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Zhao D, Han X, Mu Q, Wu Y, Shan L, Su L, Wang W, Wang P, Kang Y, Wang F. Association of cerebrospinal fluid NPY with peripheral ApoA: a moderation effect of BMI. Nutr Metab (Lond) 2024; 21:52. [PMID: 39054540 PMCID: PMC11270855 DOI: 10.1186/s12986-024-00828-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 07/08/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Apoprotein A-I (ApoA-I) and Apoprotein B (ApoB) have emerged as novel cardiovascular risk biomarkers influenced by feeding behavior. Hypothalamic appetite peptides regulate feeding behavior and impact lipoprotein levels, which effects vary in different weight states. This study explores the intricate relationship between body mass index (BMI), hypothalamic appetite peptides, and apolipoproteins with emphasis on the moderating role of body weight in the association between neuropeptide Y (NPY), ghrelin, orexin A (OXA), oxytocin in cerebrospinal fluid (CSF) and peripheral ApoA-I and ApoB. METHODS In this cross-sectional study, we included participants with a mean age of 31.77 ± 10.25 years, categorized into a normal weight (NW) (n = 73) and an overweight/obese (OW/OB) (n = 117) group based on BMI. NPY, ghrelin, OXA, and oxytocin levels in CSF were measured. RESULTS In the NW group, peripheral ApoA-I levels were higher, while ApoB levels were lower than in the OW/OB group (all p < 0.05). CSF NPY exhibited a positive correlation with peripheral ApoA-I in the NW group (r = 0.39, p = 0.001). Notably, participants with higher CSF NPY levels had higher peripheral ApoA-I levels in the NW group and lower peripheral ApoA-I levels in the OW/OB group, showing the significant moderating effect of BMI on this association (R2 = 0.144, β=-0.54, p < 0.001). The correlation between ghrelin, OXA and oxytocin in CSF and peripheral ApoB in both groups exhibited opposing trends (Ghrelin: r = -0.03 and r = 0.04; OXA: r = 0.23 and r=-0.01; Oxytocin: r=-0.09 and r = 0.04). CONCLUSION This study provides hitherto undocumented evidence that BMI moderates the relationship between CSF NPY and peripheral ApoA-I levels. It also reveals the protective role of NPY in the NW population, contrasting with its risk factor role in the OW/OB population, which was associated with the at-risk for cardiovascular disease.
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Affiliation(s)
- Danyang Zhao
- Medical Neurobiology Lab, Inner Mongolia Medical University, Huhhot, 010110, China
| | - Xiaoli Han
- Clinical Nutrition Department, Friendship hospital of Urumqi in Xinjiang, Urumqi, 830049, China
| | - Qingshuang Mu
- Xinjiang Key Laboratory of Neurological Disorder Research, the Second Affiliated Hospital of Xinjiang Medical University, Urumqi, 830063, China
| | - Yan Wu
- Beijing Hui-Long-Guan Hospital, Peking University, Beijing, 100096, China
| | - Ligang Shan
- Department of Anesthesiology, the Second Affiliated Hospital of Xiamen Medical College, Xiamen, 361021, China
| | - Lidong Su
- Department of Anesthesiology, the Third Affiliated Hospital of Inner Mongolia Medical University, BaoGang Hospital, Baotou, 014010, China
| | - Wenyan Wang
- School of Pharmacy, Yantai University, Yantai, 264005, China
| | - Pengxiang Wang
- Medical Neurobiology Lab, Inner Mongolia Medical University, Huhhot, 010110, China
| | - Yimin Kang
- Medical Neurobiology Lab, Inner Mongolia Medical University, Huhhot, 010110, China.
| | - Fan Wang
- Beijing Hui-Long-Guan Hospital, Peking University, Beijing, 100096, China.
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Almulla AF, Thipakorn Y, Algon AAA, Tunvirachaisakul C, Al-Hakeim HK, Maes M. Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: A systematic review and meta-analysis. Brain Behav Immun 2023; 113:374-388. [PMID: 37557967 DOI: 10.1016/j.bbi.2023.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses. OBJECTIVES To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD. METHODS Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027). CONCLUSION In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity.
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Affiliation(s)
- Abbas F Almulla
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Yanin Thipakorn
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | | | - Chavit Tunvirachaisakul
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria; Research Institute, Medical University in Plovdiv, Plovdiv, Bulgaria; Department of Psychiatry, IMPACT Strategic Research Centre, Deakin University, Geelong, Victoria, Australia; Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China.
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Gajewska A, Strzelecki D, Gawlik-Kotelnicka O. Ghrelin as a Biomarker of "Immunometabolic Depression" and Its Connection with Dysbiosis. Nutrients 2023; 15:3960. [PMID: 37764744 PMCID: PMC10537261 DOI: 10.3390/nu15183960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/08/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
Ghrelin, a gastrointestinal peptide, is an endogenous ligand of growth hormone secretagogue receptor 1a (GHSR1a), which is mainly produced by X/A-like cells in the intestinal mucosa. Beyond its initial description as a growth hormone (GH) secretagogue stimulator of appetite, ghrelin has been revealed to have a wide range of physiological effects, for example, the modulation of inflammation; the improvement of cardiac performance; the modulation of stress, anxiety, taste sensation, and reward-seeking behavior; and the regulation of glucose metabolism and thermogenesis. Ghrelin secretion is altered in depressive disorders and metabolic syndrome, which frequently co-occur, but it is still unknown how these modifications relate to the physiopathology of these disorders. This review highlights the increasing amount of research establishing the close relationship between ghrelin, nutrition, microbiota, and disorders such as depression and metabolic syndrome, and it evaluates the ghrelinergic system as a potential target for the development of effective pharmacotherapies.
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Affiliation(s)
- Agata Gajewska
- Faculty of Medicine, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Oliwia Gawlik-Kotelnicka
- Department of Affective and Psychotic Disorders, Medical University of Lodz, 92-216 Lodz, Poland;
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Ma Y, Zhang H, Guo W, Yu L. Potential role of ghrelin in the regulation of inflammation. FASEB J 2022; 36:e22508. [PMID: 35983825 DOI: 10.1096/fj.202200634r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 11/11/2022]
Abstract
Several diseases are caused or progress due to inflammation. In the past few years, accumulating evidence suggests that ghrelin, a gastric hormone of 28-amino acid residue length, exerts protective effects against inflammation by modulating the related pathways. This review focuses on ghrelin's anti-inflammatory and potential therapeutic effects in neurological, cardiovascular, respiratory, hepatic, gastrointestinal, and kidney disorders. Ghrelin significantly alleviates excessive inflammation and reduces damage to different target organs mainly by reducing the secretion of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and inhibiting the nuclear factor kappa-B (NF-κB) and NLRP3 inflammasome signaling pathways. Ghrelin also regulates inflammation and apoptosis through the p38 MAPK/c-Jun N-terminal kinase (JNK) signaling pathway; restores cerebral microvascular integrity, and attenuates vascular leakage. Ghrelin activates the phosphoInositide-3 kinase (PI3K)/protein kinase B (Akt) pathway and inhibits inflammatory responses in cardiovascular diseases and acute kidney injury. Some studies show that ghrelin exacerbates colonic and intestinal manifestations of colitis. Interestingly, some inflammatory states, such as non-alcoholic steatohepatitis, inflammatory bowel diseases, and chronic kidney disease, are often associated with high ghrelin levels. Thus, ghrelin may be a potential new therapeutic target for inflammation-related diseases.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Haifeng Zhang
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Weiying Guo
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Lu Yu
- Department of Endocrinology and Department of Interventional Therapy of First Hospital of Jilin University, State Key Laboratory for Zoonotic Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
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Deschaine SL, Leggio L. From "Hunger Hormone" to "It's Complicated": Ghrelin Beyond Feeding Control. Physiology (Bethesda) 2022; 37:5-15. [PMID: 34964687 PMCID: PMC8742734 DOI: 10.1152/physiol.00024.2021] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Discovered as a peptide involved in releasing growth hormone, ghrelin was initially characterized as the "hunger hormone." However, emerging research indicates that ghrelin appears to play an important part in relaying information regarding nutrient availability and value and adjusting physiological and motivational processes accordingly. These functions make ghrelin an interesting therapeutic candidate for metabolic and neuropsychiatric diseases involving disrupted nutrition that can further potentiate the rewarding effect of maladaptive behaviors.
