, Australia
| | - Nigel K Stepto
- Institute of Sport, Exercise and Active Living, Victoria University, Melbourne, Vic., Australia
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic., Australia
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11
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Caillon H, Fréour T, Bach-Ngohou K, Colombel A, Denis MG, Barrière P, Masson D. Effects of female increased body mass index on in vitro fertilization cycles outcome. Obes Res Clin Pract 2015; 9:382-8. [PMID: 25769458 DOI: 10.1016/j.orcp.2015.02.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 01/14/2015] [Accepted: 02/11/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND As being overweight can impair female spontaneous fertility or after assisted reproductive technology (ART) cycles, the aim of this study was to compare in vitro fertilization (IVF) outcome according to women's body mass index (BMI). METHODS Retrospective study conducted from 2006 to 2009 in the IVF unit of Nantes University Hospital, France. 582 patients undergoing standard infertility workup and controlled ovarian stimulation were categorized according to BMI into two groups: group 1: normal weight (20-24.9 kg/m(2); n=409) and group 2: overweight and obese (≥25 kg/m(2); n=149). Basal hormonal status, smoking habitus, infertility duration, IVF cycle parameters and outcome were recorded. RESULTS Basal LH, FSH and estradiol levels were higher in group 1 than group 2, but ovarian reserve markers were comparable across the two BMI groups. Higher doses of gonadotropins were required in group 2 to obtain equivalent ovarian response than in group 1. No difference was observed on ovarian response and embryonic parameters. Cycle outcome were not significantly different between both groups, but we found a strong trend towards increasing transfer cancellation and miscarriage rates in group 2. CONCLUSION Although overweight and obesity do not compromise ovarian stimulation results whenever adaptation of recombinant FSH doses is made, our data suggest an increased risk of cancellation transfer and miscarriage rate, leading to poorer IVF outcome.
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Affiliation(s)
- Hélène Caillon
- Hormonology and Biochemistry Laboratory, CHU Nantes, France.
| | - Thomas Fréour
- Department of Human Reproduction, CHU Nantes, France
| | | | | | - Marc G Denis
- Hormonology and Biochemistry Laboratory, CHU Nantes, France
| | - Paul Barrière
- Department of Human Reproduction, CHU Nantes, France
| | - Damien Masson
- Hormonology and Biochemistry Laboratory, CHU Nantes, France
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12
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Kiezun M, Smolinska N, Maleszka A, Dobrzyn K, Szeszko K, Kaminski T. Adiponectin expression in the porcine pituitary during the estrous cycle and its effect on LH and FSH secretion. Am J Physiol Endocrinol Metab 2014; 307:E1038-46. [PMID: 25315693 DOI: 10.1152/ajpendo.00299.2014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Female reproductive success is closely associated with nutritional status and energy balance. In this context, adiponectin appears to be a key hormone connecting reproductive system function and metabolism regulation. It is hypothesized that adiponectin expression in the pituitary depends on the phase of the estrous cycle. The effect of adiponectin on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion is also postulated. Changes in the adiponectin gene and protein expression in the porcine anterior (AP) and posterior (NP) pituitaries as well as the effect of in vitro administration of adiponectin on basal and gonadotropin-releasing hormone (GnRH)- and/or insulin-stimulated LH and FSH secretion were investigated on days 2-3, 10-12, 14-16, and 17-19 of the estrous cycle. Adiponectin gene was more pronounced on days 2-3 in AP but on days 10-12 in NP. Protein concentration in AP was the highest on days 10-12 and in NP on days 10-12 and 17-19 of the cycle. In vitro, adiponectin did not affect basal LH secretion but increased FSH release by AP cells. Adiponectin administration affected GnRH- and/or insulin-induced LH and FSH output in a manner dependent on the phase of the estrous cycle. In this study we indicated for the first time adiponectin expression in the porcine AP and NP that was dependent on the phase of the estrous cycle. In vitro studies indicated that adiponectin may affect gonadotropin secretion. The above suggests that the studied adipokine may influence female reproductive functions via its effect on LH and FSH secretion by gonadotrophs, but the cellular mechanism of its action remains unknown.
