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Rahati S, Qorbani M, Naghavi A, Pishva H. The interaction between the Circadian Locomotor Output Cycles Kaput and Melanocortin-4-receptor gene variants on obesity and parameters related to obesity. Clin Nutr 2025; 45:193-201. [PMID: 39827504 DOI: 10.1016/j.clnu.2024.12.021] [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: 10/02/2023] [Revised: 11/05/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025]
Abstract
INTRODUCTION Obesity is a multifactorial disease caused by an interaction between genetic, environmental and behavioral factors. Polymorphisms of the two genes Circadian Locomotor Output Cycles Kaput (CLOCK) rs1801260 and Melanocortin-4-receptor (MC4R) rs17782313, are associated with obesity. Knowledge is limited on the interaction between CLOCK, MC4R and obesity. The aim was to explore the interactions between the CLOCK and MC4R gene variants on markers related to obesity. METHODS There were 423 subjects with information on two genetic variants of two genes (CLOCK and MC4R). Their interaction was evaluated with: chronotype, sleeping duration, emotional eating, food timing, stress, dietary intake, appetite, physical activity (assessed by questionnaires), anthropometric measures of obesity (assessed by physical measurements), and also hormonal factors (assessed by ELISA). Generalized Linear Models were applied. RESULTS Our results revealed that significant differences were observed between the genotypes of CLOCK rs1801260 for weight, Body Mass Index (BMI), Glucagon-like peptide-1 (GLP-1), cortisol, energy, fat, sleep duration, chronotype, appetite, depression, stress, emotional eating, physical activity, breakfast, lunch, and dinner time (p˂0.05). Also, significant differences were observed between the genotypes of MC4R rs17782313 for weight, BMI, Waist Circumference (WC), Waist to Hip Ratio (WHR), ghrelin, energy, carbohydrate, fat, appetite, depression, stress, breakfast time, and emotional eating (p˂0.05). Our findings also showed significant interactions between the CLOCK (CC)∗MC4R (CT) genotypes for higher appetite, stress and CLOCK (CT)∗ MC4R (CC) genotypes for higher fat and energy intake and CLOCK (CC)∗MC4R (CC) genotypes for higher weight, BMI, energy and fat intake, appetite, emotional eating, stress, ghrelin, cortisol and lower sleep duration and GLP-1 (p˂ 0.05). CONCLUSION Due to the non-significance of the interaction in CLOCK (CT)∗ MC4R (CT) genotypes, it seems that the presence of a healthy arm in the CLOCK and MC4R polymorphism is necessary for the proper function of the genes. Thus, these results highlight that gene variants and their interaction should be considered in obesity assessment.
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Affiliation(s)
- Sara Rahati
- Department of Cellular - Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mostafa Qorbani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Anoosh Naghavi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute and Department of Genetics, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamideh Pishva
- Department of Cellular - Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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Rusu CC, Anton F, Valea A, Bondor CI. N-Terminal Pro-Brain Natriuretic Peptide Correlates with Ghrelin and Acyl-Ghrelin in Pre-Dialysis Chronic Kidney Disease. Int J Mol Sci 2024; 25:5696. [PMID: 38891884 PMCID: PMC11171691 DOI: 10.3390/ijms25115696] [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: 04/17/2024] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Pro-B amino-terminal natriuretic peptide (NT-proBNP) is a diagnostic marker for heart failure (HF), a severe complication of chronic kidney disease (CKD). However, its significance in CKD is not clear, as other factors, such as renal function, may also have an impact. Recent studies have shown that ghrelin treatment is effective in HF in the general population, but the impact of ghrelin on cardiac function in CKD patients is still unknown. Our study aimed to investigate the factors associated with NT-proBNP in pre-dialysis CKD patients and to evaluate the correlation between NT-proBNP and ghrelin and acyl-ghrelin, molecules determined using ELISA methods. In a cross-sectional observational study, we included 80 patients with pre-dialysis CKD, with a mean age of 68 years and 50% men. The median values for NT-proBNP were 351.8 pg/mL, for acyl ghrelin 16.39 pg/mL, and for ghrelin 543.32 pg/mL. NT-proBNP was correlated with ghrelin (p = 0.034, r = 0.24), acyl-ghrelin (p = 0.033, r = -0.24), estimated glomerular filtration rate (p = 0.027, r = -0.25), serum urea (p = 0.006, r = 0.31), and ferritin (p = 0.041, r = 0.28). In multivariate analysis, ghrelin (p = 0.040) and blood urea (p = 0.040) remained significant predictors for NT-proBNP levels. NT-proBNP was a significant predictor for acyl-ghrelin (p = 0.036). In conclusion, in pre-dialysis CKD patients, a high value of NT-proBNP was associated with a high value of total ghrelin and a low value of acyl-ghrelin.
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Affiliation(s)
- Crina Claudia Rusu
- Department of Nephrology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania
- “Mihai Manasia” Nephrology and Dialysis Clinic, County Emergency Clinical Hospital Cluj, 400347 Cluj-Napoca, Romania
| | - Florin Anton
- Department of Cardiology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania
- Cardiology Clinic, County Emergency Clinical Hospital Cluj, 400347 Cluj-Napoca, Romania
| | - Ana Valea
- Department of Endocrinology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400012 Cluj-Napoca, Romania
- Endocrinology Clinic, County Emergency Clinical Hospital Cluj, 400347 Cluj-Napoca, Romania
| | - Cosmina Ioana Bondor
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400349 Cluj-Napoca, Romania
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Notaro NM, Dyck DJ. Regulation of peripheral tissue substrate metabolism by the gut-derived hormone ghrelin. Metabol Open 2024; 21:100279. [PMID: 38487670 PMCID: PMC10937159 DOI: 10.1016/j.metop.2024.100279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024] Open
Abstract
Ghrelin increases in the circulation prior to entrained mealtimes, with the acylated (AG) form functioning to stimulate food intake and growth hormone release. Acutely, AG induces whole-body insulin resistance, potentially to maintain glycemia between meals. Alternatively, chronic administration of both AG and the unacylated isoform of ghrelin (unAG) is associated with improved skeletal muscle insulin sensitivity as well as reduced intramuscular lipids and inflammation. This may be due to effects on lipid metabolism, with ghrelin promoting storage of fat in adipose and liver while stimulating oxidation in skeletal muscle, preventing ectopic lipid accumulation. This is of specific relevance in the handling of meal-derived lipids, as ghrelin rises preprandially with effects persisting for 2-3 h following exposure in skeletal muscle, coinciding with elevated plasma FFAs. We hypothesize that ghrelin acts as a preparatory signal for incoming lipids, as well as a regulatory hormone for their use and storage. The effects of ghrelin on skeletal muscle are lost with high fat diet feeding and physical inactivity, potentially being implicated in the pathogenesis of metabolic disease. This review summarizes the metabolic effects of both ghrelin isoforms on peripheral tissues including the pancreas, adipose, liver, and skeletal muscle. Additionally, we speculate on the physiological relevance of these effects in vivo and suggest that ghrelin may be a key regulatory hormone for nutrient handling in the postprandial state.
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Affiliation(s)
- Nicole M. Notaro
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - David J. Dyck
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
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Zhu R, Lan Y, Qian X, Zhao J, Wang G, Tian P, Chen W. Streptococcus salivarius subsp. thermophilus CCFM1312 enhanced mice resilience to activity-based anorexia. Food Funct 2024; 15:1431-1442. [PMID: 38224462 DOI: 10.1039/d3fo04663j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Probiotic intervention, already showing promise in the treatment of various psychiatric disorders like depression, emerges as a potential therapy for anorexia nervosa (AN) with minimal side effects. In this study, we established an activity-based anorexia (ABA) model to probe the pathogenesis of AN and assess the impact of probiotics on ABA mice. ABA resulted in a compensatory increase in duodenal ghrelin levels, impairing the regulation of feeding and the brain reward system. Intervention with Streptococcus salivarius subsp. thermophilus CCFM1312 ameliorated these ABA-induced effects, and the activation of neurons in the nucleus tractus solitarius (NTS) was observed following probiotic administration, revealing the advantageous role of probiotics in AN through the vagus nerve. Furthermore, our metabolomics analysis of cecal contents unveiled that S. salivarius subsp. thermophilus CCFM1312 modulated gut microbiota metabolism and thereby regulated intestinal ghrelin levels.