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Affiliation(s)
- Sara L. Deschaine
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland
| | - Lorenzo Leggio
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland,2Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland,3Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island,4Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland,5Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia
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Ramírez ND, Luque EM, Jones XM, Torres PJ, Moreira Espinoza MJ, Cantarelli V, Ponzio MF, Arja A, Rabaglino MB, Martini AC. Modulatory effects of ghrelin on sperm quality alterations induced by a fructose-enriched diet. Heliyon 2019; 5:e02886. [PMID: 31844755 PMCID: PMC6895644 DOI: 10.1016/j.heliyon.2019.e02886] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/27/2019] [Accepted: 11/15/2019] [Indexed: 11/26/2022] Open
Abstract
The objectives of this study were: 1) to evaluate the effects of a fructose enriched diet (FED) on rat sperm quality, epididymal function (i.e. oxidative stress and alpha-glucosidase expression) and testosterone concentrations; 2) to determine if the administration of ghrelin (Ghrl), reverses the effects induced by FED. After validating the protocol as an inductor of metabolic syndrome like-symptoms, adult male rats were assigned to one of the following treatments for 8 weeks: FED = 10% fructose enriched in water (v/v); FED + Ghrl = fructose enriched diet plus Ghrl (6 nmol/animal/day, s.c.) from week 6-8; or C = water without fructose (n = 5-10 animals/group). FED significantly decreased sperm concentration and motile sperm count/ml vs C (FED: 19.0 ± 1.6 × 106sperm/ml and 834.6 ± 137.0, respectively vs C: 25.8 ± 2.8 × 106 and 1300.4 ± 202.4, respectively; p < 0.05); ghrelin injection reversed this negative effect (23.5 ± 1.6 × 106sperm/ml and 1381.7 ± 71.3 respectively). FED resulted in hypogonadism, but Ghrl could not normalize testosterone concentrations (C: 1.4 ± 0.1 ng/ml vs FED: 0.8 ± 0.2 ng/ml and FED + Ghrl: 0.6 ± 0.2 ng/ml; p < 0.05). Ghrelin did not reverse metabolic abnormalities secondary to FED. FED did not alter epididymal expression of antioxidants enzymes (superoxido-dismutase, catalase and glutathione peroxidases -Gpx-). Nevertheless, FED + Ghrl significantly increased the expression of Gpx3 (FED + Ghrl: 3.47 ± 0.48 vs FED: 0.69 ± 0.28 and C: 1.00 ± 0.14; p < 0.05). The expression of neutral alpha-glucosidase, which is a marker of epididymal function, did not differ between treatments. In conclusion, the administration of Ghrl modulated the negative effects of FED on sperm quality, possibly by an epididymal increase in Gpx3 expression. However, Ghrl could not neither normalize the metabolism of FED animals, nor reverse hypogonadism.
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Affiliation(s)
- Nicolás David Ramírez
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina
| | - Eugenia Mercedes Luque
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina
| | - Xaviar Michael Jones
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina
| | - Pedro Javier Torres
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina.,Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET-Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Pabellón de Biología Celular, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - María José Moreira Espinoza
- Instituto de Biología Celular, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - Verónica Cantarelli
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina.,Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET-Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Pabellón de Biología Celular, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - Marina Flavia Ponzio
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina.,Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET-Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Pabellón de Biología Celular, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - Ana Arja
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina
| | - María Belén Rabaglino
- Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET-Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Pabellón de Biología Celular, Ciudad Universitaria, 5016, Córdoba, Argentina
| | - Ana Carolina Martini
- Instituto de Fisiología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Santa Rosa 1085, X5000ESU, Córdoba, Argentina.,Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET-Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq, Enfermera Gordillo, Pabellón de Biología Celular, Ciudad Universitaria, 5016, Córdoba, Argentina
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Gerber H, Mosser S, Boury-Jamot B, Stumpe M, Piersigilli A, Goepfert C, Dengjel J, Albrecht U, Magara F, Fraering PC. The APMAP interactome reveals new modulators of APP processing and beta-amyloid production that are altered in Alzheimer's disease. Acta Neuropathol Commun 2019; 7:13. [PMID: 30704515 PMCID: PMC6354426 DOI: 10.1186/s40478-019-0660-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 01/11/2019] [Indexed: 12/16/2022] Open
Abstract
The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-β peptides (Aβ) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aβ production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Aβ formation) and a possible link with the pathological hallmarks of AD (memory impairment and Aβ pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Aβ production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Aβ production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Aβ generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Aβ controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases.
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Affiliation(s)
- Hermeto Gerber
- Foundation Eclosion, CH-1228, Plan-les-Ouates, Switzerland
- Campus Biotech Innovation Park, CH-1202, Geneva, Switzerland
- Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Sebastien Mosser
- Foundation Eclosion, CH-1228, Plan-les-Ouates, Switzerland
- Campus Biotech Innovation Park, CH-1202, Geneva, Switzerland
| | - Benjamin Boury-Jamot
- Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CH-1015, Lausanne, Switzerland
| | - Michael Stumpe
- Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Alessandra Piersigilli
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, CH-3012, Bern, Switzerland
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland
| | - Christine Goepfert
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, CH-3012, Bern, Switzerland
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland
| | - Joern Dengjel
- Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Urs Albrecht
- Department of Biology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Fulvio Magara
- Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, CH-1015, Lausanne, Switzerland
| | - Patrick C Fraering
- Foundation Eclosion, CH-1228, Plan-les-Ouates, Switzerland.
- Campus Biotech Innovation Park, CH-1202, Geneva, Switzerland.
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Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling. Biochem Soc Trans 2019; 47:169-178. [PMID: 30626708 DOI: 10.1042/bst20180436] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 02/08/2023]
Abstract
Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin-GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition.
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Elaghori A, Salem P, Azzam E, Abu Elfotoh N. GHRELIN LEVEL IN PATIENTS WITH LIVER CIRRHOSIS. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2019; -5:62-68. [PMID: 31149061 PMCID: PMC6535318 DOI: 10.4183/aeb.2019.62] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Ghrelin is a gastro-duodenal hormone which plays a major role in the regulation of food intake, energy balance and gastrokinesis. Ghrelin represents a novel biological marker for assessment of the presence as well as the severity of liver cirrhosis. We aimed to measure the level of plasma ghrelin in patients with liver cirrhosis (compensated and decompensated) and to correlate its level with different studied clinical and laboratory parameters. SUBJECTS AND METHODS 40 cirrhotic patients were included in a cross-sectional study and divided equally according to the Child-Pugh classification into Group I: patients with compensated liver cirrhosis (Child A), and Group II: patients with decompensated liver cirrhosis (Child B|C). Also, 20 age and sex matched healthy subjects were included as a control group (Group III). All patients were subjected to: full history taking, full clinical examination, routine biochemical studies together with estimation of plasma ghrelin level, assessment of the severity of liver disease according to Child-Pugh classification, also, abdominal ultrasonography was done. RESULTS Plasma ghrelin level was low among cirrhotic patients (both compensated and decompensated) in comparison to normal control subjects. CONCLUSION Ghrelin can be used as a serum biomarker for detection and assessment of the severity of liver cirrhosis.
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Affiliation(s)
| | - P.E.S. Salem
- Alexandria University, Faculty of Medicine, Egypt
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10
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Porchas-Quijada M, Reyes-Castillo Z, Muñoz-Valle JF, Durán-Barragán S, Aguilera-Cervantes V, López-Espinoza A, Vázquez-Del Mercado M, Navarro-Meza M, López-Uriarte P. IgG Anti-ghrelin Immune Complexes Are Increased in Rheumatoid Arthritis Patients Under Biologic Therapy and Are Related to Clinical and Metabolic Markers. Front Endocrinol (Lausanne) 2019; 10:252. [PMID: 31057488 PMCID: PMC6482250 DOI: 10.3389/fendo.2019.00252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 04/01/2019] [Indexed: 11/13/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with increased risk of cardiovascular disease and metabolic alterations. The mechanisms underlying these alterations remain unclear. Ghrelin is a gastrointestinal hormone with potent effects on food intake, body weight, metabolism, and immune response. Recent studies reported the presence of anti-ghrelin autoantibodies in healthy subjects and the levels and affinity of these autoantibodies were altered in anorectic and obese individuals. In this cross-sectional study we analyzed anti-ghrelin autoantibodies in RA patients and evaluated its relationship with clinical, body-composition and metabolic parameters. Clinical measurements of RA patients included the disease activity score-28 (DAS-28), inflammatory biomarkers, autoantibodies (RF and anti-CCP), body composition, glucose and lipid profile. Serum ghrelin levels were measured by enzyme-linked immunosorbent assay (ELISA). Free and total anti-ghrelin autoantibodies quantification (IgG and IgA isotypes) was performed by in-house ELISA. RA patients had lower IgG anti-ghrelin autoantibodies levels and higher immune complexes percentage (IgG+ghrelin) compared to the control group, while the IgA anti-ghrelin autoantibodies showed no significant differences. In the bivariate analysis, the percentage of IgG anti-ghrelin immune complexes positively correlated with BMI and ghrelin whereas in the multivariate regression model, the variables associated were DAS-28, body weight, visceral fat, LDL-C and TG (R 2 = 0.72). The percentage of IgA anti-ghrelin immune complexes positively correlated with RF and anti-CCP and the multivariate regression model showed an association with RF and body fat percentage (R 2 = 0.22). Our study shows an increased percentage of IgG anti-ghrelin immune complexes in RA patients despite ghrelin levels were similar in both groups, suggesting an increase in the affinity of these autoantibodies toward ghrelin. The associations found in the multiple regression analysis for anti-ghrelin immune complexes support the previously reported functions of these natural autoantibodies as carriers and modulators of the stability and physiological effect of the hormone. However, in RA both the disease activity and the RF appear to influence the formation of these anti-ghrelin immune complexes.
