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Slezacek J, Quillfeldt P, Kaiya H, Hykollari A, Fusani L. Circulating profile of the appetite-regulating hormone ghrelin during moult-fast and chick provisioning in southern rockhopper penguins (Eudyptes chrysocome chrysocome). Horm Behav 2024; 164:105592. [PMID: 38941765 DOI: 10.1016/j.yhbeh.2024.105592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 06/12/2024] [Accepted: 06/13/2024] [Indexed: 06/30/2024]
Abstract
A multitude of animal species undergo prolonged fasting events at regularly occurring life history stages. During such periods of food deprivation, individuals need to suppress their appetite. The satiety signalling gut hormone ghrelin has received much attention in this context in studies looking at mammalian systems. In wild birds, however, knowledge on the ghrelin system and its role during extended fasts is still scarce. In this study, we collected plasma samples for measurements of circulating ghrelin concentrations from adult southern rockhopper penguins (Eudyptes chrysocome chrysocome) during the three to four week-long moult-fast that they repeat annually to replace their feathers. We further sampled chicks before and after feeding bouts and non-moulting adults. Circulating ghrelin levels did not differ significantly between fed and unfed chicks but chicks had significantly lower plasma ghrelin levels compared to adults. Furthermore, penguins in late moult (i.e. individuals at the end of the prolonged fasting bout) had higher ghrelin levels compared to non-moulting adults. Our results show elevated levels of circulating ghrelin during moult and generally lower levels of ghrelin in chicks than in adults regardless of feeding state. Given the scarcity or absence of knowledge on the function of ghrelin in seabirds and in fasting birds in general, our results add greatly to our understanding of the avian ghrelin system.
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Affiliation(s)
- Julia Slezacek
- Konrad Lorenz Institute of Ethology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Savoyenstraße 1A, 1160 Vienna, Austria.
| | - Petra Quillfeldt
- Department of Animal Ecology & Systematics, Justus Liebig University Giessen, Heinrich-Buff-Ring 26, D-35392 Giessen, Germany
| | - Hiroyuki Kaiya
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita 564-8565, Japan
| | - Alba Hykollari
- Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna, Savoyenstraße 1A, 1160 Vienna, Austria
| | - Leonida Fusani
- Konrad Lorenz Institute of Ethology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Savoyenstraße 1A, 1160 Vienna, Austria; Department of Behavioral and Cognitive Biology, University of Vienna, Djerassiplatz 1, 1030 Vienna, Austria.
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Xiong J, Ding Y, Wu X, Zhan J, Wan Q, Wan H, Wei B, Chen H, Yang Y. Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings. Schizophr Res 2024; 264:282-289. [PMID: 38198881 DOI: 10.1016/j.schres.2024.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 12/18/2023] [Accepted: 01/01/2024] [Indexed: 01/12/2024]
Abstract
BACKGROUND Numerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. METHODS We conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. RESULTS The meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. CONCLUSIONS Our findings support the "IGF-1 deficiency hypothesis" in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.
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Affiliation(s)
- Jianwen Xiong
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China; Nanchang City Key Laboratory of Biological Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, Jiangxi, China
| | - Yudan Ding
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xiaopeng Wu
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China
| | - Jinqiong Zhan
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China; Nanchang City Key Laboratory of Biological Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, Jiangxi, China
| | - Qigen Wan
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China
| | - Hongying Wan
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China
| | - Bo Wei
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China; Nanchang City Key Laboratory of Biological Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, Jiangxi, China.
| | - Haibo Chen
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China.
| | - Yuanjian Yang
- Department of Psychiatry, Jiangxi Mental Hospital & Affiliated Mental Hospital of Nanchang University, Nanchang 330029, Jiangxi, China; Nanchang City Key Laboratory of Biological Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, Jiangxi, China.
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Boudry G, Cahu A, Romé V, Janvier R, Louvois M, Catheline D, Rioux V, Le Huërou-Luron I, Blat S. The ghrelin system follows a precise post-natal development in mini-pigs that is not impacted by dietary medium chain fatty-acids. Front Physiol 2022; 13:1010586. [PMID: 36225304 PMCID: PMC9549131 DOI: 10.3389/fphys.2022.1010586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 09/14/2022] [Indexed: 11/13/2022] Open
Abstract
The ghrelin-ghrelin receptor (GHSR1) system is one of the most important mechanisms regulating food intake and energy balance. To be fully active, ghrelin is acylated with medium-chain fatty acids (MCFA) through the ghrelin-O-acetyl transferase (GOAT). Several studies reported an impact of dietary MCFA on ghrelin acylation in adults. Our study aimed at describing early post-natal development of the ghrelin system in mini-pigs as a model of human neonates and evaluating the impact of dietary MCFA. Suckled mini-pigs were sacrificed at post-natal day (PND) 0, 2, 5, and 10 or at adult stage. In parallel, other mini-pigs were fed from birth to PND10 a standard or a dairy lipid-enriched formula with increased MCFA concentration (DL-IF). Plasma ghrelin transiently peaked at PND2, with no variation of the acylated fraction except in adults where it was greater than during the neonatal period. Levels of mRNA coding pre-proghrelin (GHRL) and GOAT in the antrum did not vary during the post-natal period but dropped in adults. Levels of antral pcsk1/3 (cleaving GHRL into ghrelin) mRNA decreased significantly with age and was negatively correlated with plasma acylated, but not total, ghrelin. Hypothalamic ghsr1 mRNA did not vary in neonates but increased in adults. The DL-IF formula enriched antral tissue with MCFA but did not impact the ghrelin system. In conclusion, the ghrelin maturation enzyme PCSK1/3 gene expression exhibited post-natal modifications parallel to transient variations in circulating plasma ghrelin level in suckling piglets but dietary MCFA did not impact this post-natal development.
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Affiliation(s)
- Gaëlle Boudry
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
- *Correspondence: Gaëlle Boudry,
| | - Armelle Cahu
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
| | - Véronique Romé
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
| | - Régis Janvier
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
| | - Margaux Louvois
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
| | - Daniel Catheline
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
- Institut Agro, Rennes, France
| | - Vincent Rioux
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
- Institut Agro, Rennes, France
| | | | - Sophie Blat
- Institut Numecan, INRAE, INSERM, Univ Rennes, Saint-Gilles-Rennes, France
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Gupta S, Mitra A. Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure. Heart Fail Rev 2020; 26:417-435. [PMID: 33025414 DOI: 10.1007/s10741-020-10032-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2020] [Indexed: 12/17/2022]
Abstract
Ghrelin, a small peptide hormone (28 aa), secreted mainly by X/A-like cells of gastric mucosa, is also locally produced in cardiomyocytes. Being an orexigenic factor (appetite stimulant), it promotes release of growth hormone (GH) and exerts diverse physiological functions, viz. regulation of energy balance, glucose, and/or fat metabolism for body weight maintenance. Interestingly, administration of exogenous ghrelin significantly improves cardiac functions in CVD patients as well as experimental animal models of heart failure. Ghrelin ameliorates pathophysiological condition of the heart in myocardial infarction, cardiac hypertrophy, fibrosis, cachexia, and ischemia reperfusion injury. This peptide also exerts significant impact at the level of vasculature leading to lowering high blood pressure and reversal of endothelial dysfunction and atherosclerosis. However, the molecular mechanism of actions elucidating the healing effects of ghrelin on the cardiovascular system is still a matter of conjecture. Some experimental data indicate its beneficial effects via complex cellular cross talks between autonomic nervous system and cardiovascular cells, some other suggest more direct receptor-mediated molecular actions via autophagy or ionotropic regulation and interfering with apoptotic and inflammatory pathways of cardiomyocytes and vascular endothelial cells. Here, in this review, we summarise available recent data to encourage more research to find the missing links of unknown ghrelin receptor-mediated pathways as we see ghrelin as a future novel therapy in cardiovascular protection.
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Affiliation(s)
- Shreyasi Gupta
- Department of Zoology, Triveni Devi Bhalotia College, Raniganj, Paschim Bardhaman, 713347, India
| | - Arkadeep Mitra
- Department of Zoology, City College , 102/1, Raja Rammohan Sarani, Kolkata, 700009, India.