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Affiliation(s)
- Ran Zhu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yuming Lan
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xin Qian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, China
| | - Gang Wang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
- (Yangzhou) Institute of Food Biotechnology, Jiangnan University, Yangzhou 225004, China
| | - Peijun Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, P. R China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, China
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Iwakura H, Ensho T, Ueda Y. Desacyl-ghrelin, not just an inactive form of ghrelin?-A review of current knowledge on the biological actions of desacyl-ghrelin. Peptides 2023:171050. [PMID: 37392995 DOI: 10.1016/j.peptides.2023.171050] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Desacyl-ghrelin is a form of ghrelin which lacks acyl-modification of the third serine residue of ghrelin. Originally, desacyl-ghrelin was considered to be just an inactive form of ghrelin. More recently, however, it has been suggested to have various biological activities, including control of food intake, growth hormone, glucose metabolism, and gastric movement, and is involved in cell survival. In this review, we summarize the current knowledge of the biological actions of desacyl-ghrelin and the proposed mechanisms by which it exerts the effects.
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Affiliation(s)
- Hiroshi Iwakura
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan.
| | - Takuya Ensho
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
| | - Yoko Ueda
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
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Rahati S, Qorbani M, Naghavi A, Pishva H. Association and interaction of the MC4R rs17782313 polymorphism with plasma ghrelin, GLP-1, cortisol, food intake and eating behaviors in overweight/obese Iranian adults. BMC Endocr Disord 2022; 22:234. [PMID: 36123585 PMCID: PMC9487018 DOI: 10.1186/s12902-022-01129-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 08/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recent studies have shown that obesity is largely influenced by heredity and created by the interactions between several genes and environmental and behavioral factors. This study aimed to examine association between variant rs17782313 near melanocortin-4 receptor (MC4R) gene and behavioral and hormonal factors then evaluated interactions between variant MC4R rs17782313 with behavioral and hormonal factors on obesity. METHODS This cross-sectional study included 403 subjects, overweight and/or obesity, aged 20-50 years from Iran. The MC4R rs17782313 data were measured by the PCR-RFLP method. Dietary intake, physical activity, stress, anxiety, depression, appetite and emotional eating were assessed by using validated questionnaires. Ghrelin, glucagon-like peptide-1 and cortisol were measured by radioimmunoassay in plasma samples. Participants were also divided into three groups based on rs17782313 genotype and BMI. RESULTS After adjustment for age, gender, energy intake and PA, significant associations were observed between food intake, appetite, emotional eating, stress and physical activity with MC4R rs17782313 (p ˂0.05). Also, significant interactions were observed between fat intake (p-interaction = 0.002), protein intake (p-interaction = 0.01), energy intake (p-interaction = 0.01), emotional eating (p-interaction = 0.02), appetite (p-interaction = 0.04), stress (p-interaction = 0.04), ghrelin (p-interaction = 0.03), cortisol (p-interaction = 0.04) and physical activity (p-interaction = 0.04) and MC4R rs17782313 in terms of BMI. CONCLUSION Interactions between the CC genotype and high intakes of fat and energy, emotional eating, high appetite, and too much stress with high levels of cortisol and ghrelin probably can have an effect on BMI in overweight/obese subjects.
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Affiliation(s)
- Sara Rahati
- Department of Cellular - Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, PO Box: 14155-6447, Tehran, Iran
| | - Mostafa Qorbani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Anoosh Naghavi
- Cellular and Molecular Research Center, Resistant Tuberculosis Institute and Department of Genetics, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Hamideh Pishva
- Department of Cellular - Molecular Nutrition, School of Nutrition Sciences and Dietetics, Tehran University of Medical Sciences, PO Box: 14155-6447, Tehran, Iran.
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Wang Y, Wu Q, Zhou Q, Chen Y, Lei X, Chen Y, Chen Q. Circulating acyl and des-acyl ghrelin levels in obese adults: a systematic review and meta-analysis. Sci Rep 2022; 12:2679. [PMID: 35177705 PMCID: PMC8854418 DOI: 10.1038/s41598-022-06636-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 02/01/2022] [Indexed: 12/15/2022] Open
Abstract
Ghrelin is the only known orexigenic gut hormone, and its synthesis, secretion and degradation are affected by different metabolic statuses. This meta-analysis aimed to investigate the potential differences in plasma acyl ghrelin (AG) and des-acyl ghrelin (DAG) concentrations between normal weight and obese adults. Systematic literature searches of PubMed, Embase and Web of Science through October 2021 were conducted for articles reporting AG or DAG levels in obesity and normal weight, and 34 studies with 1863 participants who met the eligibility criteria were identified. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to evaluate group differences in circulating AG and DAG levels. Pooled effect size showed significantly lower levels of baseline AG (SMD: - 0.85; 95% CI: - 1.13 to - 0.57; PSMD < 0.001) and DAG (SMD: - 1.06; 95% CI: - 1.43 to - 0.69; PSMD < 0.001) in obese groups compared with healthy controls, and similar results were observed when subgroup analyses were stratified by the assay technique or storage procedure. Postprandial AG levels in obese subjects were significantly lower than those in controls when stratified by different time points (SMD 30 min: - 0.85, 95% CI: - 1.18 to - 0.53, PSMD < 0.001; SMD 60 min: - 1.00, 95% CI: - 1.37 to - 0.63, PSMD < 0.001; SMD 120 min: - 1.21, 95% CI: - 1.59 to - 0.83, PSMD < 0.001). In healthy subjects, a postprandial decline in AG was observed at 120 min (SMD: - 0.42; 95% CI: - 0.77 to - 0.06; PSMD = 0.021) but not in obese subjects (SMD: - 0.28; 95% CI: - 0.60 to 0.03; PSMD = 0.074). The mean change in AG concentration was similar in both the obese and lean health groups at each time point (ΔSMD30min: 0.31, 95% CI: - 0.35 to 0.97, PSMD = 0.359; ΔSMD60min: 0.17, 95% CI: - 0.12 to 0.46, PSMD = 0.246; ΔSMD120min: 0.21, 95% CI: - 0.13 to 0.54, PSMD = 0.224). This meta-analysis strengthens the clinical evidence supporting the following: lower baseline levels of circulating AG and DAG in obese individuals; declines in postprandial circulating AG levels, both for the healthy and obese individuals; a shorter duration of AG suppression in obese subjects after meal intake. These conclusions have significance for follow-up studies to elucidate the role of various ghrelin forms in energy homeostasis.
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Affiliation(s)
- Yanmei Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China.,Ya'an Polytechnic College, No. 130 Yucai Road, Yucheng District, Yaan, 625000, Sichuan, China
| | - Qianxian Wu
- Ya'an Polytechnic College, No. 130 Yucai Road, Yucheng District, Yaan, 625000, Sichuan, China
| | - Qian Zhou
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China
| | - Yuyu Chen
- Halifa Regional Centre for Education, No. 33 Spectacle Lake Dr, Dartmouth, NS, B3B1X7, Canada
| | - Xingxing Lei
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China
| | - Yiding Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China
| | - Qiu Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Jinniu District, Chengdu, 610075, Sichuan, China.
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Stapleton JA, Hofferber EM, Meier J, Ramirez IA, Iverson NM. Single-Walled Carbon Nanotube Sensor Platform for the Study of Extracellular Analytes. ACS APPLIED NANO MATERIALS 2021; 4:33-42. [PMID: 34355133 PMCID: PMC8330402 DOI: 10.1021/acsanm.0c01998] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Single-walled carbon nanotubes (SWNT) are attractive targets for the formation of high-density sensor arrays. Their small size and high reactivity could allow for the spatial and temporal study of extracellular products to a degree which greatly surpasses contemporary sensors. However, current methods of SWNT immobilization produce a low fluorescence yield that requires a combination of high magnification, exposure time, and laser intensity to combat, thus limiting the sensor's applications. In this work, a platform for the immobilization of SWNT sensors with increased fluorescence yield, longevity, fluorescence distribution, and fast reaction times is developed.