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Affiliation(s)
- Mildren Porchas-Quijada
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
| | - Zyanya Reyes-Castillo
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
- *Correspondence: Zyanya Reyes-Castillo
| | - José Francisco Muñoz-Valle
- Instituto de Investigaciones en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Sergio Durán-Barragán
- Departamento de Reumatología, Clínica de Investigación en Reumatología y Obesidad, Guadalajara, Mexico
- Instituto de Investigación en Reumatología y del Sistema Músculo Esquelético, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Virginia Aguilera-Cervantes
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
| | - Antonio López-Espinoza
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
| | - Mónica Vázquez-Del Mercado
- Instituto de Investigación en Reumatología y del Sistema Músculo Esquelético, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Mónica Navarro-Meza
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
| | - Patricia López-Uriarte
- Instituto de Investigaciones en Comportamiento Alimentario y Nutrición, Centro Universitario del Sur, Universidad de Guadalajara, Ciudad Guzmán, Mexico
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11
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Rhea EM, Salameh TS, Gray S, Niu J, Banks WA, Tong J. Ghrelin transport across the blood-brain barrier can occur independently of the growth hormone secretagogue receptor. Mol Metab 2018; 18:88-96. [PMID: 30293893 PMCID: PMC6308033 DOI: 10.1016/j.molmet.2018.09.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/10/2018] [Accepted: 09/18/2018] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE The blood-brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain. METHODS We utilized the sensitive and quantitative multiple-time regression analysis technique to determine the transport rate of mouse and human acyl ghrelin (AG) and desacyl ghrelin (DAG) in wildtype and Ghsr null mice. We also measured the regional distribution of these ghrelin peptides throughout the brain. Lastly, we characterized the transport characteristics of human DAG by measuring the stability in serum and brain, saturability of transport, and the complete transfer across the brain endothelial cell. RESULTS We found the transport rate across the BBB of both forms of ghrelin, AG, and DAG, were not affected by the loss of GHSR. We did find differences in the transport rate between the two isoforms, with DAG being faster than AG; this was dependent on the species of ghrelin, human being faster than mouse. Lastly, based on the ubiquitous properties of ghrelin throughout the CNS, we looked at regional distribution of ghrelin uptake and found the highest levels of uptake in the olfactory bulb. CONCLUSIONS The data presented here suggest that ghrelin transport can occur independently of the GHSR, and ghrelin uptake varies regionally throughout the brain. These findings better our understanding of the gut-brain communication and may lead to new understandings of ghrelin physiology.
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Affiliation(s)
- Elizabeth M Rhea
- VA Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Therese S Salameh
- VA Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Sarah Gray
- Division of Endocrinology, Metabolism, and Nutrition, Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA
| | - Jingjing Niu
- Division of Endocrinology, Metabolism, and Nutrition, Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA
| | - William A Banks
- VA Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Jenny Tong
- Division of Endocrinology, Metabolism, and Nutrition, Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC, USA.
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12
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Cleverdon ER, Davis TR, Hougland JL. Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation. Bioorg Chem 2018; 79:98-106. [PMID: 29738973 DOI: 10.1016/j.bioorg.2018.04.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/02/2018] [Accepted: 04/13/2018] [Indexed: 12/22/2022]
Abstract
Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O-acyltransferase (GOAT) catalyzes this posttranslational modification, which is essential for ghrelin to bind and activate its cognate GHS-R1a receptor. Inhibition of GOAT offers a potential avenue for modulating ghrelin signaling for therapeutic effect. Defining the molecular characteristics of ghrelin that lead to binding and recognition by GOAT will facilitate the development and optimization of GOAT inhibitors. We show that small peptide mimics of ghrelin substituted with 2,3-diaminopropanoic acid in place of the serine at the site of octanoylation act as submicromolar inhibitors of GOAT. Using these chemically modified analogs of desacyl ghrelin, we define key functional groups within the N-terminal sequence of ghrelin essential for binding to GOAT and determine GOAT's tolerance to backbone methylations and altered amino acid stereochemistry within ghrelin. Our study provides a structure-activity analysis of ghrelin binding to GOAT that expands upon activity-based investigations of ghrelin recognition and establishes a new class of potent substrate-mimetic GOAT inhibitors for further investigation and therapeutic interventions targeting ghrelin signaling.
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Affiliation(s)
| | - Tasha R Davis
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
| | - James L Hougland
- Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA.
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13
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Cleverdon ER, McGovern-Gooch KR, Hougland JL. The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin's biological interactions and avenues for controlling ghrelin signaling. Mol Membr Biol 2017; 33:111-124. [PMID: 29143554 DOI: 10.1080/09687688.2017.1388930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Initially demonstrated to stimulate hunger and appetite, ghrelin-dependent signaling is implicated in a variety of neurological and physiological processes influencing diseases such as diabetes, obesity, and Prader-Willi syndrome. In addition to its cognate receptor, recent studies have revealed ghrelin interacts with a range of binding partners within the bloodstream. Defining the scope of ghrelin's interactions within the body, understanding how these interactions work in concert to modulate ghrelin signaling, and developing molecular tools for controlling ghrelin signaling are essential for exploiting ghrelin for therapeutic effect. In this review, we discuss recent findings regarding the biological effects of ghrelin signaling, outline binding partners that control ghrelin trafficking and stability in circulation, and summarize the current landscape of inhibitors targeting ghrelin octanoylation.
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Affiliation(s)
| | | | - James L Hougland
- a Department of Chemistry , Syracuse University , Syracuse , NY , USA
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14
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Zhu CZ, Liu D, Kang WM, Yu JC, Ma ZQ, Ye X, Li K. Ghrelin and gastrointestinal stromal tumors. World J Gastroenterol 2017; 23:1758-1763. [PMID: 28348480 PMCID: PMC5352915 DOI: 10.3748/wjg.v23.i10.1758] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.
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15
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Slama FB, Jridi N, Rayana MCB, Trimeche A, Hsairi M, Belhadj O. Plasma levels of leptin and ghrelin and their correlation with BMI, and circulating lipids and glucose in obese Tunisian women. ASIAN BIOMED 2017. [DOI: 10.5372/1905-7415.0902.382] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Abstract
Background
A National Survey on the Effect of Nutrition conducted in 1996−1997 showed a 14% overall prevalence of obesity in Tunisia with a female predominance. Leptin and ghrelin play crucial roles in regulating body weight and energy balance. Leptin, an anorectic hormone, and ghrelin, an orexigenic hormone, appear to interact with glucose and lipid metabolism.
Objectives
To determine the circulating levels of ghrelin and leptin in obese Tunisian women and to investigate the correlations of these hormones with body mass index (BMI), and circulating lipids and glucose.
Methods
Forty obese women were recruited from patients in the “C” Unit of the National Institute of Nutrition and Food Technology. Twenty normal women were recruited as controls. Plasma levels of the studied variables were measured in patients from both groups and findings were analyzed.
Results
Circulating levels of leptin were significantly higher, while high-density lipoprotein (HDL)-cholesterol and ghrelin levels were significantly lower in the obese women. In the obese women, significant positive correlations were found between circulating levels of leptin and low-density lipoprotein (LDL)-cholesterol, BMI, and glucose; and ghrelin and HDL-cholesterol. Significant negative correlations were found between circulating levels of leptin and HDL-cholesterol and ghrelin; and ghrelin and leptin, LDL-cholesterol, BMI, and glucose. Multivariate analysis revealed that ghrelin was significantly associated with HDL-cholesterol, LDL-cholesterol, and blood glucose.