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Yamada C, Iizuka S, Nahata M, Hattori T, Takeda H. Vulnerability to psychological stress-induced anorexia in female mice depends on blockade of ghrelin signal in nucleus tractus solitarius. Br J Pharmacol 2020; 177:4666-4682. [PMID: 32754963 PMCID: PMC7520439 DOI: 10.1111/bph.15219] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Background and Purpose Women have a higher incidence of eating disorders than men. We investigated whether the effects of ghrelin on feeding are affected by sex and stress, and to elucidate the mechanisms that may cause sex differences in stress‐mediated anorexia, focusing on ghrelin. Experimental Approach Acylated ghrelin was administered to naïve and psychologically stressed male and female C57BL/6J mice, followed by measurements of food intake and plasma hormone levels. Ovariectomy was performed to determine the effects of ovary‐derived oestrogen on stress‐induced eating disorders in female mice. The numbers of Agrp or c‐Fos mRNA‐positive cells and estrogen receptor α/c‐Fos protein‐double‐positive cells were assessed. Key Results Ghrelin administration to naïve female mice caused a higher increase in food intake, growth hormone secretion, Agrp mRNA expression in the arcuate nucleus and c‐Fos expression in the nucleus tractus solitarius (NTS) than in male mice. In contrast, psychological stress caused a more sustained reduction in food intake in females than males. The high sensitivity of naïve females to exogenous ghrelin was attenuated by stress exposure. The stress‐induced decline in food intake was not abolished by ovariectomy. Estrogen receptor‐α but not ‐β antagonism prevented the decrease in food intake under stress. Estrogen receptor‐α/c‐Fos‐double‐positive cells in the NTS were significantly increased by stress only in females. Conclusion and Implications Stress‐mediated eating disorders in females may be due to blockade of ghrelin signalling via estrogen receptor‐α activation in the NTS. Targeting the ghrelin signal in the brain could be a new treatment strategy to prevent these disorders.
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Affiliation(s)
- Chihiro Yamada
- Tsumura Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Seiichi Iizuka
- Tsumura Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Miwa Nahata
- Tsumura Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Tomohisa Hattori
- Tsumura Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Hiroshi Takeda
- Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.,Hokkaido University Hospital Gastroenterological Medicine, Sapporo, Hokkaido, Japan
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Ereş G, Su Akgün Demirtaş C, Toptaş E, Yılmaz AD, Sengüven B, Kamburoğlu K. Correlations between the Peptide Hormone Ghrelin and Proinflammatory Cytokines in Experimental Periodontitis Models of Female Rats at Different Stages of the Life Cycle. Arch Oral Biol 2019; 108:104518. [PMID: 31472279 DOI: 10.1016/j.archoralbio.2019.104518] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 07/20/2019] [Accepted: 08/06/2019] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The aim of this study was to examine the correlations between the levels of ghrelin and inflammatory and bone metabolism markers in rats with periodontitis. DESIGN Thirty female Wistar rats (6 trial rats and 4 control rats in each group) were divided into pubertal, adult and postmenopausal groups. Periodontitis was induced by ligatures. On the 21 st day, blood was collected and all rats were then sacrificed. The levels of osteocalcin, osteoprotegerin, alkaline phosphatase, tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), acylated ghrelin, total ghrelin and soluble receptor activator of nuclear factor-kB ligands in the blood samples were measured using enzyme-linked immunosorbent assays. The jaws were decalcified in a Tris-EDTA solution and embedded in paraffin and 4-5 μm sections were cut for IL-β, TNF -α and ghrelin staining. RESULTS Significantly higher serum alkaline phosphatase levels were detected in the trial rats in the pubertal group than in the control rats (p = 0.033). In the postmenopausal group, ghrelin levels positively correlated with interleukin 1 beta levels (r = 0.708, p < 0.05). Among all trial rats, the postmenopausal group exhibited significantly higher levels of acylated ghrelin than the other groups (p = 0.001). Significantly higher osteoprotegerin levels were observed in the control rats than in the trial rats in the postmenopausal group (p = 0.012). Inflammation scores were significantly higher in adult trial rats than in controls (p = 0.024); significantly higher TNF-α levels were detected in postmenopausal experimental rats than in the adult experimental group (p = 0.025). CONCLUSIONS We concluded that total ghrelin levels in serum only correlated with IL-β levels in postmenopausal rats.
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Affiliation(s)
- Gülden Ereş
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey.
| | | | - Ece Toptaş
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey.
| | - Ayça Dilara Yılmaz
- Molecular Biology Laboratory, Faculty of Dentistry, Ankara University, Ankara, Turkey.
| | - Burcu Sengüven
- Department of Oral Pathology, Faculty of Dentistry, Gazi University, Ankara, Turkey.
| | - Kıvanç Kamburoğlu
- Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Ankara University, Ankara, Turkey.
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Saga of ghrelin: its structure, actions, and therapeutic uses. ASIAN BIOMED 2018. [DOI: 10.2478/abm-2010-0112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Abstract
The fat-regulating hormones, adiponectin, ghrelin, and leptin have been studied extensively because therapeutic modality might be gleaned from their augmentation or blockade. Since a link between the hormone and control of hunger was found, ghrelin levels in the human body have received a great deal of attention over the past several years. This mini-review summarizes the role of ghrelin, describing its actions and therapeutic uses.
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Fan J, Li BJ, Wang XF, Zhong LL, Cui RJ. Ghrelin produces antidepressant-like effect in the estrogen deficient mice. Oncotarget 2017; 8:58964-58973. [PMID: 28938610 PMCID: PMC5601706 DOI: 10.18632/oncotarget.19768] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 07/11/2017] [Indexed: 01/23/2023] Open
Abstract
Recent evidence shows that ghrelin plays an important role in depression. However, it was little known whether ghrelin produces antidepressant-like effect in the ovariectomized mice. The present study was aimed to investigate the antidepressant-like effects of the ghrelin in ovariectomized mice. In the forced swim test, ghrelin significantly decreased immobility time, reversing the “depressive-like” effect observed in ovariectomized mice, and this effect was reversed by the tamoxifen. In addition, immunohistochemical study indicated that ghrelin treatment reversed the reductions in c-Fos expression induced by ovariectomy. An estrogen antagonist tamoxifen also antagonized the effect of ghrelin on the c-Fos expression. Furthermore, the western blotting indicated that brain-derived neurotrophic factor (BDNF) in the hippocampus, but not phosphorylated cAMP response element-binding protein (pCREB)/CREB in the frontal cortex, were affected by ghrelin treatment. Ghrelin treatment significantly increased BrdU expression. Therefore, these findings suggest that ghrelin produces antidepressant-like effects in ovariectomized mice, and estrogen receptor may be involved in the antidepressant-like effects of the ghrelin.
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Affiliation(s)
- Jie Fan
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Bing Jin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xue Feng Wang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Li Li Zhong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ran Ji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Kraemer RR, Durand RJ, Acevedo EO, Johnson LG, Kraemer GR, Hebert EP, Castracane VD. Rigorous Running Increases Growth Hormone and Insulin-Like Growth Factor-I Without Altering Ghrelin. Exp Biol Med (Maywood) 2016; 229:240-6. [PMID: 14988516 DOI: 10.1177/153537020422900304] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
It has been suggested that ghrelin may play a role in growth hormone (GH) responses to exercise. The present study was designed to determine whether ghrelin, GH, insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 (IGFBP-3) were altered by a progressively intense running protocol. Six well-trained male volunteers completed a progressively intense intermittent exercise trial on a treadmill that included four exercise intensities: 60%, 75%, 90%, and 100% of Vo2max. Blood samples were collected before exercise, after each exercise intensity, and at 15 and 30 mins following the exercise protocol. Subjects also completed a separate control trial at the same time of day that excluded exercise. GH changed significantly over time, and GH area under the curve (AUC) was significantly higher in the exercise trial than the control trial. Area under the curve IGF-I levels for the exercise trial were significantly higher than the control trial. There was no difference in the ghrelin and IGFBP-3 responses to the exercise and control trials. Pearson correlation coefficients revealed significant relationships between ghrelin and both IGF-I and IGFBP-3; however, no relationship between ghrelin and GH was found. In conclusion, intense running produces increases in total IGF-I concentrations, which differs from findings in previous studies using less rigorous running protocols and less frequent blood sampling regimens. Moreover, running exercise that produces substantial increases in GH does not affect peripheral ghrelin levels; however, significant relationships between ghrelin and both IGF-I and IGFBP-3 exist during intense intermittent running and recovery, which warrants further investigation.