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Affiliation(s)
- Joseph A Stapleton
- Department of Biological Systems Engineering, Institute of Agriculture and Natural Resources, College of Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0726, United States
| | - Eric M Hofferber
- Department of Biological Systems Engineering, Institute of Agriculture and Natural Resources, College of Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0726, United States
| | - Jakob Meier
- Department of Biological Systems Engineering, Institute of Agriculture and Natural Resources, College of Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0726, United States
| | - Ivon Acosta Ramirez
- Department of Biological Systems Engineering, Institute of Agriculture and Natural Resources, College of Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0726, United States
| | - Nicole M Iverson
- Department of Biological Systems Engineering, Institute of Agriculture and Natural Resources, College of Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0726, United States
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Yamaguchi H, Kimura Y, Imamura M, Nagayama M, Ito T, Kyuno D, Kono T, Kimura A, Akizuki E, Nishidate T, Okita K, Nobuoka T, Mizuguchi T, Hirata K, Takemasa I. Effect of Rikkunshito, a Traditional Japanese Herbal Medicine, on Delayed Gastric Emptying and Oral Dietary Intake After Pancreaticoduodenectomy: A Prospective, Randomized, Single-Center, Open-Labeled Study. Clin Exp Gastroenterol 2020; 13:577-587. [PMID: 33328753 PMCID: PMC7734068 DOI: 10.2147/ceg.s252913] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 11/12/2020] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Delayed gastric emptying (DGE) remains an important problem after pancreaticoduodenectomy (PD). There is a lack of effective treatments for early recovery of oral dietary intake. Rikkunshito (RKT), a Japanese herbal medicine, has been gaining attention as a facilitator of gastric emptying. We evaluated the effects of RKT on DGE after PD. METHODS In this prospective, randomized, open-labeled study, patients were randomly allocated before PD in a 1:1 ratio to the RKT group or the control group that received no additional treatment. The RKT group received 2.5 g of RKT three times daily (7.5 g/day) from postoperative day (POD) 1 to POD 21. The primary endpoint was the incidence of DGE. Secondary endpoints were short-term postoperative outcomes including oral dietary intake volume and perioperative changes in levels of the hormones ghrelin and leptin. Patients were observed until hospital discharge. RESULTS Twenty-six patients in each group (n = 52) completed the protocol treatment and were included in the analysis set. There were no statistically significant differences in basic characteristics and operative factors. The overall incidence of DGE was not statistically different between the RKT and control groups (30.8% vs 30.8%, p>0.9999). There were no statistically significant differences in the amount of postoperative oral dietary intake represented by total dietary intake (TDI) up to POD 14 and POD 21, complications, and length of hospital stay. No adverse events related to this study were observed. In the RKT group, total ghrelin and acyl-ghrelin were significantly upregulated and leptin was significantly downregulated earlier than in the control group. CONCLUSION RKT treatment from POD 1 to 21 did not reduce the incidence of DGE and had no clinically beneficial effect on short-term postoperative outcomes irrespective of changes in hormone levels.
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Affiliation(s)
- Hiroshi Yamaguchi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Masafumi Imamura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Minoru Nagayama
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Tatsuya Ito
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Daisuke Kyuno
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Tsuyoshi Kono
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Akina Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Emi Akizuki
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Toshihiko Nishidate
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Kenji Okita
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
| | - Toru Mizuguchi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
- Department of Nursing and Surgical Science, Sapporo Medical University School of Health Science, Sapporo, Japan
| | - Koichi Hirata
- Department of Surgery, JR Sapporo Hospital, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan
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Mak RH, Cheung W, Purnell J. Ghrelin in Chronic Kidney Disease: Too Much or Too Little? Perit Dial Int 2020. [DOI: 10.1177/089686080702700112] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Robert H. Mak
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Wai Cheung
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Jonathan Purnell
- Department of Medicine Oregon Health & Science University Portland, Oregon, USA
- Center for the Study of Weight Regulation Oregon Health & Science University Portland, Oregon, USA
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Sharma G, Nain PS, Sethi P, Ahuja A, Sharma S. Plasma ghrelin levels after laparoscopic sleeve gastrectomy in obese individuals. Indian J Med Res 2020; 149:544-547. [PMID: 31411179 PMCID: PMC6676842 DOI: 10.4103/ijmr.ijmr_984_18] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background & objectives Ghrelin is an orexigenic gut hormone expressed by the gastric fundus. Laparoscopic sleeve gastrectomy (LSG) procedure involves resection of the gastric fundus leading to a decreased appetite and weight loss. This study was undertaken to determine the levels of plasma ghrelin after sleeve gastrectomy in obese patients. Methods The study was conducted on 90 morbidly obese patients [body mass index (BMI) >40 kg/m[2]] and severely obese patients (BMI >35/kg/m[2]) who underwent sleeve gastrectomy. The patients were followed up for six months. Weight loss parameters and plasma ghrelin levels were assessed pre- and postoperatively. Results A significant weight loss and decrease in BMI were observed at three and six months postoperatively. A significant decrease in plasma ghrelin levels over six months of follow up postoperatively was also seen. Interpretation & conclusions These preliminary findings indicated inhibition of ghrelin production after LSG leading to a decrease in the plasma ghrelin levels within a few days of surgery and sustainable weight loss in obese patients.
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Affiliation(s)
- Garima Sharma
- Department of Physiology, Dayanand Medical College & Hospital, Ludhiana, India
| | - Prabhdeep S Nain
- Department of Surgery, Dayanand Medical College & Hospital, Ludhiana, India
| | - Pulkit Sethi
- Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences & Research, Kochi, India
| | - Ashish Ahuja
- Department of Surgery, Dayanand Medical College & Hospital, Ludhiana, India
| | - Sarit Sharma
- Department of Community Medicine, Dayanand Medical College & Hospital, Ludhiana, India
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12
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Gortan Cappellari G, Barazzoni R. Ghrelin forms in the modulation of energy balance and metabolism. Eat Weight Disord 2019; 24:997-1013. [PMID: 30353455 DOI: 10.1007/s40519-018-0599-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/16/2018] [Indexed: 02/06/2023] Open
Abstract
Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UnAG) forms. This narrative review aims at presenting current emerging knowledge on the impact of ghrelin forms on energy balance and metabolism. AG represents ~ 10% of total plasma ghrelin, has an appetite-stimulating effect and is the only form for which a receptor has been identified. Moreover, other metabolic AG-induced effects have been reported, including the modulation of glucose homeostasis with stimulation of liver gluconeogenesis, the increase of fat mass and the improvement of skeletal muscle mitochondrial function. On the other hand, UnAG has no orexigenic effects, however recent reports have shown that it is directly involved in the modulation of skeletal muscle energy metabolism by improving a cluster of interlinked functions including mitochondrial redox activities, tissue inflammation and insulin signalling and action. These findings are in agreement with human studies which show that UnAG circulating levels are positively associated with insulin sensitivity both in metabolic syndrome patients and in a large cohort from the general population. Moreover, ghrelin acylation is regulated by a nutrient sensor mechanism, specifically set on fatty acids availability. These recent findings consistently point towards a novel independent role of UnAG as a regulator of muscle metabolic pathways maintaining energy status and tissue anabolism. While a specific receptor for UnAG still needs to be identified, recent evidence strongly supports the hypothesis that the modulation of ghrelin-related molecular pathways, including those involved in its acylation, may be a potential novel target in the treatment of metabolic derangements in disease states characterized by metabolic and nutritional complications.Level of evidence Level V, narrative review.
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Affiliation(s)
- Gianluca Gortan Cappellari
- Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy.
| | - Rocco Barazzoni
- Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy.
- Azienda Sanitaria Universitaria Integrata di Trieste (ASUITS), Trieste, Italy.