Conclusions
The significant negative correlation between leptin and ghrelin suggests that these two hormones may be antagonistic. Increased levels of ghrelin are correlated with decreased circulating levels of HDL-cholesterol and increased levels of LDL-cholesterol.
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Affiliation(s)
- Fethi Ben Slama
- National Institute of Public Health (INSP), Ministry of Public Health , Tunis , Tunisia
| | - Nahawand Jridi
- Faculty of Pharmacy , University of Monastir , Tunis , Tunisia
| | - Mohamed Chiheb Ben Rayana
- National Institute of Nutrition and Food Technology (INNTA) , Ministry of Public Health , Tunis , Tunisia
| | - Abdelmagid Trimeche
- National Institute of Nutrition and Food Technology (INNTA) , Ministry of Public Health , Tunis , Tunisia
| | - Mohamed Hsairi
- National Institute of Public Health (INSP), Ministry of Public Health , Tunis , Tunisia
| | - Omrane Belhadj
- Biochemistry and Biotechnology Laboratory, Faculty of Sciences of Tunis , Tunis El Manar University , Tunis , Tunisia
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Matukumalli SR, Tangirala R, Rao CM. Clusterin: full-length protein and one of its chains show opposing effects on cellular lipid accumulation. Sci Rep 2017; 7:41235. [PMID: 28120874 PMCID: PMC5264606 DOI: 10.1038/srep41235] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 12/16/2016] [Indexed: 12/31/2022] Open
Abstract
Proteins, made up of either single or multiple chains, are designed to carry out specific biological functions. We found an interesting example of a two-chain protein where administration of one of its chains leads to a diametrically opposite outcome than that reported for the full-length protein. Clusterin is a highly glycosylated protein consisting of two chains, α- and β-clusterin. We have investigated the conformational features, cellular localization, lipid accumulation, in vivo effects and histological changes upon administration of recombinant individual chains of clusterin. We demonstrate that recombinant α- and β-chains exhibit structural and functional differences and differ in their sub-cellular localization. Full-length clusterin is known to lower lipid levels. In contrast, we find that β-chain-treated cells accumulate 2-fold more lipid than controls. Interestingly, α-chain-treated cells do not show such increase. Rabbits injected with β-chain, but not α-chain, show ~40% increase in weight, with adipocyte hypertrophy, liver and kidney steatosis. Many, sometimes contrasting, roles are ascribed to clusterin in obesity, metabolic syndrome and related conditions. Our findings of differential localization and activities of individual chains of clusterin should help in understanding better the roles of clusterin in metabolism.
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Affiliation(s)
| | | | - C. M. Rao
- CSIR- Centre for Cellular and Molecular Biology, Hyderabad, 500007, India
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17
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Lufrano D, Trejo SA, Llovera RE, Salgueiro M, Fernandez G, Martínez Damonte V, González Flecha FL, Raingo J, Ermácora MR, Perelló M. Ghrelin binding to serum albumin and its biological impact. Mol Cell Endocrinol 2016; 436:130-40. [PMID: 27431015 DOI: 10.1016/j.mce.2016.07.016] [Citation(s) in RCA: 9] [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] [Received: 03/31/2016] [Revised: 06/08/2016] [Accepted: 07/14/2016] [Indexed: 01/07/2023]
Abstract
Ghrelin is an octanoylated peptide hormone that plays a key role in the regulation of the body weight and glucose homeostasis. In plasma, ghrelin circulates bound to larger proteins whose identities are partially established. Here, we used size exclusion chromatography, mass spectrometry and isothermal titration microcalorimetry to show that ghrelin interacts with serum albumin. Furthermore, we found that such interaction displays an estimated dissociation constant (KD) in the micromolar range and involves albumin fatty-acid binding sites as well as the octanoyl moiety of ghrelin. Notably, albumin-ghrelin interaction reduces the spontaneous deacylation of the hormone. Both in vitro experiments-assessing ghrelin ability to inhibit calcium channels-and in vivo studies-evaluating ghrelin orexigenic effects-indicate that the binding to albumin affects the bioactivity of the hormone. In conclusion, our results suggest that ghrelin binds to serum albumin and that this interaction impacts on the biological activity of the hormone.
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Affiliation(s)
- Daniela Lufrano
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina
| | - Sebastián A Trejo
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina; Servei de Proteòmica i Biologia Estructural, Universitat Autònoma de Barcelona, Spain
| | - Ramiro E Llovera
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina
| | - Mariano Salgueiro
- Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Argentina
| | - Gimena Fernandez
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina
| | | | - F Luis González Flecha
- Instituto de Química y Fisicoquímica Biológicas, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Jesica Raingo
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina
| | - Mario R Ermácora
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina; Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Argentina
| | - Mario Perelló
- Instituto Multidisciplinario de Biología Celular, Conicet, Argentina.
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18
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Eslami Z, Ghassempour A, Aboul-Enein HY. Recent developments in liquid chromatography-mass spectrometry analyses of ghrelin and related peptides. Biomed Chromatogr 2016; 31. [DOI: 10.1002/bmc.3796] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 07/18/2016] [Accepted: 07/21/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Zahra Eslami
- Faculty of Phytochemistry, Medicinal Plants and Drug Research Institute; Shahid Beheshti University, Evin; Tehran Iran
| | - Alireza Ghassempour
- Faculty of Phytochemistry, Medicinal Plants and Drug Research Institute; Shahid Beheshti University, Evin; Tehran Iran
| | - Hassan Y. Aboul-Enein
- Pharmaceutical and Medicinal Chemistry Department; Pharmaceutical and Drug Industries Research Division; National Research Center, Dokki; Giza 12622 Egypt
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19
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Isolated low-HDL cholesterol in Japanese patients with type 2 diabetes. Diabetol Int 2015. [DOI: 10.1007/s13340-014-0200-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Abstract
PURPOSE OF REVIEW The increasing prevalence of metabolic syndrome and the consequent cardiovascular diseases has stimulated an active search for novel risk factors. The hormones regulating energy balance are of special interest as potential risk factor indicators of cardiovascular diseases. Ghrelin provides an attractive target for studies of atherosclerosis being a gastric peptide hormone having multiple functions including orexigenic and growth hormone-releasing effects and is also involved in the regulation of cardiovascular and immunomodulatory system. RECENT FINDINGS The aim of the present article is to review recent studies on the role of ghrelin in the atherosclerosis. Ghrelin seems to influence known risk factors of atherosclerosis, endothelial dysfunction, inflammation and oxidation. These themes will be covered by the present article and a summary of clinical studies of ghrelin in atherosclerosis will be given. SUMMARY Ghrelin plays a beneficial role in multiple processes of atherogenesis and vascular function. However, ghrelin's effects are not as strong as those of traditional known risk factors.
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Affiliation(s)
- Olavi Ukkola
- Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
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21
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Abstract
BACKGROUND A significant problem to be solved for patients after liver transplantation (LT) is malnutrition with anorexia in the early posttransplant period. We hypothesized that this problem was due to the change in ghrelin metabolism during LT. The aim of this study was to examine the balance of acyl ghrelin (AG) and desacyl ghrelin and the dependence of the regulation mechanism on hepatic-related enzymes in patients during LT. MATERIALS AND METHODS AG, desacyl ghrelin, and acyl/total ghrelin (A/T) concentrations in blood samples were measured in 15 patients with liver failure (LF), 15 patients after LT, and 10 controls. The correlations between the participants' ghrelin profiles and hepatic function-related data, including liver enzymes, were evaluated. In vitro assays using synthetic AG for assessment of deacylation activity in serum were performed. RESULTS AG and A/T ratio were significantly higher in the LF patients than the patients after LT and controls (AG: 25.9 ± 12.6 versus 16.4 ± 12.6 and 9.8 ± 7.6 fmol/mL, P < 0.05; A/T ratio: 17.4 ± 4.1 versus 12.2 ± 5.5 and 11.8% ± 5.9%, P < 0.05). The serum cholinesterase level was inversely correlated with AG and A/T ratio (P < 0.01). In vitro assays showed that deacylation activity was significantly lower in patients with LF than controls (10.5% versus 42.4%, 90 min; P < 0.01). Degradation of AG was partially suppressed by a cholinesterase inhibitor. CONCLUSIONS Deacylation activity was lower in LF patients, which could cause elevation of AG levels. Serum cholinesterase may be responsible for deacylation in humans.