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Affiliation(s)
- Marta Kiezun
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Nina Smolinska
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Anna Maleszka
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Kamil Dobrzyn
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Karol Szeszko
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
| | - Tadeusz Kaminski
- Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn-Kortowo, Poland
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13
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Yuan MJ, Huang H, Huang CX. Potential new role of the GHSR-1a-mediated signaling pathway in cardiac remodeling after myocardial infarction (Review). Oncol Lett 2014; 8:969-971. [PMID: 25120643 PMCID: PMC4114710 DOI: 10.3892/ol.2014.2245] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 05/15/2014] [Indexed: 11/17/2022] Open
Abstract
The gastrointestinal hormone ghrelin has important cardiovascular protective effects, however, its specific mechanisms are not yet completely understood. Recent studies have shown that the ghrelin receptor, growth hormone secretagogue receptor type 1a (GHSR-1a), regulates cell proliferation, apoptosis and inflammation-related signaling pathways. In human aortic endothelial cells, ghrelin activates NO production through AMP-activated protein kinase (AMPK) and Akt activation, and these effects can be blocked by knockdown of GHSR-1a. Obese mice have been found to exhibit an increased GHSR-1a content and expression in the heart, associated with an increase in phosphatidylinositol 3-kinase (PI3K) content and an increase AKT content and phosphorylation. Furthermore, GHSR-1a expression was observed to be increased in heart failure after myocardial infarction (MI) in rats. Given such complexity in GHSR-1a signaling and crosstalk with the AMPK and PI3K/Akt signaling pathways, both of which are well-known factors involved in cardiac remodeling after MI, we speculate that GHSR-1a signaling may play a regulatory role in cardiac protection and hope to identify new drugs targets. However, to date, no direct association between GHSR-1a and cardiac remodeling has been found. Therefore, further studies are required.
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Affiliation(s)
- Ming-Jie Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - He Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Cong-Xin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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14
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Catak Z, Aydin S, Sahin I, Kuloglu T, Aksoy A, Dagli AF. Regulatory neuropeptides (ghrelin, obestatin and nesfatin-1) levels in serum and reproductive tissues of female and male rats with fructose-induced metabolic syndrome. Neuropeptides 2014; 48:167-177. [PMID: 24786976 DOI: 10.1016/j.npep.2014.04.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/02/2014] [Accepted: 04/07/2014] [Indexed: 12/15/2022]
Abstract
Although, the exact mechanisms underlying the development of the metabolic syndrome (MetS) are not still completely understood, obesity, circulated peptide hormone levels and their interaction with genetic factors are considered largely responsible. The purpose of this study is to explore how the levels of ghrelin, obestatin (OBS) and NUCB2/nesfatin-1 (NES)/NUCB2 change in serum and the reproductive tissues of female and male rats with fructose-induced metabolic syndrome, and whether the levels of each hormone is correlated with the hormones involved with fertility. Experiments were conducted on 5-week-old Sprague-Dawley male and female rats assigned to either a control group or a MetS group. Controls were fed standard rat food and water ad libitum, while the MetS group was fed standard food with 10% (v/v) fructose solution added to their drinking water for 12 weeks with a 12/12h photoperiod circle. Then, all animals were sacrificed after a one night fast. Peptides levels in the serum and reproductive tissues of rats were studied using the ELISA method while the immunoreactivity of reproductive system peptide hormones were shown by immunohistochemical staining method. Furthermore, the other biochemical parameters were measured using Konelab-60 equipment and infertility hormones were measured with Immulite2000. Fasting serum insulin, glucose, triglyceride, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels were statistically significantly higher, and the amount of high density lipoprotein cholesterol (HDL-C) was significantly lower, in the MetS groups. Serum and tissue supernatant NES levels were significantly higher in the rats with MetS than the control group. Ghrelin, OBS and NES were expressed in the cytoplasm, concentrated around the apical parts of the epithelial cells in the reproductive tissues of the rats. The amounts of ghrelin were lower in the reproductive tissues of the animals with MetS, while NES levels in the same tissues increased. Obestatin also decreased, though not in the seminal glands.