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13
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Mills JG, Larkin TA, Deng C, Thomas SJ. Weight gain in Major Depressive Disorder: Linking appetite and disordered eating to leptin and ghrelin. Psychiatry Res 2019; 279:244-251. [PMID: 30878306 DOI: 10.1016/j.psychres.2019.03.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 01/12/2023]
Abstract
Major Depressive Disorder (MDD) involves changes in appetite and weight, with a subset of individuals at an increased risk of weight gain. Pathways to weight gain may include appetite disturbances, excess eating, and dysregulation of appetite hormones. However, little research has simultaneously examined relationships between hormones, eating behaviours and MDD symptoms. Plasma ghrelin and leptin, biometrics, eating behaviours and psychopathology were compared between depressed (n = 60) and control (n = 60) participants. Depressed participants were subcategorised into those with increased or decreased appetite/weight for comparison by subtype. The Dutch Eating Behaviours Questionnaire and Yale Food Addiction Scale measured eating behaviours. Disordered eating was higher in MDD than controls, in females than males, and in depressed individuals with increased, compared to decreased, appetite/weight. Leptin levels were higher in females only. Leptin levels correlated positively, and ghrelin negatively, with disordered eating. The results provide further evidence for high levels of disordered eating in MDD, particularly in females. The correlations suggest that excessive eating in MDD is significantly linked to appetite hormones, indicating that it involves physiological, rather than purely psychological, factors. Further, longitudinal, research is needed to better understand whether hormonal factors play a causal role in excessive eating in MDD.
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Affiliation(s)
- Jessica G Mills
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
| | - Theresa A Larkin
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia
| | - Chao Deng
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia; Antipsychotic Research Laboratory, University of Wollongong, Australia
| | - Susan J Thomas
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia
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14
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Pamuk B, Yilmaz H, Kebapçilar L, Kirbiyik H, Alacacioğlu A, Bozkaya G, Pamuk G, Demirpence M. The effect of orlistat and weight loss diet on plasma ghrelin and obestatin. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2018; 23:95. [PMID: 30595703 PMCID: PMC6282548 DOI: 10.4103/jrms.jrms_928_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 05/05/2018] [Accepted: 08/01/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND The objective of this study was to evaluate the effect of weight loss with hypocaloric diet and orlistat treatment in addition to hypocaloric diet on gut-derived hormones ghrelin and obestatin. MATERIALS AND METHODS A total of 52, euglycemic and euthyroid, obese female patients were involved in the study. The patients were assigned to two groups: Group 1 (n = 26) received hypocaloric diet alone and Group 2 (n = 26) received orlistat in addition to hypocaloric diet for 12 weeks. Anthropometric measurements, serum lipid, insulin levels, and obestatin and ghrelin values were assessed at the beginning of the study and after 12 weeks of therapy. RESULTS Baseline clinical characteristics and laboratory parameters including serum ghrelin and obestatin concentrations and ghrelin/obestatin ratio were similar between the two groups. After 12 weeks, mean change in BMI, fat mass, and fat-free mass (FFM) were -1.97 ± 1.56 kg/m2 (P = 0.003), -2.63% ±2.11% (P = 0.003), and -1.06 ± 0.82 kg (P = 0.003), respectively, in Group 1. In Group 2, mean change in BMI was -2.11 ± 1.24 kg/m2 (P = 0.001), fat mass was -3.09% ±2.28% (P = 0.002), and FFM was -1.26 ± 0.54 kg (P = 0.001). However, fasting glucose, lipid, and insulin levels did not change in Group 1. Furthermore, except serum high-density lipoprotein cholesterol and triglyceride levels, no significant change was observed in Group 2. Although serum ghrelin and obestatin concentrations increased significantly in both groups (Group 1: pGhrelin: 0.047, pobestatin: 0.001 and Group 2: pGhrelin: 0.028, pobestatin: 0.006), ghrelin/obestatin ratio did not change significantly. When the changes in anthropometric assessments and laboratory parameters were compared, no significant difference was observed between the two groups. Furthermore, no correlation was observed between ghrelin or obestatin and any other hormonal and metabolic parameters. CONCLUSION Weight loss with diet and diet plus orlistat is both associated with increased ghrelin and obestatin concentrations.
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Affiliation(s)
- Baris Pamuk
- Department of Internal Medicine, Katip Celebi University Hospital, Izmir, Turkey
| | - Hamiyet Yilmaz
- Department of Endocrinology, Tepecik Research and Training Hospital, Izmir, Turkey
| | - Levent Kebapçilar
- Department of Endocrinology, Bozyaka Research and Training Hospital, Izmir, Turkey
| | - Halil Kirbiyik
- Department of Internal Medicine, Bozyaka Research and Training Hospital, Izmir, Turkey
| | - Ahmet Alacacioğlu
- Department of Medical Oncology, Ataturk Training and Research Hospital, Izmir, Turkey
| | - Giray Bozkaya
- Department of Biochemistry, Bozyaka Research and Training Hospital, Izmir, Turkey
| | - Gülseren Pamuk
- Department of Family Medicine, Bozyaka Research and Training Hospital, Izmir, Turkey
| | - Mustafa Demirpence
- Department of Endocrinology, Tepecik Research and Training Hospital, Izmir, Turkey
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15
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Rusu CC, Racasan S, Moldovan D, Potra A, Tirinescu D, Budurea C, Orasan R, Patiu IM, Bondor C, Vladutiu D, Delean D, Danu A, Kacso IM. Ghrelin and acyl ghrelin levels are associated with inflammatory and nutritional markers and with cardiac and vascular dysfunction parameters in hemodialysis patients. Int Urol Nephrol 2018; 50:1897-1906. [PMID: 30006785 DOI: 10.1007/s11255-018-1933-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 07/06/2018] [Indexed: 11/26/2022]
Abstract
PURPOSE Exogenous ghrelin is associated with cardiovascular protection in experimental and human studies. Nevertheless ESRD patients have increased ghrelin levels and severe cardiovascular comorbidities. This study aims to elucidate the metabolic factors influencing endogenous ghrelin/acyl ghrelin levels and to analyze the relation between endogenous ghrelin/acyl ghrelin levels and cardiac and vascular function markers in hemodialysis patients. METHODS The cross-sectional study was conducted in hemodialysis patients (n = 88); 50 of them were men, mean age 61.1 ± 13.5 years, 17% had diabetes. We assessed nutritional and inflammatory status and analyzed the determinants of ghrelin/acyl ghrelin and their relation with cardiac and vascular function. RESULTS Ghrelin is correlated with IL-1β (r = 0.88, p < 0.0001), triglycerides, total cholesterol (TC), and Kt/V. IL-1β is the strongest predictor of ghrelin levels (p < 0.0001). Acyl ghrelin is correlated with TC (r = 0.36, p = 0.001), LDL-cholesterol, serum bicarbonate, body mass index. TC is the strongest predictor for acyl ghrelin levels (p = 0.038). Patients with high ghrelin levels had significantly decreased nitroglycerin-mediated dilation (p = 0.05) and higher IL-1β levels (p < 0.001); increased NT-proBNP is associated with lower levels of acyl ghrelin (r = - 0.33, p = 0.02) in male patients. CONCLUSION The inflammatory marker IL-1β is in our study the strongest predictor of ghrelin levels while the nutritional marker-total cholesterol is the strongest predictor for acyl ghrelin levels in HD patients. High endogenous ghrelin level is associated with high IL-1β and with vascular smooth muscle cell dysfunction. Low acyl ghrelin level is associated with high NT-proBNP (a cardiac dysfunction marker) in male HD patients. There is a direct correlation between endogenous ghrelin level and inflammatory markers, which is not related with cardiovascular protection.