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22
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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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23
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Kirsten H, Al-Hasani H, Holdt L, Gross A, Beutner F, Krohn K, Horn K, Ahnert P, Burkhardt R, Reiche K, Hackermüller J, Löffler M, Teupser D, Thiery J, Scholz M. Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†. Hum Mol Genet 2015; 24:4746-63. [PMID: 26019233 PMCID: PMC4512630 DOI: 10.1093/hmg/ddv194] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 05/21/2015] [Indexed: 12/24/2022] Open
Abstract
Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.
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Affiliation(s)
- Holger Kirsten
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases, Cognitive Genetics, Department of Cell Therapy
| | - Hoor Al-Hasani
- Department for Computer Science, Analysis Strategies Group, Department of Diagnostics, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and
| | - Lesca Holdt
- Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Arnd Gross
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases
| | - Frank Beutner
- LIFE - Leipzig Research Center for Civilization Diseases, Department of Internal Medicine/Cardiology, Heart Center
| | - Knut Krohn
- Interdisciplinary Center for Clinical Research, Faculty of Medicine and
| | - Katrin Horn
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases
| | - Peter Ahnert
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases
| | - Ralph Burkhardt
- LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany
| | - Kristin Reiche
- Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and
| | - Jörg Hackermüller
- Department for Computer Science, RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology- IZI, Leipzig, Germany, Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany and
| | - Markus Löffler
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases
| | - Daniel Teupser
- Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Joachim Thiery
- LIFE - Leipzig Research Center for Civilization Diseases, Institute of Laboratory Medicine, University of Leipzig, Leipzig, Germany
| | - Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology, LIFE - Leipzig Research Center for Civilization Diseases,
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24
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Exploring the impact of bariatric surgery on high density lipoprotein. Surg Obes Relat Dis 2015; 11:238-47. [DOI: 10.1016/j.soard.2014.07.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 07/14/2014] [Accepted: 07/16/2014] [Indexed: 01/06/2023]
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Invernizzi M, Carda S, Cisari C. Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure. Aging Clin Exp Res 2014; 26:341-51. [PMID: 24347122 DOI: 10.1007/s40520-013-0186-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 11/29/2013] [Indexed: 12/24/2022]
Abstract
The occurrence of cachexia of multifactorial etiology in chronic heart failure (CHF) is a common and underestimated condition that usually leads to poor outcome and low survival rates, with high direct and indirect costs for the Health Care System. Recently, a consensus definition on cachexia has been reached, leading to a growing interest by the scientific community in this condition, which characterizes the last phase of many chronic diseases (i.e., cancer, acquired immunodeficiency syndrome). The etiology of cachexia is multifactorial and the underlying pathophysiological mechanisms are essentially the following: anorexia and malnourishment; immune overactivity and systemic inflammation; and endocrine disorders (anabolic/catabolic imbalance and resistance to growth hormone). In this paper, we review the main pathophysiological mechanisms underlying CHF cachexia, focusing also on the broad spectrum of actions of ghrelin and ghrelin agonists, and their possible use in combination with physical exercise to contrast CHF cachexia.
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Catak Z, Aydin S, Sahin I, Kuloglu T, Aksoy A, Dagli AF. Regulatory neuropeptides (ghrelin, obestatin and nesfatin-1) levels in serum and reproductive tissues of female and male rats with fructose-induced metabolic syndrome. Neuropeptides 2014; 48:167-177. [PMID: 24786976 DOI: 10.1016/j.npep.2014.04.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/02/2014] [Accepted: 04/07/2014] [Indexed: 12/15/2022]
Abstract
Although, the exact mechanisms underlying the development of the metabolic syndrome (MetS) are not still completely understood, obesity, circulated peptide hormone levels and their interaction with genetic factors are considered largely responsible. The purpose of this study is to explore how the levels of ghrelin, obestatin (OBS) and NUCB2/nesfatin-1 (NES)/NUCB2 change in serum and the reproductive tissues of female and male rats with fructose-induced metabolic syndrome, and whether the levels of each hormone is correlated with the hormones involved with fertility. Experiments were conducted on 5-week-old Sprague-Dawley male and female rats assigned to either a control group or a MetS group. Controls were fed standard rat food and water ad libitum, while the MetS group was fed standard food with 10% (v/v) fructose solution added to their drinking water for 12 weeks with a 12/12h photoperiod circle. Then, all animals were sacrificed after a one night fast. Peptides levels in the serum and reproductive tissues of rats were studied using the ELISA method while the immunoreactivity of reproductive system peptide hormones were shown by immunohistochemical staining method. Furthermore, the other biochemical parameters were measured using Konelab-60 equipment and infertility hormones were measured with Immulite2000. Fasting serum insulin, glucose, triglyceride, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels were statistically significantly higher, and the amount of high density lipoprotein cholesterol (HDL-C) was significantly lower, in the MetS groups. Serum and tissue supernatant NES levels were significantly higher in the rats with MetS than the control group. Ghrelin, OBS and NES were expressed in the cytoplasm, concentrated around the apical parts of the epithelial cells in the reproductive tissues of the rats. The amounts of ghrelin were lower in the reproductive tissues of the animals with MetS, while NES levels in the same tissues increased. Obestatin also decreased, though not in the seminal glands.
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Affiliation(s)
- Zekiye Catak
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey
| | - Suleyman Aydin
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey.
| | - Ibrahim Sahin
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey; Department of Histology and Embryology, Medical School, Erzincan University, 24030 Erzincan, Turkey
| | - Tuncay Kuloglu
- Department of Histology and Embryology, Medical School, Firat University, 23119 Elazig, Turkey
| | - Aziz Aksoy
- Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research Group), Medical School, Firat University, 23119 Elazig, Turkey; Department of Nutrition and Dietetics, Bitlis Eren University, 13000 Bitlis, Turkey
| | - Adile Ferda Dagli
- Department of Medical Pathology, Medical School, Inonu University, 44280 Malatya, Turkey
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Delporte C. Structure and physiological actions of ghrelin. SCIENTIFICA 2013; 2013:518909. [PMID: 24381790 PMCID: PMC3863518 DOI: 10.1155/2013/518909] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 11/10/2013] [Indexed: 05/30/2023]
Abstract
Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a unique n-octanoylation modification on its serine in position 3, catalyzed by ghrelin O-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin.
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Affiliation(s)
- Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 808 Route de Lennik, Bat G/E-CP611, 1070 Brussels, Belgium
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Effect of Intragastric Balloon on Gastric Emptying Time in Humans for Weight Control. Clin Nucl Med 2013; 38:863-8. [DOI: 10.1097/rlu.0000000000000224] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Azevedo-Pinto S, Pereira-Silva P, Rocha-Sousa A. Ghrelin in ocular pathophysiology: from the anterior to the posterior segment. Peptides 2013; 47:12-9. [PMID: 23816797 DOI: 10.1016/j.peptides.2013.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 06/20/2013] [Accepted: 06/20/2013] [Indexed: 12/15/2022]
Abstract
Ghrelin is a 28 amino acid acylated peptide produced in several organs that binds the growth hormone secretagogues receptor type 1a (GHSR-1a). It acts over a wide range of systems, e.g. the endocrine, cardiovascular, musculoskeletal and immune systems and the eye. The aim of this work is to review the physiologic and pathologic implications of the ghrelin-GHSR-1a in the eye. A systematic revision of studies published between 2000 and 2013 in English, Spanish or Portuguese in MEDLINE, EMBASE and Scopus was performed. Search words used included: ghrelin, GHSR-1a, ocular production, iris muscular kinetics, ciliary body, glaucoma, retinopathy and uvea. The production of ghrelin by the ocular tissue has been detected both in the anterior and posterior segments, as well as the presence of GHSR-1a. This peptide promotes the relaxation of the iris sphincter and dilator muscles, being this effect independent from GHSR-1a and dependent on prostaglandins release in the first case and dependent on GHSR-1a in the second. Regarding ocular pathology, ghrelin levels in the aqueous humor appear to be decreased in individuals with glaucoma. Moreover, ghrelin has been shown to decrease the intraocular pressure in animal models of ocular hypertension through GHSR-1a. In the posterior segment, the ghrelin-GHSR-1a system interferes with the development of oxygen-induced retinopathy, being protective in the vaso-obliterative phase and deleterious in the vaso-proliferative stage of the disease. Thus, the ghrelin-GHSR-1a system presents as a possible local regulatory mechanism in the eye, with pathophysiological implications, constituting a target for future clinical and therapeutic research and interventions.
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Affiliation(s)
- Sara Azevedo-Pinto
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Portugal
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30
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Gupta RK, Kuppusamy T, Patrie JT, Gaylinn B, Liu J, Thorner MO, Bolton WK. Association of plasma des-acyl ghrelin levels with CKD. Clin J Am Soc Nephrol 2013; 8:1098-105. [PMID: 23744005 DOI: 10.2215/cjn.09170912] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site-specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C-reactive protein, TNF-α, and IL-6 were also measured. RESULTS Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF-α, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-α, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages ≤2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage ≤2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages ≤2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage ≤2 patients (GM 77.0 pg/ml). CONCLUSIONS This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG.