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Affiliation(s)
- R R Kraemer
- Department of Kinesiology and Health Studies, Southeastern Louisiana University, Hammond, Louisiana 70402, USA.
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10
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Yin Y, Zhang W. The Role of Ghrelin in Senescence: A Mini-Review. Gerontology 2015; 62:155-62. [PMID: 26160147 DOI: 10.1159/000433533] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 05/21/2015] [Indexed: 11/19/2022] Open
Abstract
Ghrelin, a 28-amino acid hormone produced mainly by the X/A-like endocrine cells in gastric mucosa, has a widespread tissue distribution and diverse physiological functions such as hormonal, orexigenic, metabolic, cardiovascular, neurological, and immunological activities. Considerable evidence has suggested that ghrelin plays an important role in organism senescence or aging. The present review provides a comprehensive picture of this new development. We first reviewed the aging (senescence)-dependent reduction of ghrelin signaling, and then highlighted its relationship with the aging-associated alteration in food intake, energy metabolism, cardiovascular function, neurological activity, and adaptive immunity. Our literature review suggests that ghrelin is an innovative and promising agent in the treatment of these pathophysiological conditions associated with senescence.
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Affiliation(s)
- Yue Yin
- Diabetes Center, Shenzhen University Health Science Center, Shenzhen, China
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11
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Mayerl S, Liebsch C, Visser TJ, Heuer H. Absence of TRH receptor 1 in male mice affects gastric ghrelin production. Endocrinology 2015; 156:755-67. [PMID: 25490146 DOI: 10.1210/en.2014-1395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
TRH not only functions as a thyrotropin releasing hormone but also acts as a neuropeptide in central circuits regulating food intake and energy expenditure. As one suggested mode of action, TRH expressed in the caudal brainstem influences vagal activity by activating TRH receptor 1 (TRH-R1). In order to evaluate the impact of a diminished medullary TRH signaling on ghrelin metabolism, we analyzed metabolic changes of TRH-R1 knockout (R1ko) mice in response to 24 hours of food deprivation. Because R1ko mice are hypothyroid, we also studied eu- and hypothyroid wild-type (wt) animals and R1ko mice rendered euthyroid by thyroid hormone treatment. Independent of their thyroidal state, R1ko mice displayed a higher body weight loss than wt animals and a delayed reduction in locomotor activity upon fasting. Ghrelin transcript levels in the stomach as well as total ghrelin levels in the circulation were equally high in fasted wt and R1ko mice. In contrast, only wt mice responded to fasting with a rise in ghrelin-O-acyltransferase mRNA expression and consequently an increase in serum levels of acylated ghrelin. Together, our data suggest that an up-regulation of medullary TRH expression and subsequently enhanced activation of TRH-R1 in the vagal system represents a critical step in the stimulation of ghrelin-O-acyltransferase expression upon starvation that in turn is important for adjusting the circulating levels of acylated ghrelin to the fasting condition.
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Affiliation(s)
- Steffen Mayerl
- Leibniz Institute for Age Research/Fritz Lipmann Institute (S.M., C.L., H.H.), D-07745 Jena, Germany; Brandenburg University of Technology Cottbus-Senftenberg (C.L.), D-01968 Senftenberg, Germany; Department of Internal Medicine (T.J.V.), Erasmus Medical Center, Rotterdam, The Netherlands; and Leibniz Research Institute for Environmental Medicine (H.H.), Düsseldorf, Germany
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Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur J Endocrinol 2014; 171:R21-32. [PMID: 24714083 DOI: 10.1530/eje-14-0183] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). AG acts on the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have gluco-regulatory action, which adds an additional layer of complexity to ghrelin's regulation of glucose metabolism. This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT) with specific emphasis aimed toward distinguishing AG vs dAG action.
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Affiliation(s)
- Kristy M Heppner
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
| | - Jenny Tong
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
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13
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Du G, Liu M, Parvizi N, Zhao R. Ectopic expression of ghrelin affects gastric H+–K+-ATPase activity and expression of GHR/IGF-1 system in weaned mice. ACTA ACUST UNITED AC 2013; 186:12-7. [DOI: 10.1016/j.regpep.2013.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 03/10/2013] [Accepted: 06/19/2013] [Indexed: 10/26/2022]
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Miandare HK, Farahmand H, Akbarzadeh A, Ramezanpour S, Kaiya H, Miyazato M, Rytkönen KT, Nikinmaa M. Developmental transcription of genes putatively associated with growth in two sturgeon species of different growth rate. Gen Comp Endocrinol 2013; 182:41-7. [PMID: 23229003 DOI: 10.1016/j.ygcen.2012.11.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Revised: 10/13/2012] [Accepted: 11/13/2012] [Indexed: 12/22/2022]
Abstract
In the present study, we surveyed developmental changes in the transcription of growth hormone (gh), insulin-like growth factor-I (igf-I), ghrelin (ghrl) and vascular endothelial growth factor (vegf) genes in the largest freshwater fish, European sturgeon (Beluga, Huso huso) and compared the same parameters to that of its phylogenically close moderate-sized species, Persian sturgeon (Acipenser persicus). The transcripts of gh, igf-I, ghrl and vegf were detected at all developmental time-points of Persian sturgeon and Beluga from embryos to juvenile fish. Changes in normalized gh, igf-I, ghrl and vegf transcription by using the geometric average of genes encoding ribosomal protein L6 (RPL6) and elongation factor (EF1A) over the time of development of Persian sturgeon and Beluga were statistically significant (P<0.05). Our results showed that the mRNA expression levels of both igf-I and ghrl were low during early larval development and then increased significantly to the late larval time-points when larvae started exogenous feeding. In both Beluga and Persian sturgeon, after a low mRNA expression during the embryonic stage, the transcript levels of vegf displayed an increasing trend during yolk-sac fry, consistent with organogenesis. The vegf level remained constantly high in the time of exogenous feeding. The highest detection of gh transcripts coincided with the end of the embryonic stage (hatching time) in Persian sturgeon and 3 days-post-hatching (dph) in Beluga. In Persian sturgeon, the gh transcript started to decrease to the rest of the developmental time-points, whereas in Beluga gh transcript had a marked second increase from the time of exogenous feeding (20-dph). This Beluga specific increase in gh transcription may be associated with the marked growth rate and extraordinary size of this fish species.
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Affiliation(s)
- Hamed Kolangi Miandare
- Department of Fisheries, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan 49138-15739, Iran.
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Gagnon J, Anini Y. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology 2012; 153:3646-56. [PMID: 22691550 DOI: 10.1210/en.2012-1040] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Ghrelin is a peptide hormone primarily produced in the previously unidentified X/A endocrine cells of the stomach. Extensive studies have focused on the effects of ghrelin on growth hormone release and appetite regulation. However, the mechanisms regulating ghrelin secretion are less understood. In the present study, we developed a primary culture of newborn rat stomach cells to investigate the mechanisms regulating ghrelin synthesis and secretion. We demonstrated that this cell preparation secretes ghrelin in a regulated manner through the increase of cAMP, intracellular calcium, and activation of protein kinase C. Norepinephrine (NE) (0.1-10 μm) stimulated ghrelin secretion through the β1-adrenergic receptor via increased cAMP and protein kinase A activity, whereas acetylcholine had no effect. Because circulating ghrelin levels were previously shown to be inversely correlated with insulin levels, we investigated the effect of insulin on ghrelin secretion. We first demonstrated that ghrelin cells express the insulin receptor α- and β-subunits. Next, we determined that insulin (1-10 nm) inhibited both basal and NE-stimulated ghrelin secretion, caused an increase in phosphorylated serine-threonine kinase (AKT) and a reduction in intracellular cAMP, but did not alter proghrelin mRNA levels. The inhibitory effect of insulin was blocked by inhibiting phospho-inositol-3 kinase and AKT but not MAPK. Higher dose insulin (100 nm) did not suppress ghrelin secretion, which prompted the investigation of cellular insulin resistance by pretreating the cells with 100 nm insulin for 24 h. This caused a reduction in insulin receptor expression and prevented the insulin-mediated AKT activation and the suppression of ghrelin secretion with no impact on NE-stimulated ghrelin secretion. Our findings highlight the role of the sympathetic nervous system, insulin, and insulin resistance in the regulation of ghrelin secretion.