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Affiliation(s)
- Crina Claudia Rusu
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania.
| | - Simona Racasan
- Nefromed Dialysis Center, 40 Ana Aslan Street, Cluj-Napoca, Romania
| | - Diana Moldovan
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania
| | - Alina Potra
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania
| | - Dacian Tirinescu
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania
| | - Cristian Budurea
- Nefromed Dialysis Center, 40 Ana Aslan Street, Cluj-Napoca, Romania
| | - Remus Orasan
- Nefromed Dialysis Center, 40 Ana Aslan Street, Cluj-Napoca, Romania
| | - Ioan Mihai Patiu
- Nefromed Dialysis Center, 40 Ana Aslan Street, Cluj-Napoca, Romania
| | - Cosmina Bondor
- Department of Informatics and Biostatistics, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 6 Pasteur Street, 400349, Cluj-Napoca, Romania
| | - Dan Vladutiu
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania
| | - Dan Delean
- Nefromed Dialysis Center, 40 Ana Aslan Street, Cluj-Napoca, Romania
| | - Alexandra Danu
- Nephrocare Dialysis Center Dej, 9 Gutinului Street, 405200, Dej, Romania
| | - Ina Maria Kacso
- Department of Nephrology, University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj, 3-5 Clinicilor Street, 400006, Cluj-Napoca, Romania
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16
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Henderson LJ, Cockcroft RC, Kaiya H, Boswell T, Smulders TV. Peripherally injected ghrelin and leptin reduce food hoarding and mass gain in the coal tit ( Periparus ater). Proc Biol Sci 2018; 285:rspb.2018.0417. [PMID: 29794047 DOI: 10.1098/rspb.2018.0417] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 04/20/2018] [Indexed: 12/17/2022] Open
Abstract
In birds little is known about the hormonal signals that communicate nutritional state to the brain and regulate appetitive behaviours. In mammals, the peptide hormones ghrelin and leptin elevate and inhibit consumption and food hoarding, respectively. But in birds, administration of both ghrelin and leptin inhibit food consumption. The role of these hormones in the regulation of food hoarding in avian species has not been examined. To investigate this, we injected wild caught coal tits (Periparus ater) with leptin, high-dose ghrelin, low-dose ghrelin and a saline control in the laboratory. We then measured food hoarding and mass gain, as a proxy of food consumption, every 20 min for 2 h post-injection. Both high-dose ghrelin and leptin injections significantly reduced hoarding and mass gain compared with controls. Our results provide the first evidence that hoarding behaviour can be reduced by both leptin and ghrelin in a wild bird. These findings add to evidence that the hormonal control of food consumption and hoarding in avian species differs from that in mammals. Food hoarding and consumptive behaviours consistently show the same response to peripheral signals of nutritional state, suggesting that the hormonal regulation of food hoarding has evolved from the consumption regulatory system.
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Affiliation(s)
- Lindsay J Henderson
- Centre for Behaviour and Evolution, Newcastle University, Newcastle upon Tyne NE2 4HH, UK .,Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Rowan C Cockcroft
- Centre for Behaviour and Evolution, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.,School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Hiroyuki Kaiya
- National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Timothy Boswell
- Centre for Behaviour and Evolution, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.,School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Tom V Smulders
- Centre for Behaviour and Evolution, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.,Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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17
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Sasaki K, Asaoka T, Eguchi H, Fukuda Y, Iwagami Y, Yamada D, Miyazaki Y, Noda T, Takahashi T, Gotoh K, Kawamoto K, Kurokawa Y, Kobayashi S, Takiguchi S, Mori M, Doki Y. Plasma ghrelin suppression as an early predictor for postoperative complications after pancreatoduodenectomy. Pancreatology 2018; 18:73-78. [PMID: 29248543 DOI: 10.1016/j.pan.2017.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 11/29/2017] [Accepted: 12/01/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES The gut peptide hormone ghrelin induces appetite and exhibits an anti-inflammatory effect. Serial perioperative changes in ghrelin have been examined in several surgical procedures, but few in pancreatectomy. The present study analyzed perioperative changes in plasma ghrelin levels after pancreaduodenectomy (PD). METHODS The study included 24 patients undergoing PD between May 2015 and January 2016 at Osaka University Hospital. Plasma ghrelin and interleukin-6 (IL-6) levels, as well as white blood cells (WBCs) and C-reactive protein (CRP), were measured preoperatively and on postoperative day (POD) 1, 3, 7, and 14 by enzyme-linked immunosorbent assay. The relationship between the individual ghrelin ratio relative to preoperative value (IGR) and the development of grade IIIa-V Clavien-Dindo (CD) complications was examined. RESULTS Twelve patients (50%) developed grade IIIa CD complications (n = 6 [25%] pancreatic fistula, n = 7 [29%] intraabdominal abscess, n = 3 [13%] post-pancreatectomy hemorrhage, n = 5 [21%] wound infection, and n = 1 [4%] lymphorrhea). The IGR on POD 1 was significantly lower (p = 0.014) in patients who developed the complications compared to those who did not, but no significant differences were found in terms of WBC, CRP, or IL-6 on POD 1. When the IGR cut-off was set to 82% by receiver operative curve analysis, the sensitivity was 83%, specificity 75% and area under the curve 0.80. The lower IGR group (≤82%) had more postoperative complications and longer hospital stay. CONCLUSIONS The IGR on POD 1 after PD is a useful marker for predicting postoperative complications.
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Affiliation(s)
- Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan.
| | - Yasunari Fukuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Shuji Takiguchi
- Gastroenterological Surgery, Graduate School of Medical Sciences, Nagoya City University, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Japan
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18
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Brink HS, van der Lely AJ, Delhanty PJD, Huisman M, van der Linden J. Gestational diabetes mellitus and the ghrelin system. DIABETES & METABOLISM 2017; 45:393-395. [PMID: 29289478 DOI: 10.1016/j.diabet.2017.10.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 10/27/2017] [Accepted: 10/29/2017] [Indexed: 11/16/2022]
Affiliation(s)
- H S Brink
- Department of Internal Medicine, Maasstad Hospital, P.O. Box 9100, 3007, Rotterdam, CA, The Netherlands.
| | - A J van der Lely
- Department of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - P J D Delhanty
- Department of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - M Huisman
- Department of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - J van der Linden
- Department of Internal Medicine, Maasstad Hospital, P.O. Box 9100, 3007, Rotterdam, CA, The Netherlands
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19
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Zanetti M, Gortan Cappellari G, Semolic A, Burekovic I, Fonda M, Cattin L, Barazzoni R. Gender-Specific Association of Desacylated Ghrelin with Subclinical Atherosclerosis in the Metabolic Syndrome. Arch Med Res 2017; 48:441-448. [PMID: 29031563 DOI: 10.1016/j.arcmed.2017.09.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 09/18/2017] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Ghrelin, a gastric hormone with pleiotropic effects modulates vascular function and may influence atherosclerosis. Plasma ghrelin is reduced in the metabolic syndrome (MS), which is also characterized by early atherosclerosis. Ghrelin circulates in acylated (AG) and desacylated (DAG) forms. Their relative impact and that of gender on subclinical atherosclerosis in MS is unknown. AIM OF THE STUDY To investigate potential associations of total, AG and DAG with carotid atherosclerosis and with gender in the MS. METHODS Plasma total ghrelin, AG, DAG and carotid artery IMT (cIMT) were measured in 46 MS patients (NCEP-ATP III criteria, 22M/24F). RESULTS Compared with males, females had higher (p <0.05) total and DAG. In the association analysis, age and plasma glucose were positively (p <0.05) correlated with cIMT in all MS patients. The positive (p <0.05) association between cIMT and age was also confirmed in males, while that between cIMT and glucose was significant in women. In contrast, neither total ghrelin nor AG and DAG were associated with cIMT in all MS patients nor in the male subgroup. In females, a negative (p <0.05) association between carotid artery IMT, DAG and glucose was detected, but not between cIMT, total ghrelin and AG. In multivariate modeling, DAG remained negatively (p <0.05) associated with cIMT after adjusting for plasma glucose and cardiovascular risk factors. CONCLUSIONS These data indicate a negative independent association between DAG and cIMT in middle-aged women with the MS and suggest a gender-specific modulatory function of DAG in the development of atherosclerosis.