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Affiliation(s)
- Rohit K Gupta
- Division of Nephrology, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA
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Ghrelins, obestatin, nesfatin-1 and leptin levels in pregnant women with and without hyperemesis gravidarum. Clin Biochem 2013; 46:828-30. [DOI: 10.1016/j.clinbiochem.2013.01.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 01/16/2013] [Accepted: 01/19/2013] [Indexed: 11/19/2022]
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Seim I, Lubik AA, Lehman ML, Tomlinson N, Whiteside EJ, Herington AC, Nelson CC, Chopin LK. Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer. J Mol Endocrinol 2013; 50:179-91. [PMID: 23267039 DOI: 10.1530/jme-12-0150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.
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Affiliation(s)
- Inge Seim
- Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology, Kelvin Grove, Brisbane, Queensland 4059, Australia
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Lopes AL, T Fayh AP, de Souza Campos LG, Teixeira BC, Kreismann Carteri RB, Ribeiro JL, Friedman R, Reischak-Oliveira Á. The effects of diet- and diet plus exercise-induced weight loss on basal metabolic rate and acylated ghrelin in grade 1 obese subjects. Diabetes Metab Syndr Obes 2013; 6:469-75. [PMID: 24348060 PMCID: PMC3848645 DOI: 10.2147/dmso.s53501] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Diet and exercise are often prescribed as primary intervention regarding obesity-related disorders. Additionally, recent studies have shown beneficial effects of weight loss through diet and exercise in ghrelin concentrations in obese subjects. The aim of this study was to evaluate the effects of a 5% weight loss on lipid profile, resting metabolic rate (RMR), and acylated ghrelin (AG) using two different methods of intervention (diet or diet plus exercise). MATERIALS AND METHODS Eighteen subjects (twelve women and six men) aged 20-40 years with a body mass index of 30-34.9 kg/m(2) (grade 1 obesity) were randomized into two intervention groups: diet (n=9) or diet plus exercise (n=9). Both groups underwent treatment until 5% of the initial body weight was lost. At baseline and upon completion, RMR and AG were analyzed. RESULTS Both groups showed a significant decrease in body fat percentage and fat mass. The diet-plus-exercise group showed a decrease in AG (pre: 54.4±25.3 pg/mL and post: 33.2±19.1 pg/mL) and an increase in RMR (pre: 1,363±379 kcal/day, post: 1,633±223 kcal/day). CONCLUSION These data suggest that diet plus exercise induced weight loss and had beneficial effects on AG concentration and RMR, essential factors to ensure the benefits of a weight-loss program.
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Affiliation(s)
- André L Lopes
- Exercise Research Laboratory, School of Physical Education, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ana Paula T Fayh
- Endocrine Unit, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Health Sciences College of Trairi, Universidade Federal do Rio Grande do Norte, Santa Cruz, RN, Brazil
| | | | - Bruno C Teixeira
- Exercise Research Laboratory, School of Physical Education, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Randhall B Kreismann Carteri
- Exercise Research Laboratory, School of Physical Education, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Jerri L Ribeiro
- Centro Universitário Metodista – IPA, Porto Alegre, RS, Brazil
| | - Rogério Friedman
- Endocrine Unit, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Álvaro Reischak-Oliveira
- Exercise Research Laboratory, School of Physical Education, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Correspondence: Álvaro Reischak-Oliveira, Exercise Research Laboratory (LAPEX) School of Physical Education, Universidade Federal do Rio Grande do Sul, Rua Felizardo, 750, Porto Alegre, RS, Brazil 90690-200, Tel +55 51 3308 5862, Fax +55 51 3308 5842, Email
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Paspala I, Katsiki N, Kapoukranidou D, Mikhailidis DP, Tsiligiroglou-Fachantidou A. The role of psychobiological and neuroendocrine mechanisms in appetite regulation and obesity. Open Cardiovasc Med J 2012; 6:147-55. [PMID: 23346258 PMCID: PMC3549543 DOI: 10.2174/1874192401206010147] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 09/01/2012] [Indexed: 12/19/2022] Open
Abstract
Obesity is a multifactorial disease. Among its causes are physical inactivity and overeating. In addition, other factors may play an important role in the development of overweight/obesity. For example, certain hormones including leptin, insulin and ghrelin, may influence appetite and consequently body weight. Obesity frequently co-exists with metabolic disorders including dyslipidemia, hypertension and insulin resistance, thus constituting the metabolic syndrome which is characterized by increased cardiovascular risk. Lack of comprehensive knowledge on obesity-related issues makes both prevention and treatment difficult. This review considers the psychobiological and neuroendocrine mechanisms of appetite and food intake. Whether these factors, in terms of obesity prevention and treatment, will prove to be relevant in clinical practice (including reducing the cardiovas-cular risk associated with obesity) remains to be established.
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Affiliation(s)
- Ioanna Paspala
- Laboratory of Hygiene & Sports Nutrition, Department of Physical Education and Sport Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Amini P, Wadden D, Cahill F, Randell E, Vasdev S, Chen X, Gulliver W, Zhang W, Zhang H, Yi Y, Sun G. Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study. PLoS One 2012; 7:e45657. [PMID: 23029165 PMCID: PMC3447757 DOI: 10.1371/journal.pone.0045657] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/21/2012] [Indexed: 11/19/2022] Open
Abstract
Objective Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study. Design A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of β cell function (HOMA-β) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance. Results Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations. Conclusion Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.
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Affiliation(s)
- Peyvand Amini
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Danny Wadden
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Farrell Cahill
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Edward Randell
- Discipline of Laboratory Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Sudesh Vasdev
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Xihua Chen
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Wayne Gulliver
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, People’s Republic of China
| | - Hongwei Zhang
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Yanqing Yi
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Guang Sun
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
- * E-mail:
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The Past and Present of Paraoxonase Enzyme: Its Role in the Cardiovascular System and Some Diseases. J Med Biochem 2012. [DOI: 10.2478/v10011-012-0006-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The Past and Present of Paraoxonase Enzyme: Its Role in the Cardiovascular System and Some DiseasesAlthough paraoxonase is synthesized in many tissues including the heart, colon, kidneys, lungs, small intestines and brain, its major locus of synthesis is the liver. PON1 is in close association with apolipoproteins and protects LDL against oxidation. It was reported that PON1 quantities dropped to 40 times lower than normal in cardiovascular diseases and diseases like diabetes, ulcerative colitis, Crohn's disease, chronic renal failure, SLE, Behcet's disease, cancer, hepatitis B, obesity, metabolic syndrome, Alzheimer's and dementia. It is speculated that the concerning decline in serum PON1 amount results from single nucleotide polymorphism in the coding (Q192R, L55M) and promoter (T-108C) sites of the PON1 gene. Additionally, circulating amounts of PON1 are affected by vitamins, antioxidants, fatty acids, dietary factors, drugs, age and lifestyle. This collection attempts to review and examine the past and present studies of paraoxonase and its relation with the cardiovascular system and some relevant diseases.
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Nogueira JP, Maraninchi M, Béliard S, Lorec AM, Berthet B, Bégu-Le Corroller A, Dubois N, Grangeot R, Mattei C, Gaudart J, Nicolay A, Portugal H, Vialettes B, Valéro R. Unacylated Ghrelin is associated with the isolated low HDL-cholesterol obese phenotype independently of insulin resistance and CRP level. Nutr Metab (Lond) 2012; 9:17. [PMID: 22413940 PMCID: PMC3317856 DOI: 10.1186/1743-7075-9-17] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 03/13/2012] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Low plasma high-density lipoprotein-cholesterol (HDL-c) level is commonly present in obesity and represents an independent cardiovascular risk factor. However, obese patients are a very heterogeneous population and the factors and mechanisms that contribute to low HDL-c remain unclear. The aim of this study was to investigate the association between plasma HDL-c levels and plasma hormonal profiles (insulin, adiponectin, resistin, leptin and ghrelin) in subsets of class II and III obese patients. METHODS Fasting plasma levels of glucose, total cholesterol, LDL-c, HDL-c, triglycerides, free fatty acids, apoproteins A-I, B-100, B-48, C-II, C-III, insulin, hs-CRP, adipocytokines (adiponectin, resistin, leptin), unacylated ghrelin, body composition (DXA) and resting energy expenditure were measured in three subsets of obese patients: 17 metabolically abnormal obese (MAO) with metabolic syndrome and the typical metabolic dyslipidaemia, 21 metabolically healthy obese (MHO) without metabolic syndrome and with a normal lipid profile, and 21 isolated low HDL-c obese patients (LHO) without metabolic syndrome, compared to 21 healthy lean control subjects. RESULTS Insulin resistance (HOMA-IR) increased gradually from MHO to LHO and from LHO to MAO patients (p < 0.05 between MHO and MAO and between LHO and MAO). In multiple regression analysis, serum unacylated ghrelin levels were only positively and independently associated with HDL-c levels in the LHO group (p = 0.032). CONCLUSIONS These results suggest that, in class II and III obese patients with an isolated low HDL-c phenotype, unacylated ghrelin is positively associated with HDL-c level independently of insulin resistance and CRP levels, and may contribute to the highly prevalent low HDL-c level seen in obesity.