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Affiliation(s)
- Zekiye Catak
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey
| | - Suleyman Aydin
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey.
| | - Ibrahim Sahin
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey; Department of Histology and Embryology, Medical School, Erzincan University, 24030 Erzincan, Turkey
| | - Tuncay Kuloglu
- Department of Histology and Embryology, Medical School, Firat University, 23119 Elazig, Turkey
| | - Aziz Aksoy
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey; Department of Nutrition and Dietetics, Bitlis Eren University, 13000 Bitlis, Turkey
| | - Adile Ferda Dagli
- Department of Medical Pathology, Medical School, Inonu University, 44280 Malatya, Turkey
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15
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Moretti E, Figura N, Collodel G, Ponzetto A. Can Helicobacter pylori infection influence human reproduction? World J Gastroenterol 2014; 20:5567-5574. [PMID: 24914316 PMCID: PMC4024765 DOI: 10.3748/wjg.v20.i19.5567] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/29/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection could be associated with extra-digestive diseases. Here, we report the evidences concerning the decrease in reproductive potential occurring in individuals infected by H. pylori, especially by strains expressing CagA. This infection is more prevalent in individuals with fertility disorders. Infected women have anti-H. pylori antibodies in cervical mucus and follicular fluid that may decrease sperm motility and cross react immunologically with spermatozoa, conceivably hampering the oocyte/sperm fusion. Infection by CagA positive organisms enhances the risk of preeclampsia, which is a main cause of foetus death. These findings are supported by the results of experimental infections of pregnant mice, which may cause reabsorption of a high number of foetuses and alter the balance between Th1 and Th2 cell response. Infected men have decreased sperm motility, viability and numbers of normally shaped sperm and augmented systemic levels of inflammatory cytokines, such as tumor necrosis factor-α, which may damage spermatozoa. In countries where parasitic infestation is endemic, detrimental effects of infection upon spermatozoa may not occur, because the immune response to parasites could determine a switch from a predominant Th1 type to Th2 type lymphocytes, with production of anti-inflammatory cytokines. In conclusion, the evidences gathered until now should be taken into consideration for future studies aiming to explore the possible role of H. pylori infection on human reproduction.
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16
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Plasma nesfatin-1 is not affected by long-term food restriction and does not predict rematuration among iteroparous female rainbow trout (Oncorhynchus mykiss). PLoS One 2014; 9:e85700. [PMID: 24416444 PMCID: PMC3887096 DOI: 10.1371/journal.pone.0085700] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/05/2013] [Indexed: 12/21/2022] Open
Abstract
The metabolic peptide hormone nesfatin-1 has been linked to the reproductive axis in fishes. The purpose of this study was to determine how energy availability after spawning affects plasma levels of nesfatin-1, the metabolic peptide hormone ghrelin, and sex steroid hormones in rematuring female rainbow trout (Oncorhynchus mykiss). To limit reproductive maturation, a group of female trout was food-restricted after spawning and compared with a control group that was fed a standard broodstock ration. The experiment was conducted twice, once using two-year-old trout (second-time spawners) and once using three-year-old trout (third-time spawners). During monthly sampling, blood was collected from all fish, and a subset of fish from each treatment was sacrificed for pituitaries. Pituitary follicle-stimulating hormone-beta (fsh-β) mRNA expression was analyzed with q-RT-PCR; plasma hormone levels were quantified by radioimmunoassay (17β-estradiol and ghrelin) and enzyme-linked immunosorbent assay (11-keto-testosterone and nesfatin-1). Although plasma nesfatin-1 levels increased significantly in the months immediately after spawning within both feeding treatments, plasma nesfatin-1 did not differ significantly between the two treatments at any point. Similarly, plasma ghrelin levels did not differ significantly between the two treatments at any point. Food restriction arrested ovarian development by 15–20 weeks after spawning, shown by significantly lower plasma E2 levels among restricted-ration fish. Pituitary fsh-β mRNA levels were higher among control-ration fish than restricted-ration fish starting at 20 weeks, but did not differ significantly between treatment groups until 30 weeks after spawning. Within both treatment groups, plasma 11-KT was elevated immediately after spawning and rapidly decreased to and persisted at low levels; starting between 20 and 25 weeks after spawning, plasma 11-KT was higher among control-ration fish than restricted-ration fish. The results from these experiments do not provide support for plasma nesfatin-1 as a signal for the initiation of reproductive development in rematuring female rainbow trout.