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Affiliation(s)
- Jeffrey Gagnon
- Department of Obstetrics, Faculty of Medicine,Dalhousie University, Halifax, Nova Scotia, Canada
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Nanjo Y, Adachi H, Hirai Y, Enomoto M, Fukami A, Otsuka M, Yoshikawa K, Yokoi K, Ogata K, Tsukagawa E, Kasahara A, Murayama K, Yasukawa H, Kojima M, Imaizumi T. Factors associated with plasma ghrelin level in Japanese general population. Clin Endocrinol (Oxf) 2011; 74:453-8. [PMID: 21092051 DOI: 10.1111/j.1365-2265.2010.03938.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Ghrelin is a novel gastric peptide identified in 1999 as a 'hunger hormone'. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. METHODS Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005-2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. RESULTS In our population, the mean BMI was 23·8 kg/m(2) , indicating a nonobese population. Results of univariate analysis showed that age (P<0·001), BMI (P<0·001), waist (P<0·001), triglycerides (P<0·01), FPG (P<0·01), insulin (P<0·001) and uric acid (P<0·05) were inversely associated with ghrelin. High-density lipoprotein (HDL) cholesterol (P<0·001) and eGFR (P<0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P<0·001). Results of the multiple stepwise regression analysis revealed that age (P<0·001; inversely), female gender (P<0·001), insulin (P<0·001; inversely), HDL cholesterol (P=0·005), BMI (P=0·01; inversely) and uric acid (P=0·045; inversely) were significantly and independently associated with ghrelin. CONCLUSIONS The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.
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Affiliation(s)
- Yasuki Nanjo
- Department of Internal Medicine, Division of Cardio-Vascular Medicine, Institute of Life Science, Kurume University, 67 Asahi-machi, Kurume, Japan
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Hsu YW, Pan YJ, Cho YM, Liou TH, Chou P, Wang PS. Aging effects on exercise-induced alternations in plasma acylated ghrelin and leptin in male rats. Eur J Appl Physiol 2010; 111:809-17. [DOI: 10.1007/s00421-010-1704-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2010] [Indexed: 01/06/2023]
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Cacicedo L, Sánchez Franco F. [The GH-IGF-I system and cerebral aging]. ENDOCRINOLOGIA Y NUTRICION : ORGANO DE LA SOCIEDAD ESPANOLA DE ENDOCRINOLOGIA Y NUTRICION 2010; 57:235-239. [PMID: 20538530 DOI: 10.1016/j.endonu.2010.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Accepted: 04/22/2010] [Indexed: 05/29/2023]
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Osterstock G, Escobar P, Mitutsova V, Gouty-Colomer LA, Fontanaud P, Molino F, Fehrentz JA, Carmignac D, Martinez J, Guerineau NC, Robinson ICAF, Mollard P, Méry PF. Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus. PLoS One 2010; 5:e9159. [PMID: 20161791 PMCID: PMC2820089 DOI: 10.1371/journal.pone.0009159] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2009] [Accepted: 01/08/2010] [Indexed: 11/26/2022] Open
Abstract
Background Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin. Principal Findings Here, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by γ-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate. Conclusion Thus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.
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Affiliation(s)
- Guillaume Osterstock
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Pauline Escobar
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Violeta Mitutsova
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Laurie-Anne Gouty-Colomer
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Pierre Fontanaud
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - François Molino
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Jean-Alain Fehrentz
- Université Montpellier 1, 2, Montpellier, France
- CNRS UMR 5247, Institut des Biomolécules Max Mousseron, Montpellier, France
| | - Danielle Carmignac
- Division of Molecular Neuroendocrinology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom
| | - Jean Martinez
- Université Montpellier 1, 2, Montpellier, France
- CNRS UMR 5247, Institut des Biomolécules Max Mousseron, Montpellier, France
| | - Nathalie C. Guerineau
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Iain C. A. F. Robinson
- Division of Molecular Neuroendocrinology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom
| | - Patrice Mollard
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
| | - Pierre-François Méry
- Inserm U-661, Montpellier, France
- CNRS UMR 5203, Institut de Génomique Fonctionnelle, Montpellier, France
- Université Montpellier 1, 2, Montpellier, France
- * E-mail:
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Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH. Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 2010; 31:44-60. [PMID: 19896496 DOI: 10.1016/j.yfrne.2009.10.008] [Citation(s) in RCA: 243] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2009] [Revised: 10/26/2009] [Accepted: 10/26/2009] [Indexed: 12/25/2022]
Abstract
Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.
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Affiliation(s)
- T R Castañeda
- Dept. of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH, USA
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Wells T. Ghrelin – Defender of fat. Prog Lipid Res 2009; 48:257-74. [DOI: 10.1016/j.plipres.2009.04.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Revised: 04/09/2009] [Accepted: 04/21/2009] [Indexed: 12/21/2022]
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Aleman A, Torres-Alemán I. Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan. Prog Neurobiol 2009; 89:256-65. [PMID: 19665513 DOI: 10.1016/j.pneurobio.2009.07.008] [Citation(s) in RCA: 142] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Revised: 07/15/2009] [Accepted: 07/31/2009] [Indexed: 12/14/2022]
Abstract
Insulin-like growth factor I (IGF-I) is central to the somatotropic (growth hormone) axis. It promotes tissue growth and continues to have anabolic effects in adulthood. Accumulating evidence from the last decade, however, reveals that circulating levels of IGF-I also significantly affects cognitive brain function. Specifically, the decline of serum IGF-I might be associated with the age-related cognitive decline in elderly people. Moreover, psychiatric and neurological conditions characterized by cognitive impairment may be characterized by altered levels of IGF-I. Some evidence is emerging that interventions that target the GH/IGF-I axis may improve cognitive functioning, at least in deficient states. As there is evidence linking high serum IGF-I levels with cancer risk, these interventions should be carefully evaluated. On a cellular and molecular level, IGF-I may be a crucial component of neural homeostasis since disturbed IGF-I input is inevitably linked to perturbed function. Consistent with this, all nerve cells are potential targets of IGF-I actions, including neurons, glia, endothelial, epithelial, and perivascular cells. Indeed, many key cellular processes in the brain are affected by IGF-I's neurotrophic and modulatory actions. We review the regulation by IGF-I of neurotransmission and neuronal plasticity and conclude that serum IGF-I is an important mediator of neuronal growth, survival and function throughout the lifespan. The role of IGF-I in synaptic plasticity render its neurotrophic potential a key target for remediating the cognitive impairment associated with a range of neurological conditions.
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Affiliation(s)
- André Aleman
- Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands; Department of Psychology, University of Groningen, Groningen, The Netherlands.
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Yin X, Li Y, Xu G, An W, Zhang W. Ghrelin fluctuation, what determines its production? Acta Biochim Biophys Sin (Shanghai) 2009; 41:188-97. [PMID: 19280057 DOI: 10.1093/abbs/gmp001] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Ghrelin, a 28 amino acid gut brain peptide, acts as an endogenous ligand for its receptor, the growth hormone secretagogue receptor, to exercise a variety of functions ranging from stimulation of growth hormone secretion, regulation of appetite and energy metabolism, and cell protection to modulation of inflammation. This review summarizes the advance in the regulation of ghrelin expression and secretion. We introduce the structure of ghrelin promoter, the processing and modification of ghrelin precursor, and the regulation mechanism in these processes. Then we discuss factors found to be important in the regulation of ghrelin production, including nutrients, hormones, and autonomic nervous system. Finally, we outline the alteration in the level of ghrelin in certain physiological and pathological status.