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Delporte C. Recent advances in potential clinical application of ghrelin in obesity. J Obes 2012; 2012:535624. [PMID: 22523666 PMCID: PMC3317165 DOI: 10.1155/2012/535624] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 12/04/2011] [Indexed: 02/07/2023] Open
Abstract
Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets.
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Affiliation(s)
- Christine Delporte
- Laboratory of Biological Chemistry and Nutrition, Faculty of Medicine, Université libre de Bruxelles, 1070 Brussels, Belgium
- *Christine Delporte:
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Muccioli G, Lorenzi T, Lorenzi M, Ghè C, Arnoletti E, Raso GM, Castellucci M, Gualillo O, Meli R. Beyond the metabolic role of ghrelin: a new player in the regulation of reproductive function. Peptides 2011; 32:2514-21. [PMID: 22074955 DOI: 10.1016/j.peptides.2011.10.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 10/23/2011] [Accepted: 10/23/2011] [Indexed: 11/30/2022]
Abstract
Ghrelin is a gastric peptide, discovered by Kojima et al. (1999) [55] as a result of the search for an endogenous ligand interacting with the "orphan receptor" GHS-R1a (growth hormone secretagogue receptor type 1a). Ghrelin is composed of 28 aminoacids and is produced mostly by specific cells of the stomach, by the hypothalamus and hypophysis, even if its presence, as well as that of its receptors, has been demonstrated in many other tissues, not least in gonads. Ghrelin potently stimulates GH release and participates in the regulation of energy homeostasis, increasing food intake, decreasing energy output and exerting a lipogenetic effect. Furthermore, ghrelin influences the secretion and motility of the gastrointestinal tract, especially of the stomach, and, above all, profoundly affects pancreatic functions. Despite of these previously envisaged activities, it has recently been hypothesized that ghrelin regulates several aspects of reproductive physiology and pathology. In conclusion, ghrelin not only cooperates with other neuroendocrine factors, such as leptin, in the modulation of energy homeostasis, but also has a crucial role in the regulation of the hypothalamic-pituitary gonadal axis. In the current review we summarize the main targets of this gastric peptide, especially focusing on the reproductive system.
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Affiliation(s)
- Giampiero Muccioli
- Department of Drug Science and Technology, Division of Medical Pharmacology, University of Torino, Via P. Giuria 13, 10125 Torino, Italy
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Satou M, Nakamura Y, Ando H, Sugimoto H. Understanding the functional significance of ghrelin processing and degradation. Peptides 2011; 32:2183-90. [PMID: 21763742 DOI: 10.1016/j.peptides.2011.06.029] [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] [Received: 02/02/2011] [Revised: 06/08/2011] [Accepted: 06/30/2011] [Indexed: 10/18/2022]
Abstract
Post-translational modification, cleavage and processing of circulating hormones are common themes in the control of hormone activities. Full-length ghrelin is a 28 amino acid protein that exists in several modified and processed forms, including addition of an acyl moiety at the third serine of the N-terminus. When modified with octanoic acid, the first five N-terminal residues of ghrelin can modulate a signaling pathway via the ghrelin receptor GHSR1a. Although modification via a lipid moiety is essential for binding and activation of GHSR1a by ghrelin, many reports suggest that a desacyl form of ghrelin exists and has synergistic, opposing and distinct properties as compared to the acyl form. Therefore, it is important to clarify the physiological relevance of ghrelin derivatives. Based on lines of evidence from various studies, we propose that a larger proportion of secreted ghrelin is present in the deacylated form and furthermore, that circulating acyl and desacyl forms of ghrelin may be hydrolyzed to form short peptide fragments. Here, we summarize the results of studies aimed at understanding ghrelin processing and its implications for physiological function, as well as our recent findings regarding enzymes in the blood capable of generating processed forms of ghrelin.
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Affiliation(s)
- Motoyasu Satou
- Departments of Biochemistry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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Delhanty PJD, van der Lely AJ. Ghrelin and glucose homeostasis. Peptides 2011; 32:2309-18. [PMID: 21396419 DOI: 10.1016/j.peptides.2011.03.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 03/01/2011] [Accepted: 03/01/2011] [Indexed: 12/25/2022]
Abstract
Ghrelin plays an important physiological role in modulating GH secretion, insulin secretion and glucose metabolism. Ghrelin has direct effects on pancreatic islet function. Also, ghrelin is part of a mechanism that integrates the physiological response to fasting. However, pharmacologic studies indicate the important obesogenic/diabetogenic properties of ghrelin. This is very likely of physiological relevance, deriving from a requirement to protect against seasonal periods of food scarcity by building energy reserves, predominantly in the form of fat. Available data indicate the potential of ghrelin blockade as a means to prevent its diabetogenic effects. Several studies indicate a negative correlation between ghrelin levels and the incidence of type 2 diabetes and insulin resistance. However, it is unclear if low ghrelin levels are a risk factor or a compensatory response. Direct antagonism of the receptor does not always have the desired effects, however, since it can cause increased body weight gain. Pharmacological suppression of the ghrelin/des-acyl ghrelin ratio by treatment with des-acyl ghrelin may also be a viable alternative approach which appears to improve insulin sensitivity. A promising recently developed approach appears to be through the blockade of GOAT activity, although the longer term effects of this treatment remain to be investigated.
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Affiliation(s)
- P J D Delhanty
- Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
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Breastmilk ghrelin, leptin, and fat levels changing foremilk to hindmilk: is that important for self-control of feeding? Eur J Pediatr 2011; 170:1273-80. [PMID: 21384109 DOI: 10.1007/s00431-011-1438-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2010] [Accepted: 02/22/2011] [Indexed: 12/11/2022]
Abstract
The aim of this study was to evaluate the changes in the ghrelin, leptin, and fat levels in the foremilk and hindmilk and the possible relationship between these levels with the age and growth of term healthy infants. Sixty-two babies were subdivided (according to their nutrition) into breastfed (BF), formula-fed (FF), and BF plus FF (BF + FF) groups. The total and active ghrelin and tryglyceride levels and the total cholesterol levels in the foremilk and hindmilk were studied at the first and second visits (mean of the second and fifth months, respectively). At both visits, the total and active ghrelin and the total cholesterol levels were lower in the hindmilk than in the foremilk. However, the triglyceride levels were higher in the hindmilk than in the foremilk (p < 0.001). The leptin levels were also higher in the hindmilk, but this difference was not statistically significant. At the second visit, the mean total foremilk ghrelin (p < 0.01), leptin (p < 0.05), tryglyceride (p < 0.001), and cholesterol (p < 0.01) levels in the BF group were decreased compared with the levels at the first visit, whereas the active ghrelin levels increased (p < 0.001). At the second visit, we observed a 3.5% increase in the body mass index in BF infants, a 14.6% increase in FF infants, and an 11.8% increase in BF + FF infants (p < 0.01). The foremilk leptin levels were lower in the BF + FF group than in the BF group at both visits. In conclusion, at the first and second visits, the decreased ghrelin and increased tryglyceride and leptin levels in the hindmilk might be associated with the important role of self-control when feeding BF infants. The stable content of formulas might be associated with a lack of self-control during feeding and increased nutrition. Changing the breast milk ghrelin, leptin, and fat levels between the foremilk and hindmilk and between the first and second visits might explain the differences in the weight gain patterns of BF and FF infants.