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17
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Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Hum Reprod Update 2013; 20:153-74. [PMID: 24173881 DOI: 10.1093/humupd/dmt033] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Reproductive function is tightly regulated by nutritional status. Indeed, it has been well described that undernutrition or obesity can lead to subfertility or infertility in humans. The common regulatory pathways which control energy homeostasis and reproductive function have, to date, been poorly understood due to limited studies or inconclusive data. However, gut hormones and adipose tissue hormones have recently emerged as potential regulators of both energy homeostasis and reproductive function. METHODS A PubMed search was performed using keywords related to gut and adipose hormones and associated with keywords related to reproduction. RESULTS Currently available evidence that gut (ghrelin, obestatin, insulin, peptide YY, glucagon-like peptide-1, glucose-dependent insulinotropic peptide, oxyntomodulin, cholecystokinin) and adipose hormones (leptin, adiponectin, resistin, omentin, chemerin) interact with the reproductive axis is presented. The extent, site and direction of their effects on the reproductive axis are variable and also vary depending on species, sex and pubertal stage. CONCLUSIONS Gut and adipose hormones interact with the reproductive axis as well as with each other. While leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on hypothalamic GnRH secretion, there is increasing evidence for their roles in other sites of the reproductive axis as well as evidence for the roles of other gut and adipose hormones in the complex interplay between nutrition and reproduction. As our understanding improves, so will our ability to identify and design novel therapeutic options for reproductive disorders and accompanying metabolic disorders.
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Affiliation(s)
- Alexander N Comninos
- Department of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
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18
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Farkas I, Vastagh C, Sárvári M, Liposits Z. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS One 2013; 8:e78178. [PMID: 24124622 PMCID: PMC3790731 DOI: 10.1371/journal.pone.0078178] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Accepted: 09/16/2013] [Indexed: 12/11/2022] Open
Abstract
The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca2+-imaging revealed a ghrelin-triggered increase of the Ca2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40nM-4μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.
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Affiliation(s)
- Imre Farkas
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
- * E-mail:
| | - Csaba Vastagh
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Miklós Sárvári
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
- Department of Neuroscience, Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, Hungary
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19
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CagA-positive Helicobacter pylori infection and reduced sperm motility, vitality, and normal morphology. DISEASE MARKERS 2013; 35:229-34. [PMID: 24167371 PMCID: PMC3780520 DOI: 10.1155/2013/919174] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 08/20/2013] [Accepted: 08/26/2013] [Indexed: 12/17/2022]
Abstract
Helicobacter pylori (HP) infection, particularly when caused by strains expressing CagA, may be considered a concomitant cause of male and female reduced fertility. This study explored, in 87 HP-infected males, the relationship between infection by CagA-positive HP strains and sperm parameters. HP infection and CagA status were determined by ELISA and Western blotting; semen analysis was performed following WHO guidelines. The amino acid sequence of human enzymes involved in glycolysis and oxidative metabolism were “blasted” with peptides expressed by HP J99.
Thirty-seven patients (42.5%) were seropositive for CagA. Sperm motility (18% versus 32%; P < 0.01), sperm vitality (35% versus 48%; P < 0.01) and the percentage of sperm with normal forms (18% versus 22%; P < 0.05) in the CagA-positive group were significantly reduced versus those in the CagA-negative group. All the considered enzymes showed partial linear homology with HP peptides, but four enzymes aligned with four different segments of the same cag island protein. We hypothesize a relationship between infection by strains expressing CagA and decreased sperm quality. Potentially increased systemic levels of inflammatory cytokines that occur in infection by CagA-positive strains and autoimmune phenomena that involve molecular mimicry could explain the pathogenetic mechanism of alterations observed.
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20
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Seim I, Lubik AA, Lehman ML, Tomlinson N, Whiteside EJ, Herington AC, Nelson CC, Chopin LK. Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer. J Mol Endocrinol 2013; 50:179-91. [PMID: 23267039 DOI: 10.1530/jme-12-0150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.