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Affiliation(s)
- Michela Zanetti
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
| | | | - Annamaria Semolic
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Ismet Burekovic
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Maurizio Fonda
- Service for Diabetes and Metabolic Diseases, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy
| | - Luigi Cattin
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy; Service for Diabetes and Metabolic Diseases, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy
| | - Rocco Barazzoni
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
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20
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Muhammad A, Delhanty PJD, Huisman M, Visser JA, Jan van der Lelij A, Neggers SJCMM. The Acylated/Unacylated Ghrelin Ratio Is Similar in Patients With Acromegaly During Different Treatment Regimens. J Clin Endocrinol Metab 2017; 102:2425-2432. [PMID: 28402548 DOI: 10.1210/jc.2017-00147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 04/06/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND Data on plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in acromegaly are limited. High AG/UAG ratios are linked with type 2 diabetes, obesity, and hyperphagia (e.g., in Prader-Willi syndrome). OBJECTIVE To assess fasting plasma AG and UAG levels, and the AG/UAG ratio in acromegaly patients receiving combination treatment of long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV; n = 60). We used as controls acromegaly patients whose disease was controlled with PEGV monotherapy and medically naïve patients with active acromegaly. METHODS Fasting venous blood samples were collected and directly stabilized to inhibit deacylation of AG. Plasma AG and UAG levels were determined by double-antibody sandwich enzyme immunoassay, and the AG/UAG ratio was calculated. RESULTS Plasma AG and UAG levels were significantly lower in patients with acromegaly receiving combination treatment [median, interquartile range (IQR): AG: 8.5 pg/mL, 2.9 to 21.1 pg/mL; UAG: 26.9 pg/mL, 11.2 to 42.1 pg/mL] compared with patients using PEGV alone [AG: 60.5 pg/mL (IQR, 58.8 to 77.4 pg/mL); UAG: 153.7 pg/mL (IQR, 127.3 to 196.0 pg/mL)] and medically naïve patients with acromegaly [AG: 24.0 pg/mL (IQR, 12.6 to 49.7 pg/mL); UAG: 56.3 pg/mL (IQR, 43.4 to 61.5 pg/mL)]. However, AG/UAG ratios were similar in all groups. CONCLUSIONS Although plasma AG and UAG are suppressed during combination treatment with LA-SSAs and PEGV, the AG/UAG ratio remained similar. This shows that SSAs decrease both AG and UAG levels, which suggests that they do not alter metabolism significantly in acromegaly patients.
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Affiliation(s)
- Ammar Muhammad
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
| | - Patric J D Delhanty
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
| | - Martin Huisman
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
| | - Jenny A Visser
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
| | - Aart Jan van der Lelij
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
| | - Sebastian J C M M Neggers
- Department of Internal Medicine, Section of Endocrinology, Erasmus University MC, 3000 CA Rotterdam, The Netherlands
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Ghrelin affects stopover decisions and food intake in a long-distance migrant. Proc Natl Acad Sci U S A 2017; 114:1946-1951. [PMID: 28167792 DOI: 10.1073/pnas.1619565114] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Billions of birds migrate long distances to either reach breeding areas or to spend the winter at more benign places. On migration, most passerines frequently stop over to rest and replenish their fuel reserves. To date, we know little regarding how they decide that they are ready to continue their journey. What physiological signals tell a bird's brain that its fuel reserves are sufficient to resume migration? A network of hormones regulates food intake and body mass in vertebrates, including the recently discovered peptide hormone, ghrelin. Here, we show that ghrelin reflects body condition and influences migratory behavior of wild birds. We measured ghrelin levels of wild garden warblers (Sylvia borin) captured at a stopover site. Further, we manipulated blood concentrations of ghrelin to test its effects on food intake and migratory restlessness. We found that acylated ghrelin concentrations of garden warblers with larger fat scores were higher than those of birds without fat stores. Further, injections of unacylated ghrelin decreased food intake and increased migratory restlessness. These results represent experimental evidence that appetite-regulating hormones control migratory behavior. Our study lays a milestone in migration physiology because it provides the missing link between ecologically dependent factors such as condition and timing of migration. In addition, it offers insights in the regulation of the hormonal system controlling food intake and energy stores in vertebrates, whose disruption causes eating disorders and obesity.
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22
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Sever S, White DL, Garcia JM. Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review. Endocr Relat Cancer 2016; 23:R393-409. [PMID: 27552970 PMCID: PMC5064755 DOI: 10.1530/erc-16-0130] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 07/14/2016] [Indexed: 12/14/2022]
Abstract
Ghrelin is a hormone with multiple physiologic functions, including promotion of growth hormone release, stimulation of appetite and regulation of energy homeostasis. Treatment with ghrelin/ghrelin-receptor agonists is a prospective therapy for disease-related cachexia and malnutrition. In vitro studies have shown high expression of ghrelin in cancer tissue, although its role including its impact in cancer risk and progression has not been established. We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelin-receptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses. Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations. Differences in serum ghrelin levels in cancer cases vs controls (typically lower) were reported for some but not all cancers. The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers, suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia. Additional large-scale prospective clinical trials as well as basic bioscientific research are warranted to further evaluate the safety and benefits of ghrelin treatment in patients with cancer.
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Affiliation(s)
- Sakine Sever
- Division of EndocrinologyDiabetes, and Metabolism, Baylor College of Medicine, Alkek Building for Biomedical Research, Houston, Texas, USA
| | - Donna L White
- Section of Gastroenterology and HepatologyBaylor College of Medicine Medical Center, Houston, Texas, USA Clinical Epidemiology and Comparative Effectiveness ProgramSection of Health Services Research (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, HSR&D Center of Innovation (152), Houston, Texas, USA Texas Medical Center Digestive Disease CenterBaylor College of Medicine, Houston, Texas, USA Dan L. Duncan Comprehensive Cancer CenterBaylor College of Medicine, Houston, Texas, USA Center for Translational Research on Inflammatory Diseases (CTRID)Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - José M Garcia
- Division of EndocrinologyDiabetes, and Metabolism, Baylor College of Medicine, Alkek Building for Biomedical Research, Houston, Texas, USA Center for Translational Research on Inflammatory Diseases (CTRID)Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA Department of Molecular and Cellular BiologyBaylor College of Medicine, Houston, Texas, USA Huffington Center on AgingBaylor College of Medicine, Houston, Texas, USA Geriatrics Research Education and Clinical CenterVeterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington, USA
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23
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Wieczerzak M, Namieśnik J, Kudłak B. Bioassays as one of the Green Chemistry tools for assessing environmental quality: A review. ENVIRONMENT INTERNATIONAL 2016; 94:341-361. [PMID: 27472199 DOI: 10.1016/j.envint.2016.05.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 05/17/2016] [Accepted: 05/19/2016] [Indexed: 05/12/2023]
Abstract
For centuries, mankind has contributed to irreversible environmental changes, but due to the modern science of recent decades, scientists are able to assess the scale of this impact. The introduction of laws and standards to ensure environmental cleanliness requires comprehensive environmental monitoring, which should also meet the requirements of Green Chemistry. The broad spectrum of Green Chemistry principle applications should also include all of the techniques and methods of pollutant analysis and environmental monitoring. The classical methods of chemical analyses do not always match the twelve principles of Green Chemistry, and they are often expensive and employ toxic and environmentally unfriendly solvents in large quantities. These solvents can generate hazardous and toxic waste while consuming large volumes of resources. Therefore, there is a need to develop reliable techniques that would not only meet the requirements of Green Analytical Chemistry, but they could also complement and sometimes provide an alternative to conventional classical analytical methods. These alternatives may be found in bioassays. Commercially available certified bioassays often come in the form of ready-to-use toxkits, and they are easy to use and relatively inexpensive in comparison with certain conventional analytical methods. The aim of this study is to provide evidence that bioassays can be a complementary alternative to classical methods of analysis and can fulfil Green Analytical Chemistry criteria. The test organisms discussed in this work include single-celled organisms, such as cell lines, fungi (yeast), and bacteria, and multicellular organisms, such as invertebrate and vertebrate animals and plants.