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Affiliation(s)
- Xuefeng Yin
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
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Fanciulli G, Delitala A, Delitala G. Growth hormone, menopause and ageing: no definite evidence for 'rejuvenation' with growth hormone. Hum Reprod Update 2009; 15:341-58. [DOI: 10.1093/humupd/dmp005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Jürimäe J, Cicchella A, Jürimäe T, Lätt E, Haljaste K, Purge P, Hamra J, von Duvillard SP. Regular Physical Activity Influences Plasma Ghrelin Concentration in Adolescent Girls. Med Sci Sports Exerc 2007; 39:1736-41. [PMID: 17909400 DOI: 10.1249/mss.0b013e31812e5294] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE We examined the effect of regular physical activity on plasma ghrelin concentration after onset of puberty in girls. In addition, we also examined the association of fasting plasma ghrelin concentration with various plasma biochemical, body composition, and aerobic capacity variables in healthy adolescent girls. METHOD Fifty healthy schoolgirls ages 11 to 16 yr were divided either into a physically active (N = 25) or a physically inactive (N = 25) group. The physically active group consisted of swimmers who had trained on an average of 6.2 +/- 2.0 h.wk(-1) for the last 2 yr, whereas the inclusion criterion for the physically inactive group was the participation in physical education classes only. The subjects were matched for age (+/- 1 yr) and body mass index (BMI; +/- 2 kg.m(-2)). Maturation I group (14 matched pairs) included pubertal stages 2 and 3, and maturation II group (11 matched pairs) included pubertal stages 4 and 5. RESULTS Physically active girls had significantly higher (P < 0.05) mean plasma ghrelin levels than the physically inactive girls (maturation I: 1152.1 +/- 312.9 vs 877.7 +/- 114.8 pg.mL(-1); maturation II: 1084.0 +/- 252.5 vs 793.4 +/- 164.9 pg.mL(-1)). Plasma ghrelin concentration was negatively related to percent body fat, fat mass, peak oxygen consumption per kilogram of body mass, leptin, estradiol, insulin, and insulin-like growth factor-I (IGF-I) (r > -0.298; P < 0.05). Multivariate linear regression analysis to determine the predictors of ghrelin concentration using the variables that were significantly associated with ghrelin concentration demonstrated that plasma IGF-I was the most important predictor of plasma ghrelin concentration (beta = -0.396; P = 0.008). CONCLUSION Regular physical activity influences plasma ghrelin concentrations in girls with different pubertal maturation levels. Plasma IGF-I concentration seems to be the main determinant of circulating ghrelin in healthy, normal-weight adolescent girls.
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Affiliation(s)
- Jaak Jürimäe
- Institute of Sport Pedagogy and Coaching Sciences, Center of Behavioral and Health Sciences, University of Tartu, Tartu, Estonia
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Abstract
In well-nourished humans, GH and IGF-I decline during aging, and the responsiveness of the GH axis to exogenous ghrelin is attenuated with age. Intriguingly, the GH/IGF-I axis is rejuvenated by chronic treatment with the ghrelin mimetic MK-0677, resulting in improvements in body composition, suggesting that frail elderly subjects might benefit from treatment with ghrelin and ghrelin mimetics. Mouse models are widely used to study the effects of ghrelin, but the impact of age on the ghrelin pathway is unclear. In this study, total and active ghrelin peptides were measured in plasma, and ghrelin mRNA was quantitated in brain tissue from different aged C57BL/6J mice. Surprisingly, plasma levels of ghrelin peptide slightly increased with age; ghrelin mRNA levels were similar in brains from mice aged 2, 6, 12, and 28 months but higher in mice aged 18 and 24 months. The tissue distribution of Ghsr1a mRNA (ghrelin receptor) was also characterized, and pituitary and brain exhibited the highest levels of expression. In the pituitary gland, the highest concentration of Ghsr1a mRNA was observed at age 1-2 months, it was lower at 6 months, and remained unchanged for up to 30 months of age. This result is consistent with the finding that GH release in response to exogenous ghrelin was not significantly different in mice aged 7-30 months. In the brain, Ghsr1a mRNA levels remained stable during aging. Hence, in C57BL/6J male mice, aging is not associated with changes in circulating ghrelin levels or changes in ghrelin receptor expression in the pituitary gland and brain.
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Affiliation(s)
- Yuxiang Sun
- Huffington Center on Aging, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030, USA.
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Aging influences the level and functions of fasting plasma ghrelin levels: the POWIRS-Study. ACTA ACUST UNITED AC 2006; 139:65-71. [PMID: 17113660 DOI: 10.1016/j.regpep.2006.10.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2006] [Revised: 09/18/2006] [Accepted: 10/03/2006] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Ghrelin, known for its orexigenic activity, also have functions such as vasodilation and a growth hormone releasing action. It is uncertain whether these functions change with increasing age. This study aimed to determine whether ghrelin levels differ between young and older women with different levels of obesity; and secondly whether the associations of ghrelin with metabolic syndrome (MS) components, adipocytokines, coagulation factors, and cortisol change with increasing age. METHODS AND RESULTS Caucasian women (N=107) were divided into young (19-29 years) and older groups (30-56 years). Fasting ghrelin, leptin, adiponectin, glucose, insulin, cortisol, fibrinogen and plasminogen activator inhibitor-1 (PAI-1) levels were determined. Blood pressure (BP), body mass index and waist circumferences were measured. Older lean women showed lower levels of ghrelin (p<0.05) than young lean women, with no differences regarding BP, obesity, lipids, adipokines or insulin resistance (IR). Ghrelin levels of older women remained constant with increasing obesity, but younger women showed significantly reduced ghrelin levels in obese groups. Only younger women showed significant correlations between ghrelin and leptin, adiponectin, fibrinogen and PAI-1 (adjusted for age, obesity and menstrual phase), whereas both age groups showed significant correlations with IR. In younger women factor analysis grouped ghrelin with coagulation factors and all MS components. In older women ghrelin was absent from the MS cluster, but was associated with lower BP, cortisol and IR. CONCLUSIONS Ghrelin levels were not significantly elevated in lean older women, and did not change with increased obesity in older women--as were observed in younger women. The functions of ghrelin also seem to change with increased age since only in young women ghrelin was associated with obesity, coagulation factors and leptin.
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Iñiguez G, Salazar T, Roman R, Avila A, Gunn RD, Cassorla F. Effects of the IGF-I/IGFBP-3 complex on GH and ghrelin nocturnal concentrations in low birth weight children. Clin Endocrinol (Oxf) 2006; 65:687-92. [PMID: 17054474 DOI: 10.1111/j.1365-2265.2006.02650.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE There is limited information regarding the effects of IGF-I and/or IGFBP-3 on circulating ghrelin concentrations. To determine the effects of IGF-I on GH and ghrelin concentrations, we examined the GH and ghrelin nocturnal profiles before and after the administration of the IGF-I/-IGFBP-3 complex (Iplex) to low birth weight children. DESIGN The children were studied on two separate occasions, the first under basal conditions, and the second time after the sc administration of 1 mg/kg of Iplex at 2100 h. Blood samples for determination of GH and ghrelin were obtained every 20 min between 2300 h and 0700 h, while the children were sleeping. In each patient, we calculated the mean GH and ghrelin area under the curve (GH AUC and GHR AUC), both under basal conditions and after the administration of the IGF-I/IGFBP-3 complex. SETTING The study was performed at a University Research Centre located at a General Hospital in Santiago, Chile. PATIENTS Twenty prepubertal children (11 boys and 9 girls), born after a full-term pregnancy with a birth weight below 2.8 kg were studied at a mean +/- SEM age of 7.3 +/- 0.5 years (range 4-11 years). Their mean height was -1.8 +/- 0.3 standard deviation score (SDS) and their mean BMI was 0.1 +/- 0.2 SDS at the time of the study. MAIN OUTCOME AND RESULTS Mean nocturnal GH AUC exhibited a significant decrease (2903 +/- 185 vs 1860 +/- 122 ng/ml min, P < 0.01), whereas mean GHR AUC showed a significant increase after administration of the IGF-I/IGFBP-3 complex (68 +/- 16 vs 288 +/- 36 ng/ml min, P < 0.01). CONCLUSIONS These findings indicate that the IGF-I/IGFBP-3 complex appears to have opposite effects on circulating GH and ghrelin concentrations in low birth weight children, suggesting that, in addition to its known negative feed-back effect on GH, IGF-I and/or IGFBP-3 may have a positive feed-back effect on ghrelin.