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Aydin S, Dag E, Ozkan Y, Arslan O, Koc G, Bek S, Kirbas S, Kasikci T, Abasli D, Gokcil Z, Odabasi Z, Catak Z. Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides 2011; 32:1276-1280. [PMID: 21554911 DOI: 10.1016/j.peptides.2011.04.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 04/21/2011] [Accepted: 04/22/2011] [Indexed: 11/24/2022]
Abstract
A relationship between hormones and seizures has been reported in animals and humans. Therefore, the purpose of this study was to investigate the association between serum levels of prolactin, nesfatin-1 and ghrelin measured different times after a seizure or non-epileptic event and compared with controls. The study included a total of 70 subjects, and of whom 18 patients had secondary generalized epilepsy (SGE), 16 patients had primary generalized epilepsy (PGE), 16 patients exhibited paroxysmal event (psychogenic) and 20 healthy males were control subjects. The first sample was taken within 5min of a seizure, with further samples taken after 1, 24, and 48h so long as the patient did not exhibit further clinically observable seizures; blood samples were taken once from control subjects. Prolactin was measured immediately using TOSOH Bioscience hormone assays. Nesfatin-1 and ghrelin peptides were measured using a commercial immunoassay kit. Patients suffering from focal epilepsy with secondary generalization and primary generalized epilepsy presented with significantly higher levels of serum prolactin and nesfatin-1 and lower ghrelin levels 5min, 1 and 24h after a seizure than patients presenting with paroxysmal events (psychogenic) and control subjects; the data were similar but not statistically significant after 48h. The present study suggests that increased serum prolactin and nesfatin-1 concentrations, decreased ghrelin concentrations could be used as markers to identify patients that have suffered a recent epileptic seizure or other paroxysmal event (psychogenic).
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Affiliation(s)
- Suleyman Aydin
- Firat University, Medical School, Department of Medical Biochemistry, Elazig, Turkey.
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Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin. Nutr Res Rev 2011; 24:132-54. [DOI: 10.1017/s0954422411000035] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.
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Yoh J, Nishi Y, Hosoda H, Tajiri Y, Yamada K, Yanase T, Doi R, Yonemoto K, Kangawa K, Kojima M, Tanaka E, Kusukawa J. Plasma levels of n-decanoyl ghrelin, another acyl- and active-form of ghrelin, in human subjects and the effect of glucose- or meal-ingestion on its dynamics. ACTA ACUST UNITED AC 2011; 167:140-8. [DOI: 10.1016/j.regpep.2010.12.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Revised: 12/08/2010] [Accepted: 12/29/2010] [Indexed: 10/18/2022]
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Katsiki N, Mikhailidis DP, Gotzamani-Psarrakou A, Yovos JG, Karamitsos D. Effect of various treatments on leptin, adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus. Expert Opin Ther Targets 2011; 15:401-20. [DOI: 10.1517/14728222.2011.553609] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Alterations in appetite-regulating hormones influence protein-energy wasting in pediatric patients with chronic kidney disease. Pediatr Nephrol 2010; 25:2295-301. [PMID: 20607302 DOI: 10.1007/s00467-010-1588-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Revised: 05/20/2010] [Accepted: 06/09/2010] [Indexed: 02/04/2023]
Abstract
Protein-energy wasting is a common problem in pediatric patients with chronic kidney disease (CKD). Disturbances in appetite-regulating hormones have been suggested as causative factors. Acyl ghrelin is a potent orexigenic hormone, whereas desacyl ghrelin and obestatin have the opposite effect. The regulation of acyl ghrelin and its anorexigenic opponents and its role in the development of CKD-associated protein-energy wasting is poorly understood. We measured total and acylated ghrelin, obestatin, leptin, and adiponectin in children with CKD (n=29), children undergoing hemodialysis (HD) or peritoneal dialysis (PD; n=29), renal transplant recipients (RTx; n=91), and healthy controls (n=27), and analyzed the data in relation to body mass index (BMI) and height. Patients with renal insufficiency showed lower BMI standard deviation score (SDS) values and height SDS compared with controls and RTx patients. Total ghrelin was elevated in CKD and dialyzed patients compared with controls or transplant recipients (P<0.001). Acyl ghrelin did not differ between groups, and the acyl ghrelin/total ghrelin ratio was reduced in uremic patients (P<0.05). Obestatin plasma levels were increased in patients with renal insufficiency compared with controls and RTx patients (P<0.01). Uremia leads to an accumulation of the anorexigenic hormones desacyl ghrelin and obestatin. Orexigens like acyl ghrelin are not elevated. A disturbed balance between anorexigenic and orexigenic hormones may influence development of CKD-associated protein-energy wasting in pediatric patients.
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Satou M, Nishi Y, Yoh J, Hattori Y, Sugimoto H. Identification and characterization of acyl-protein thioesterase 1/lysophospholipase I as a ghrelin deacylation/lysophospholipid hydrolyzing enzyme in fetal bovine serum and conditioned medium. Endocrinology 2010; 151:4765-75. [PMID: 20685872 DOI: 10.1210/en.2010-0412] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Ghrelin contains an octanoic acid at the third residue serine, and the presence of octanoic acid on ghrelin is critical to its physiological functions. The precise mechanism for the deacylation of ghrelin in circulation remains to be clarified, although the level of deacylated ghrelin (des-acyl ghrelin) is higher than that of acylated ghrelin in serum. In this study, rapid identification of ghrelin deacylation activity was achieved by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and a ghrelin deacylation enzyme was purified 1515-fold from fetal bovine serum. Chromatographic separation showed a 24-kDa band on SDS-PAGE corresponding to ghrelin deacylation activity, and the protein band was identified as acyl-protein thioesterase 1 (APT1)/lysophospholipase I. A ghrelin deacylation enzyme in medium from HepG2 cells was also purified and identified as APT1. Although it lacks a secretion signal sequence, APT1 may be released by cells expressing APT1, mainly from liver in vivo. APT1 was originally purified as a cytosolic lysophospholipid hydrolyzing enzyme (lysophospholipase I), and recombinant APT1 exhibited deacylation activity as well as lysophospholipase activity in vitro. APT1 is released at high levels from RAW264.7 macrophage-like cells into the culture medium after stimulation with lipopolysaccharide (LPS), and LPS suppresses APT1 mRNA and protein expressions in these cells. More potent ghrelin deacylase activities were detected in sera from LPS-treated rats than in control sera. These results suggested that the serum activity of APT1 may play an important role in determination of the concentration of des-acyl ghrelin in circulation, especially under septic inflammation.
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Affiliation(s)
- Motoyasu Satou
- Department of Biochemistry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
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Staes E, Absil PA, Lins L, Brasseur R, Deleu M, Lecouturier N, Fievez V, Rieux AD, Mingeot-Leclercq MP, Raussens V, Préat V. Acylated and unacylated ghrelin binding to membranes and to ghrelin receptor: towards a better understanding of the underlying mechanisms. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2010; 1798:2102-13. [PMID: 20637180 DOI: 10.1016/j.bbamem.2010.07.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 07/02/2010] [Accepted: 07/06/2010] [Indexed: 10/19/2022]
Abstract
The O-octanoylation of human ghrelin is a natural post-translational modification that enhances its binding to model membranes and could potentially play a central role in ghrelin biological activities. Here, we aimed to clarify the mechanisms that drive ghrelin to the membrane and hence to its receptor that mediates most of its endocrinological effects. As the acylation enhances ghrelin lipophilicity and that ghrelin contains many basic residues, we examined the electrostatic attraction and/or hydrophobic interactions with membranes. Using various liposomes and buffer conditions in binding, zeta potential and isothermal titration calorimetry studies, we found that whereas acylated and unacylated ghrelin were both electrostatically attracted towards the membrane, only acylated ghrelin penetrated into the headgroup and the lipid backbone regions of negatively charged membranes. The O-acylation induced a 120-fold increase in ghrelin local concentration in the membrane. However, acylated ghrelin did not deeply penetrate the membrane nor did it perturb its organisation. Conformational studies by circular dichroism and attenuated total reflection Fourier transformed infrared as well as in silico modelling revealed that both forms of ghrelin mainly adopted the same structure in aqueous, micellar and bilayer environments even though acylated ghrelin structure is slightly more α-helical in a lipid bilayer environment. Altogether our results suggest that membrane acts as a "catalyst" in acylated ghrelin binding to the ghrelin receptor and hence could explain why acylated and unacylated ghrelin are both full agonists of this receptor but in the nanomolar and micromolar range, respectively.
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Affiliation(s)
- Edith Staes
- Université catholique de Louvain, Unité de Pharmacie Galénique, 1200 Brussels, Belgium.
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De Vriese C, Perret J, Delporte C. Focus on the short- and long-term effects of ghrelin on energy homeostasis. Nutrition 2010; 26:579-84. [DOI: 10.1016/j.nut.2009.09.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Accepted: 09/17/2009] [Indexed: 02/06/2023]
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