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Affiliation(s)
- Inge Seim
- Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia
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21
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Michalakis K, Mintziori G, Kaprara A, Tarlatzis BC, Goulis DG. The complex interaction between obesity, metabolic syndrome and reproductive axis: a narrative review. Metabolism 2013; 62:457-78. [PMID: 22999785 DOI: 10.1016/j.metabol.2012.08.012] [Citation(s) in RCA: 203] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 08/13/2012] [Accepted: 08/18/2012] [Indexed: 12/16/2022]
Abstract
The aim of this narrative review is to provide current evidence for the interaction between obesity, metabolic syndrome (MS) and reproductive axis. Gonadotropin-releasing hormone (GnRH) pulses and, consequently, normal function of reproductive (hypothalamus-pituitary-gonadal) axis depend on normal energy balance, which presupposes sufficient food intake, reasonable energy consumption and average thermoregulatory costs. In case of an energy imbalance, reproductive dysfunction may occur. In young women, excessive leanness is accompanied by puberty delay, whereas premature puberty might be a manifestation of obesity. In a similar way, obesity in men affects fertility. Excess adipose tissue results in increased conversion of testosterone to estradiol, which may lead to secondary hypogonadism through reproductive axis suppression. Moreover, oxidative stress at the level of the testicular micro-environment may result in decreased spermatogenesis and sperm damage. Products of the adipocyte, such as leptin, adiponectin and resistin, and gut peptides, such as ghrelin, are considered to be crucial in the interaction between energy balance and reproduction. Finally, an indirect evidence for the interplay between MS and reproductive axis is the fact that when treating components of one, parameters of the other can be improved as well. These therapeutic interventions include lifestyle modifications, pharmacological agents, such as sex hormone replacement therapy, and surgical procedures. Although many issues remain unclear, the elucidation of the complex interaction between MS and reproductive axis will have obvious clinical implications in the therapeutic approach of both entities.
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Affiliation(s)
- Konstantinos Michalakis
- First Department of Internal Medicine, Laikon University Hospital, Athens University Medical School, Greece
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22
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Méquinion M, Langlet F, Zgheib S, Dickson S, Dehouck B, Chauveau C, Viltart O. Ghrelin: central and peripheral implications in anorexia nervosa. Front Endocrinol (Lausanne) 2013; 4:15. [PMID: 23549309 PMCID: PMC3581855 DOI: 10.3389/fendo.2013.00015] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 02/01/2013] [Indexed: 11/15/2022] Open
Abstract
Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.
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Affiliation(s)
- Mathieu Méquinion
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
| | - Fanny Langlet
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
| | - Sara Zgheib
- Pathophysiology of inflammatory of bone diseases, Université Lille Nord de France-ULCO – Lille 2Boulogne sur Mer, France
| | - Suzanne Dickson
- Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
- Department of Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Bénédicte Dehouck
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
- Université Lille Nord de France – Université d’ArtoisLiévin, France
| | - Christophe Chauveau
- Pathophysiology of inflammatory of bone diseases, Université Lille Nord de France-ULCO – Lille 2Boulogne sur Mer, France
| | - Odile Viltart
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
- Université Lille Nord de France-USTL (Lille 1)Villeneuve d’Ascq, France
- *Correspondence: Odile Viltart, Development and Plasticity of the Postnatal Brain, Team 2, Jean-Pierre Aubert Research Center, UMR INSERM 837, Bât Biserte, 1 place de Verdun, 59,045 Lille cedex, France. e-mail:
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Gao M, Yang J, Liu G, Wei R, Zhang L, Wang H, Wang G, Gao H, Chen G, Hong T. Ghrelin promotes the differentiation of human embryonic stem cells in infarcted cardiac microenvironment. Peptides 2012; 34:373-9. [PMID: 22386650 DOI: 10.1016/j.peptides.2012.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 02/04/2012] [Accepted: 02/06/2012] [Indexed: 11/23/2022]
Abstract
Ghrelin is broadly expressed in myocardial tissues, where it exerts different functions. It also has been found to have a wide variety of biological functions on cell differentiation and tissue development. The aim of this study was to investigate the effect of ghrelin on human embryonic stem cell (hESC) differentiation in infarcted cardiac microenvironment. The hESCs grown on feeder layers expressed several pluripotential markers including alkaline phosphatase (AKP). Four weeks after transplantation into rat infarcted hearts, the hESCs and their progeny cells survived and formed intracardiac grafts were 54.7% and 19.6% respectively in ghrelin- and phosphate-buffered saline (PBS)-treated groups. Double immunostaining with anti-human Sox9 and anti-HNA or anti-human fetal liver kinase-1 (Flk1) and anti β-tubulin showed that the human grafts were in development. However, double positive stains were only found in the ghrelin-treated group. In addition, the hESC injection protocol was insufficient to restore heart function of the acute myocardial infarction model. Our study, therefore, provides a new insight of ghrelin on promoting hESC survival and differentiation in rat infarcted cardiac microenvironment. This may give a clue for therapy for myocardial infarction by hESCs or progeny cells.
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Affiliation(s)
- Meijuan Gao
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
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