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Affiliation(s)
- German Iñiguez
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
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Du GM, Shi ZM, Wei XH, Liu MJ, Zhang L, Zhao RQ. Expression of gastric ghrelin and H(+)-K(+)-ATPase mRNA in weanling piglets and effect of ghrelin on H(+)-K(+)-ATPase expression and activity in gastric mucosal cells in vitro. Res Vet Sci 2006; 82:99-104. [PMID: 16920167 DOI: 10.1016/j.rvsc.2006.06.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2005] [Revised: 05/07/2006] [Accepted: 06/22/2006] [Indexed: 11/23/2022]
Abstract
This study was designed to investigate the effect of ghrelin on gastric acid secretion in weaning piglets both in vivo and in vitro. Thirty newborn piglets were selected from six litters and on 28, 35 (weaning), 38, 42 and 45d of age, respectively, one piglet from each litter was killed and the mucosal tissue from gastric fundus was collected for detecting ghrelin mRNA as well as H(+)-K(+)-ATPase mRNA expression and activity. Primary cultures of gastric mucosal cells from 5-week-old weaning piglets were challenged with 3x10(-5), 3x10(-4), 3x10(-3), 3x10(-2) and 3x10(-1)nmol/ml h-ghrelin, respectively, for 4h in order to further clarify the effect of ghrelin on gastric H(+)-K(+)-ATPase mRNA expression and activity. Ghrelin mRNA expression in gastric fundus kept stable from 28d to 42d, followed by a sudden increase on 45d, exhibiting a peak that was significantly higher than any other age groups investigated. H(+)-K(+)-ATPase activity and mRNA expression showed similar trends of increase with slightly different timing. H(+)-K(+)-ATPase mRNA expression tended to increase on 42d, while H(+)-K(+)-ATPase activity started to rise from 35d, but neither of them reached significantly higher levels until 45d. In vitro, ghrelin significantly increased H(+)-K(+)-ATPase activity of gastric mucosal cells at 3x10(-4), 3x10(-3), and 3x10(-2)nmol/ml, but augmented H(+)-K(+)-ATPase mRNA expression only at 3x10(-4)nmol/ml. The results indicate that ghrelin mRNA expression is up-regulated 10 days after weaning in the gastric fundus of piglets, coinciding with the increase of H(+)-K(+)-ATPase mRNA expression and activity. Ghrelin acts on gastric mucosal cells to stimulate both mRNA expression and activity of H(+)-K(+)-ATPase in vitro.
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Affiliation(s)
- Gai Mei Du
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, Nanjing Agricultural University, Nanjing 210095, PR China
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Schuessler P, Uhr M, Ising M, Schmid D, Weikel J, Weikel J, Steiger A. Nocturnal ghrelin levels--relationship to sleep EEG, the levels of growth hormone, ACTH and cortisol--and gender differences. J Sleep Res 2006; 14:329-36. [PMID: 16364133 DOI: 10.1111/j.1365-2869.2005.00486.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue receptor, stimulates sleep, appetite and weight gain as well as the secretion of GH, adrenocorticotropic hormone (ACTH), cortisol in humans and rodents. The interaction between nocturnal ghrelin levels, sleep EEG and the secretion of these hormones was not investigated systematically so far. Furthermore conflicting data exist on gender differences in nocturnal ghrelin secretion. We examined simultaneously sleep EEG and the nocturnal levels of ghrelin, GH, ACTH and cortisol in young and middle-aged normal human subjects (eight males, eight females). A significant interaction between gender and the course of ghrelin concentration was observed to the interval between 20:00 and 23:00 hours. In males a continuous increase of ghrelin levels before sleep onset was found. In females, however, a rise of ghrelin during the night was missed. We found a trend suggesting a lower time spent in stage I sleep in subjects with high nocturnal ghrelin levels. Other systematic interactions between plasma ghrelin, sleep EEG and other hormones were not found. No peak in plasma ghrelin levels resembling the GH surge was observed. We suggest that under naturalistic conditions plasma ghrelin levels show no distinct interaction with sleep.
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Lebenthal Y, Gat-Yablonski G, Shtaif B, Padoa A, Phillip M, Lazar L. Effect of sex hormone administration on circulating ghrelin levels in peripubertal children. J Clin Endocrinol Metab 2006; 91:328-31. [PMID: 16249289 DOI: 10.1210/jc.2005-0204] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
BACKGROUND Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.
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Affiliation(s)
- Y Lebenthal
- Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tiqva 49202, Israel
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Abstract
The GH secretagogues (GHS) were developed by reverse pharmacology. The objective was to develop small molecules with pharmacokinetics suitable for once-daily oral administration that would rejuvenate the GH/IGF-I axis. Neither the receptor nor the ligand that controlled pulse amplitude of hormone release was known; therefore, identification of lead structures was based on function. I reasoned that GH pulse amplitude could be increased by four possible mechanisms: 1) increasing GHRH release; 2) amplifying GHRH signaling in somatotrophs of the anterior pituitary gland; 3) reducing somatostatin release; and 4) antagonizing somatostatin receptor signaling. Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture. Furthermore, restoration of thymic function was induced in old mice. The GHS receptor (GHS-R) was subsequently identified by expression cloning and found to be a previously unknown G protein-coupled receptor expressed predominantly in brain, pituitary gland, and pancreas. Reverse pharmacology was completed when the cloned GHS-R was exploited to identify an endogenous agonist (ghrelin) and a partial agonist (adenosine); ghsr-knockout mice studies confirmed that GHS are ghrelin mimetics.
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Affiliation(s)
- Roy G Smith
- Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Room M320, Houston, Texas 77030-3498, USA
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34
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Abstract
Exogenous administration of ghrelin increases caloric intake and stimulates growth hormone (GH) secretion, two effects that are mediated through binding of ghrelin to the GH secretagogue receptor (GHS-R). In addition, ghrelin is thought to inhibit adipogenesis by GHS-R-independent mechanisms. In adults, ghrelin is mainly produced by the stomach. In contrast, in the fetal and early postnatal period, ghrelin gene expression is abundant in the pancreas but not in the stomach. While knockout animal studies demonstrate that ghrelin is not required for perinatal development under normal nutritional conditions, the characteristics of ghrelin metabolism during fetal development suggest that ghrelin could contribute to the programming of mechanisms involved in energy balance, such as beta-cell maturation, orexigenic pathways and adipogenesis. In humans, ghrelin concentrations progressively decrease during childhood and adolescence, as well as with advancing puberty. In adolescents, similar to adults, ghrelin concentrations are inversely related to body mass index and to circulating insulin. One notable exception is the presence of elevated ghrelin concentrations in subjects with Prader-Willi syndrome, raising the possibility that ghrelin could be part of the etiology of excess food intake in this condition. These data raise a number of fascinating questions on the potential physiologic role of this hormone during growth and development.
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Affiliation(s)
- J-P Chanoine
- Endocrinology and Diabetes Unit, British Columbia's Children's Hospital, University of British Columbia, Vancouver, B.C., Canada.
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35
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Abstract
Aging is associated with a progressive decline in physical and cognitive functions. The impact of age-dependent endocrine changes regulated by the central nervous system on the dynamics of neuronal behavior, neurodegeneration, cognition, biological rhythms, sexual behavior, and metabolism are reviewed. We also briefly review how functional deficits associated with increases in glucocorticoids and cytokines and declining production of sex steroids, GH, and IGF are likely exacerbated by age-dependent molecular misreading and alterations in components of signal transduction pathways and transcription factors.
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Affiliation(s)
- Roy G Smith
- Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, M320, Houston, TX 77030, USA.
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36
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Isomoto H, Ueno H, Nishi Y, Wen CY, Nakazato M, Kohno S. Impact of Helicobacter pylori infection on ghrelin and various neuroendocrine hormones in plasma. World J Gastroenterol 2005; 11:1644-8. [PMID: 15786542 PMCID: PMC4305946 DOI: 10.3748/wjg.v11.i11.1644] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, influences appetite, energy balance, gastric motility and acid secretion. The stomach is the main source of circulating ghrelin. There are inconsistent reports on the influence of Helicobacter pylori (H pylori) infection on circulating ghrelin levels. We sought to elucidate the relationship between ghrelin and various peptides in plasma, with special reference to H pylori.