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Affiliation(s)
- M Wieczerzak
- Department of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., Gdańsk 80-233, Poland.
| | - J Namieśnik
- Department of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., Gdańsk 80-233, Poland
| | - B Kudłak
- Department of Analytical Chemistry, Faculty of Chemistry, Gdańsk University of Technology, 11/12 Narutowicza Str., Gdańsk 80-233, Poland
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24
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Eslami Z, Torabizadeh M, Talebpour Z, Talebpour M, Ghassempour A, Aboul-Enein HY. Simple and Sensitive Quantification of Ghrelin Hormone in Human Plasma Using SBSE-HPLC/DAD-MS. J Chromatogr Sci 2016; 54:1652-1660. [DOI: 10.1093/chromsci/bmw125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 06/15/2016] [Indexed: 11/14/2022]
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25
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Yanagimoto Y, Takiguchi S, Miyazaki Y, Makino T, Takahashi T, Kurokawa Y, Yamasaki M, Miyata H, Nakajima K, Mori M, Doki Y. Plasma ghrelin levels as a predictor of adverse renal events due to cisplatin-based chemotherapy in patients with esophageal cancer. Jpn J Clin Oncol 2016; 46:421-6. [DOI: 10.1093/jjco/hyw004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 01/04/2016] [Indexed: 12/15/2022] Open
Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yasuhiro Miyazaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan
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Bayliss JA, Lemus M, Santos VV, Deo M, Elsworth JD, Andrews ZB. Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease. J Neurochem 2016; 137:460-71. [PMID: 26872221 PMCID: PMC4836972 DOI: 10.1111/jnc.13576] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/20/2016] [Accepted: 02/01/2016] [Indexed: 12/11/2022]
Abstract
The gut hormone ghrelin is widely beneficial in many disease states. However, ghrelin exists in two distinctive isoforms, each with its own metabolic profile. In Parkinson's Disease (PD) acylated ghrelin administration is neuroprotective, however, the role of des-acylated ghrelin remains unknown. In this study, we wanted to identify the relative contribution each isoform plays using the MPTP model of PD. Chronic administration of acylated ghrelin in mice lacking both isoforms of ghrelin (Ghrelin KO) attenuated the MPTP-induced loss on tyrosine hydroxylase (TH) neuronal number and volume and TH protein expression in the nigrostriatal pathway. Moreover, acylated ghrelin reduced the increase in glial fibrillary acidic protein and Ionized calcium binding adaptor molecule 1 microglia in the substantia nigra. However, injection of acylated ghrelin also elevated plasma des-acylated ghrelin, indicating in vivo deacetylation. Next, we chronically administered des-acylated ghrelin to Ghrelin KO mice and observed no neuroprotective effects in terms of TH cell number, TH protein expression, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 cell number. The lack of a protective effect was mirrored in ghrelin-O-acyltransferase KO mice, which lack the ability to acylate ghrelin and consequently these mice have chronically increased plasma des-acyl ghrelin. Plasma corticosterone was elevated in ghrelin-O-acyltransferase KO mice and with des-acylated ghrelin administration. Overall, our studies suggest that acylated ghrelin is the isoform responsible for in vivo neuroprotection and that pharmacological approaches preventing plasma conversion from acyl ghrelin to des-acyl ghrelin may have clinical efficacy to help slow or prevent the debilitating effects of PD. Ghrelin exists in the plasma as acyl and des-acyl ghrelin. We determined the form responsible for in vivo neuroprotection in a mouse model of Parkinson's disease. Although exogenous acyl ghrelin is deacylated in situ to des-acyl, only acyl ghrelin was neuroprotective by attenuating dopamine cell loss and glial activation. Acyl ghrelin is a therapeutic option to reduce Parkinson's Disease progression. Cover Image for this issue: doi: 10.1111/jnc.13316.
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Affiliation(s)
- Jacqueline A Bayliss
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia
| | - Moyra Lemus
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia
| | - Vanessa V Santos
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia
| | - Minh Deo
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia
| | - John D Elsworth
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Zane B Andrews
- Department of Physiology, School of Biomedical and Psychological Sciences, Monash University, Melbourne, Vic., Australia
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27
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Fernandez G, Cabral A, Cornejo MP, De Francesco PN, Garcia-Romero G, Reynaldo M, Perello M. Des-Acyl Ghrelin Directly Targets the Arcuate Nucleus in a Ghrelin-Receptor Independent Manner and Impairs the Orexigenic Effect of Ghrelin. J Neuroendocrinol 2016; 28:12349. [PMID: 26661382 DOI: 10.1111/jne.12349] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 11/12/2015] [Accepted: 12/06/2015] [Indexed: 12/16/2022]
Abstract
Ghrelin is a stomach-derived octanoylated peptide hormone that plays a variety of well-established biological roles acting via its specific receptor known as growth hormone secretagogue receptor (GHSR). In plasma, a des-octanoylated form of ghrelin, named des-acyl ghrelin (DAG), also exists. DAG is suggested to be a signalling molecule that has specific targets, including the brain, and regulates some physiological functions. However, no specific receptor for DAG has been reported until now, and, consequently, the potential role of DAG as a hormone has remained a matter of debate. In the present study, we show that DAG specifically binds to and acts on a subset of arcuate nucleus (ARC) cells in a GHSR-independent manner. ARC cells labelled by a DAG fluorescent tracer include the neuropeptide Y (NPY) and non-NPY neurones. Given the well-established role of the ARC in appetite regulation, we tested the effect of centrally administered DAG on food intake. We found that DAG failed to affect dark phase feeding, as well as food intake, after a starvation period; however, it impaired the orexigenic actions of peripherally administered ghrelin. Thus, we conclude that DAG directly targets ARC neurones and antagonises the orexigenic effects of peripherally administered ghrelin.
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Affiliation(s)
- G Fernandez
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - A Cabral
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - M P Cornejo
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - P N De Francesco
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - G Garcia-Romero
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - M Reynaldo
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
| | - M Perello
- Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology, [IMBICE dependent on the Argentine Research Council (CONICET) and Scientific Research Commission, Province of Buenos Aires (CIC-PBA)], La Plata, Buenos Aires, Argentina
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28
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Bianchi E, Boekelheide K, Sigman M, Lamb DJ, Hall SJ, Hwang K. Ghrelin ameliorates adhesions in a postsurgical mouse model. J Surg Res 2015; 201:226-34. [PMID: 26850207 DOI: 10.1016/j.jss.2015.10.044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 10/03/2015] [Accepted: 10/29/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Peritoneal adhesion formation is a well-recognized consequence of abdominal and pelvic surgery, causing infertility, chronic pelvic pain, and intestinal obstruction. We hypothesized that ghrelin, a 28-amino acid peptide predominantly found in the stomach, plays an important role in preventing postoperative surgical adhesions. The purpose of this study was to develop a new surgical peritoneal adhesion model to define the role that ghrelin plays in wound healing and adhesion formation. MATERIALS AND METHODS C57BL/6 wild-type mice (n = 40) and growth hormone secretagogue receptor-knockout (GHSR KO) mice (n = 20) underwent a midline laparotomy to establish a peritoneal adhesion model characterized by the combination of two different techniques: ischemic peritoneal buttons and cecal multiple abrasion. All mice received intraperitoneal injections with ghrelin (0.16 mg/kg) or saline twice daily for 20 d after surgery. Peritoneal ischemic buttons were harvested to determine protein expression of collagen (Masson trichrome, picrosirius red stain, and Western blot). RESULTS The novel mouse model demonstrated consistent and easily reproducible formation of intra-abdominal adhesions. Ghrelin administration significantly reduced postoperative adhesion formation (P < 0.001) in wild-type mice. The antifibrotic effect of ghrelin in wild-type mice was confirmed by measuring collagen I protein levels via Western blot analysis. The anti-adhesion effect of ghrelin seen in wild-type mice was not detected in GHSR KO mice demonstrating that this effect is mediated by the GHSR-1a receptor. CONCLUSIONS Ghrelin administration may improve surgical outcome by reducing peritoneal adhesion formation and fibrotic response in a mouse model.
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Affiliation(s)
- Enrica Bianchi
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Kim Boekelheide
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Mark Sigman
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Dolores J Lamb
- Department of Urology, Baylor College of Medicine, Houston, Texas
| | - Susan J Hall
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
| | - Kathleen Hwang
- Department of Surgery, Division of Urology, Brown University, Providence, Rhode Island; Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island.