METHODS: Plasma ghrelin levels were measured by radioimmunoassay in 89 subjects who were referred for upper gastrointestinal endoscopy, consisting of 42 H pylori infected and 47 uninfected ones. Plasma gastrin, somatostatin, leptin, insulin-like growth hormone 1 (IGF-1) and chromogranin A concentrations were also measured. Twelve patients were treated with anti- H pylori regimen.
RESULTS: Ghrelin circulating levels were greatly decreased in H pylori-positive than negative individuals (194.2±90.2 fmol/mL and 250.4±84.1 respectively, P<0.05), but did not significantly alter following the cure of infection (176.5±79.5 vs 191.3±120.4). There was a significant negative correlation between circulating ghrelin and leptin levels, as well as body mass index, for the whole and uninfected population, but not in H pylori-infected patients. Plasma ghrelin concentrations correlated positively with IGF-1 in H pylori-negative group and negatively with chromogranin A in the infected group. There were no significant correlations among circulating levels of ghrelin, gastrin and somatostatin irrespective of H pylori status.
CONCLUSION: H pylori infection influences plasma ghrelin dynamics and its interaction with diverse bioactive peptides involved in energy balance, growth and neuroendocrine function.
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Affiliation(s)
- Hajime Isomoto
- Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, Japan.
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Pöykkö SM, Ukkola O, Kauma H, Kellokoski E, Hörkkö S, Kesäniemi YA. The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes. Diabetologia 2005; 48:309-16. [PMID: 15688209 DOI: 10.1007/s00125-004-1635-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2004] [Accepted: 09/15/2004] [Indexed: 12/11/2022]
Abstract
AIMS/HYPOTHESIS Ghrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association. METHODS We analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middle-aged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI. RESULTS IGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (beta=-0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (beta=-0.40, p<0.001). The association was particularly strong in males and in the higher BMI tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r(2)=6.5% (p<0.001), insulin resistance without type 2 diabetes: r(2)=21.0% (p<0.001), type 2 diabetes: r(2)=25.4 (p<0.001). IGF-I levels explained larger proportion (r(2)=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r(2)=3.0%) and BMI (r(2)=1.5%). CONCLUSIONS/INTERPRETATION There is a negative and independent association between ghrelin and IGF-I concentrations in middle-aged subjects. The interaction between IGF-I and ghrelin is modified by obesity, IR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states.
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Affiliation(s)
- S M Pöykkö
- Department of Internal Medicine, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
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38
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Moesgaard SG, Ahrén B, Carr RD, Gram DX, Brand CL, Sundler F. Effects of high-fat feeding and fasting on ghrelin expression in the mouse stomach. ACTA ACUST UNITED AC 2005; 120:261-7. [PMID: 15177945 DOI: 10.1016/j.regpep.2004.03.018] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2003] [Revised: 03/18/2004] [Accepted: 03/26/2004] [Indexed: 10/26/2022]
Abstract
Ghrelin is a peptide identified as an endogenous ligand for the growth hormone secretagogue receptor. Studies have shown that ghrelin stimulates growth hormone, promotes food intake and decreases energy expenditure. Furthermore, feeding status seems to influence plasma ghrelin levels, as these are increased during fasting, whereas feeding and oral glucose intake reduce plasma ghrelin. This study examined whether standardized obesity and fasting affect cellular expression of ghrelin. Specimens from the gastrointestinal tract of fed or 18-h fasted, low-fat or high-fat fed (10 weeks on diet) C57BL/6J mice were studied by immunocytochemistry (ICC) for ghrelin and in situ hybridization (ISH) for ghrelin mRNA. Ghrelin was expressed in especially the corpus but also the antrum of the stomach of all groups studied. Cells positive for ghrelin and ghrelin mRNA in the stomach were reduced in high-fat fed mice. In contrast, ghrelin expression was not affected by fasting. The reduction in ghrelin expression in the high-fat fed mice was associated with a reduction in plasma levels of ghrelin, whereas after fasting, when expression rate was not altered, there was an increase in plasma ghrelin. In conclusion, ghrelin is highly expressed in the corpus and antrum of the stomach of C57BL/6J mice. This expression is reduced in obesity, whereas fasting has no effect.
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Smith RG, Sun Y, Betancourt L, Asnicar M. Growth hormone secretagogues: prospects and potential pitfalls. Best Pract Res Clin Endocrinol Metab 2004; 18:333-47. [PMID: 15261841 DOI: 10.1016/j.beem.2004.04.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The growth hormone secretagogues (GHSs) are the first well-characterised agents that rejuvenate the growth hormone (GH)/insulin-like growth factor (IGF-1) axis. This property was discovered during investigations of the underlying causative mechanisms of age-related endocrine changes. Chronic administration of the long acting GHS, MK-0677, reverses the age-related decline in pulse-amplitude of GH secretion and restores IGF-1 levels producing profiles typical of young adults. This restoration is accompanied by improvements in body composition in frail elderly subjects. When given acutely, the GHSs also increase appetite. Following cloning and characterisation of the GHS-receptor (GHS-R) an endogenous ligand, ghrelin, was isolated and identified. Ghrelin shares the GH releasing and orexigenic properties of the GHSs. Studies using Ghsr-null mice confirmed that the GHS-R was the ghrelin-receptor; hence, the GHSs should be considered to be 'ghrelin mimetics.' Ghrelin levels are reported to decline during ageing, therefore long-acting GHSs are ideal candidates for ghrelin replacement therapy.
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Affiliation(s)
- Roy G Smith
- Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza N704, M320, Houston, TX 77030 3498, USA.
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40
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Chanoine JP, Wong ACK. Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004; 145:3813-20. [PMID: 15142981 DOI: 10.1210/en.2004-0053] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Ghrelin is an orexigenic peptide secreted mainly by the stomach in adult rats. Ghrelin concentrations increase with fasting and decrease after food intake. Ghrelin is also present in the placenta and in the fetal stomach, but the role of fetal ghrelin remains unclear. In this study, we compared changes in plasma ghrelin, insulin, and glucose concentrations and in ghrelin gene expression in stomach, pancreas, and placenta in response to fasting and feeding in adult nonpregnant rats and in 20-d pregnant dams and their fetuses. Plasma total ghrelin concentrations were three times higher in the fetus than in the dam but did not increase in response to fasting. In contrast to total ghrelin, plasma active ghrelin concentrations wee 50% lower in the fetus compared with the adult pregnant rat. Ghrelin mRNA and total ghrelin were markedly elevated in the fetal pancreas and six to seven times greater than in the fetal stomach but were not affected by fasting. In contrast, fetal pancreas and stomach active ghrelin concentrations increased two to three times after maternal fasting. Ghrelin receptor mRNA was present in all fetal pancreas samples. Placenta ghrelin gene expression was detectable but low. These data raise the possibility that in the fetus, in contrast to the adult, the pancreas and not the stomach is a major source of circulating immunoreactive ghrelin. Furthermore, the presence of a strong ghrelin gene expression and of ghrelin receptor mRNA in the fetal pancreas is intriguing and suggests that ghrelin may play an important role in beta-cell development.
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Affiliation(s)
- Jean-Pierre Chanoine
- Endocrinology and Diabetes Unit, British Columbia's Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V4.
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41
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Wierup N, Yang S, McEvilly RJ, Mulder H, Sundler F. Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. J Histochem Cytochem 2004; 52:301-10. [PMID: 14966197 DOI: 10.1177/002215540405200301] [Citation(s) in RCA: 154] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Ghrelin is produced mainly by endocrine cells in the stomach and is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). It also influences feeding behavior, metabolic regulation, and energy balance. It affects islet hormone secretion, and expression of ghrelin and GHS-R in the pancreas has been reported. In human islets, ghrelin expression is highest pre- and neonatally. We examined ghrelin and GHS-R in rat islets during development with immunocytochemistry and in situ hybridization. We also studied the effect of ghrelin on insulin secretion from INS-1 (832/13) cells and the expression of GHS-R in these cells. We found ghrelin expression in rat islet endocrine cells from mid-gestation to 1 month postnatally. Islet expression of GHS-R mRNA was detected from late fetal stages to adult. The onset of islet ghrelin expression preceded that of gastric ghrelin. Islet ghrelin cells constitute a separate and novel islet cell population throughout development. However, during a short perinatal period a minor subpopulation of the ghrelin cells co-expressed glucagon or pancreatic polypeptide. Markers for cell lineage, proliferation, and duct cells revealed that the ghrelin cells proliferate, originate from duct cells, and share lineage with glucagon cells. Ghrelin dose-dependently inhibited glucose-stimulated insulin secretion from INS-1 (832/13) cells, and GHS-R was detected in the cells. We conclude that ghrelin is expressed in a novel developmentally regulated endocrine islet cell type in the rat pancreas and that ghrelin inhibits glucose-stimulated insulin secretion via a direct effect on the beta-cell.
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Affiliation(s)
- N Wierup
- Department of Physiological Science, Lund University, Lund, Sweden.
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42
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Matsubara M, Sakata I, Wada R, Yamazaki M, Inoue K, Sakai T. Estrogen modulates ghrelin expression in the female rat stomach. Peptides 2004; 25:289-97. [PMID: 15063011 DOI: 10.1016/j.peptides.2003.12.020] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2003] [Accepted: 12/09/2003] [Indexed: 12/11/2022]
Abstract
Ghrelin was recently identified as an endogenous ligand for GH secretagogue receptor. In this study, we investigated the effects of ovariectomy on the numbers of ghrelin-immunopositive and -expressing cells, ghrelin mRNA levels, and plasma ghrelin concentrations in 4- and 9-week-old female rats. Three days after ovariectomy, the number of ghrelin cells and plasma ghrelin level significantly increased in both 4- and 9-week-old rats and the ghrelin mRNA level also increased in 4-week-old rats. These responses were reversed by 17beta-estradiol replacement. We also found that ghrelin-immunopositive cells express estrogen receptor alpha. These results suggested that estrogen is involved in the regulation of ghrelin expression.
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Affiliation(s)
- Maki Matsubara
- Department of Regulation Biology, Faculty of Science, Saitama University, 255 Shimo-ohkubo, Sakura-ku, Saitama 338-8570, Japan
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Abstract
Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.
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Affiliation(s)
- Yuxiang Sun
- Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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44
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Whatmore AJ, Hall CM, Jones J, Westwood M, Clayton PE. Ghrelin concentrations in healthy children and adolescents. Clin Endocrinol (Oxf) 2003; 59:649-54. [PMID: 14616891 DOI: 10.1046/j.1365-2265.2003.01903.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined. DESIGN Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5-18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available. METHODS Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses. RESULTS Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60-493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between ghrelin and age (rs = -0.39, P < 0.001) and pubertal stage (rs = -0.42, P < 0.001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = -0.24, P = 0.006) and to weight SD (rs = -0.24, P = 0.008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = -0.48, P < 0.001), IGFBP-3 (rs = -0.32, P < 0.001) and leptin (rs = -0.22, P = 0.02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0.46, P < 0.001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%). CONCLUSIONS The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty.
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Affiliation(s)
- A J Whatmore
- Endocrine Science Research Group, University of Manchester, UK
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45
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Pöykkö SM, Kellokoski E, Hörkkö S, Kauma H, Kesäniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003; 52:2546-53. [PMID: 14514639 DOI: 10.2337/diabetes.52.10.2546] [Citation(s) in RCA: 366] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Experimental studies have suggested that ghrelin plays a role in glucose homeostasis and in the regulation of blood pressure (BP). We therefore assessed the hypothesis that a low ghrelin concentration may be a risk factor for type 2 diabetes and hypertension. We also characterized the effect of the ghrelin Arg51Gln and Leu72Met mutations on ghrelin concentrations in the population-based hypertensive (n = 519) and control (n = 526) cohorts of our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. The fasting plasma ghrelin concentrations of 1,040 subjects were analyzed using the radioimmunoassay method. Insulin sensitivity was assessed using the quantitative insulin sensitivity check index (QUICKI). Ghrelin concentrations were negatively associated with fasting insulin (P < 0.001), systolic (P = 0.026) and diastolic BP (P = 0.018), and the prevalence of type 2 diabetes (P = 0.015) and insulin resistance (P < 0.001) in the multivariate models. In the control cohort, low ghrelin was associated with hypertension (BP >140/90 mmHg) (P = 0.031). The subjects with the ghrelin 51Gln allele had lower ghrelin concentrations than the Arg51Arg homozygotes (P = 0.001). We conclude that low ghrelin is independently associated with type 2 diabetes, insulin concentration, insulin resistance, and elevated BP. Therefore, it might have some role in the etiology of type 2 diabetes and the regulation of BP. The ghrelin Arg51Gln mutation is associated with low plasma ghrelin concentrations.
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Affiliation(s)
- Seppo M Pöykkö
- Department of Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
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Kawamura K, Sato N, Fukuda J, Kodama H, Kumagai J, Tanikawa H, Nakamura A, Honda Y, Sato T, Tanaka T. Ghrelin inhibits the development of mouse preimplantation embryos in vitro. Endocrinology 2003; 144:2623-33. [PMID: 12746326 DOI: 10.1210/en.2003-0033] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Although ghrelin acts as a modulator of feeding behavior and energy metabolism in the central nervous system, recent studies have implicated the peripheral actions of ghrelin in reproductive tissues. Here, we investigated the expression of ghrelin and its receptor (GHS-R) in mouse oocyte and preimplantation embryos, and we examined the role of ghrelin in the regulation of early embryo development. Both ghrelin and GHS-R mRNAs were detected in morula or more advanced embryo stages. As for the origin of ghrelin, both ghrelin mRNA and protein were identified in the uterine endometrium. The levels of ghrelin in uterine fluid as well as plasma were significantly increased in fasting mice compared with animals with free access to foods. Addition of ghrelin to culture media inhibited the development of two-cell embryos to the hatched blastocysts, and the inhibitory effects of ghrelin were abolished by an antagonist for the GHS-R. In addition, ghrelin significantly decreased the number of total cells, inner cell mass, and trophectoderm cells in blastocysts. These observations suggest that ghrelin could inhibit the development of preimplantation embryos during fasting. Thus, ghrelin may act as a peripheral factor to avoid the excess metabolic demands imposed by pregnancy during malnutritional states.
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Affiliation(s)
- Kazuhiro Kawamura
- Department of Obstetrics and Gynecology, Akita University School of Medicine, Akita 010-8543, Japan.
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Abstract
BACKGROUND/AIMS Ghrelin is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor involved in energy metabolism, glucose homeostasis and food intake. We investigated the role of ghrelin and insulin-like growth factor-1 (IGF-1), the mediator of the GH axis, in patients with chronic liver diseases (CLD). METHODS Ghrelin and IGF-1 serum levels were determined in 105 CLD patients and 97 healthy controls and correlated with clinical and biochemical parameters. RESULTS Ghrelin was significantly elevated and IGF-1 reduced in CLD patients compared with healthy controls. IGF-1 serum levels inversely correlated with Child's classification. Ghrelin levels were significantly elevated in Child C cirrhosis patients independent of the aetiology of liver disease. Ghrelin levels did not correlate with liver function. In contrast, there was a correlation of ghrelin with clinical (gastrointestinal bleeding, ascites, encephalopathy) and biochemical (anaemia, inflammatory markers, hypoglycaemia, renal dysfunction) parameters. In a subgroup of patients with CLD and hepatocellular carcinoma (HCC), we observed a strong inverse correlation between alpha-fetoprotein (AFP) and ghrelin levels. CONCLUSIONS Unlike IGF-1, ghrelin is not correlated with liver function, but increases in Child C cirrhosis and with complications of CLD. The inverse correlation with AFP in HCC patients requires further studies on the potential impact of ghrelin on the pathogenesis of anorexia-cachexia syndrome.
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Affiliation(s)
- Frank Tacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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