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Kobayashi T, Masaki T, Kogawa K, Matsuoka H, Sugiyama M. Efficacy of Gum Chewing on Bowel Movement After Open Colectomy for Left-Sided Colorectal Cancer: A Randomized Clinical Trial. Dis Colon Rectum 2015; 58:1058-63. [PMID: 26445178 DOI: 10.1097/dcr.0000000000000452] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Prolonged intestinal paralysis can be a problem after gastrointestinal surgery. Several systematic reviews and meta-analyses have suggested the efficacy of gum chewing for the prevention of postoperative ileus. OBJECTIVE The purpose of this study was to examine the efficacy of gum chewing for the recovery of bowel function after surgery for left-sided colorectal cancer and to determine the physiological mechanism underlying the effect of gum chewing on bowel function. DESIGN This was a single-center, placebo-controlled, parallel-group, prospective randomized trial. SETTINGS The study was conducted at a general hospital in Japan. PATIENTS Forty-eight patients with left-sided colorectal cancer were included. INTERVENTIONS The patients were randomly assigned to a gum group (N = 25) and a control group (N = 23). Four patients in the gum group and 1 in the control group were subsequently excluded because of difficulties in continuing the trial, resulting in the analysis of 21 and 22 patients in the respective groups. Patients in the gum group chewed commercial gum 3 times a day for ≥5 minutes each time from postoperative day 1 to the first day of food intake. MAIN OUTCOME MEASURES The time to first flatus and first bowel movement after the operation were recorded, and the colonic transit time was measured. Gut hormones (gastrin, des-acyl ghrelin, motilin, and serotonin) were measured preoperatively, perioperatively, and on postoperative days 1, 3, 5, 7, and 10. RESULTS Gum chewing did not significantly shorten the time to the first flatus (53 ± 2 vs. 49 ± 26 hours; p = 0.481; gum vs. control group), time to first bowel movement (94 ± 44 vs. 109 ± 34 hours; p = 0.234), or the colonic transit time (88 ± 28 vs. 88 ± 21 hours; p = 0.968). However, gum chewing significantly increased the serum levels of des-acyl ghrelin and gastrin. LIMITATIONS The main limitation was a greater rate of complications than anticipated, which limited the significance of the findings. CONCLUSIONS Gum chewing changed the serum levels of des-acyl ghrelin and gastrin, but we were unable to demonstrate an effect on the recovery of bowel function.
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Affiliation(s)
- Takaaki Kobayashi
- 1 Department of Surgery, Kyorin University Hospital, Tokyo, Japan 2 Department of Surgery, Kanto Central Hospital, Tokyo, Japan
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Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues. Biochem Pharmacol 2015; 98:732-9. [PMID: 26514871 DOI: 10.1016/j.bcp.2015.10.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 10/21/2015] [Indexed: 11/24/2022]
Abstract
A high-throughput radiometric assay was developed to characterize enzymatic hydrolysis of ghrelin and to track the peptide's fate in vivo. The assay is based on solvent partitioning of [(3)H]-octanoic acid liberated from [(3)H]-octanoyl ghrelin during enzymatic hydrolysis. This simple and cost-effective method facilitates kinetic analysis of ghrelin hydrolase activity of native and mutated butyrylcholinesterases or carboxylesterases from multiple species. In addition, the assay's high sensitivity facilitates ready evaluation of ghrelin's pharmacokinetics and tissue distribution in mice after i.v. bolus administration of radiolabeled peptide.
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Li G, Xia J, Jia P, Zhao J, Sun Y, Wu C, Liu B. Plasma Levels of Acylated Ghrelin in Children with Pulmonary Hypertension Associated with Congenital Heart Disease. Pediatr Cardiol 2015; 36:1423-8. [PMID: 25981561 DOI: 10.1007/s00246-015-1178-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 04/28/2015] [Indexed: 12/29/2022]
Abstract
This study aims to estimate plasma levels of acylated ghrelin in children with pulmonary hypertension (PH) associated with congenital heart disease (CHD) and to correlate the levels of acylated ghrelin with endothelin-1 (ET-1), nitric oxide (NO), and clinical hemodynamic parameters. We investigated the plasma concentration of acylated ghrelin, ET-1, NO, and the hemodynamic parameters in 20 children with CHD, 20 children with PH-CHD, and 20 normal children. Plasma-acylated ghrelin and NO levels were significantly higher in CHD group than in control subjects (P < 0.001). Moreover, plasma-acylated ghrelin, ET-1, and NO levels were significantly elevated in PH-CHD group compared with the CHD group (P < 0.05). In PH-CHD children, plasma-acylated ghrelin levels correlated positively with pulmonary artery systolic pressure (PASP; r = 0.740, P < 0.001), pulmonary artery diastolic pressure (PADP; r = 0.613, P = 0.004), right ventricular systolic pressure (RVSP; r = 0.642, P = 0.002), mean pulmonary arterial hypertension (mPAP; r = 0.685, P = 0.001), right ventricle diameter (RVD; r = 0.473, P = 0.035), pulmonary artery trunk diameter (PAD; r = 0.613, P = 0.004), NO (r = 0.463, P = 0.04), and ET-1 (r = 0.524, P = 0.018). Plasma-acylated ghrelin levels were elevated both in CHD and in PH-CHD. Increased acylated ghrelin levels correlated positively with ET-1, NO, PASP, PADP, RVSP, mPAP, RVD, and PAD. Acylated ghrelin may be a new biomarker of PH-CHD.
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Affiliation(s)
- Gang Li
- Department of Pediatrics, The Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, 646000, Sichuan, China
| | - Jiyi Xia
- Research Center for Drug and Functional Foods of Luzhou Medical College, Luzhou, 646000, Sichuan, China
| | - Peng Jia
- Department of Pediatrics, The Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, 646000, Sichuan, China
| | - Jian Zhao
- Department of Pediatrics, The Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, 646000, Sichuan, China
| | - Yuqin Sun
- Department of Pediatrics, The Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, 646000, Sichuan, China
| | - Changxue Wu
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Luzhou Medical College, Luzhou, 646000, Sichuan, China
| | - Bin Liu
- Department of Pediatrics, The Affiliated Hospital of Luzhou Medical College, No. 25 Taiping Street, Luzhou, 646000, Sichuan, China.
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Randomized Phase II Study of the Anti-inflammatory Effect of Ghrelin During the Postoperative Period of Esophagectomy. Ann Surg 2015; 262:230-6. [PMID: 25361222 DOI: 10.1097/sla.0000000000000986] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE A prospective randomized phase II trial was conducted to evaluate the efficacy of ghrelin administration in reducing systemic inflammatory response syndrome (SIRS) duration after esophagectomy. BACKGROUND Esophagectomy for esophageal cancer is highly invasive and leads to prolonged SIRS duration and postoperative complications. Ghrelin has multiple effects, including anti-inflammatory effects. METHODS Forty patients undergoing esophagectomy were randomly assigned to either the ghrelin group (n = 20), which received continuous infusion of ghrelin (0.5 μg/kg/h) for 5 days, or the placebo group (n = 20), which received pure saline for 5 days. The primary endpoint was SIRS duration. The secondary endpoints were the incidence of postoperative complications, time of a negative nitrogen balance, changes in body weight and composition, and levels of inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS The ghrelin group had a shorter SIRS duration and lower CRP and IL-6 levels than did the placebo group. The incidence of pulmonary complications was lower in the ghrelin group than in the placebo group, whereas other complications did not differ between the groups. Although time of the negative nitrogen balance was shorter in the ghrelin group than in the placebo group, changes in total body weight and lean body weight did not differ significantly. CONCLUSIONS Postoperative ghrelin administration was effective for inhibiting inflammatory mediators and improving the postoperative clinical course of patients with esophageal cancer.
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Ibrahim Abdalla MM. Ghrelin - Physiological Functions and Regulation. EUROPEAN ENDOCRINOLOGY 2015; 11:90-95. [PMID: 29632576 DOI: 10.17925/ee.2015.11.02.90] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 07/13/2015] [Indexed: 01/01/2023]
Abstract
Ghrelin is an orexigenic peptide predominantly secreted from the stomach and stimulates appetite and growth hormone (GH) release. Studies have provided evidence that ghrelin exercises a wide range of functions, including regulation of food intake and energy metabolism, modulation of cardiovascular function, stimulation of osteoblast proliferation and bone formation and stimulation of neurogenesis and myogenesis. In the gastrointestinal system, ghrelin affects multiple functions, including secretion of gastric acid, gastric motility and pancreatic protein output. Most of these functions have been attributed to the actions of acylated ghrelin. The balance among its secretion rate, degradation rate and clearance rate determines the circulating level of ghrelin. This review explains what ghrelin is, its physiological functions and the factors that influence its level.
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Inverse association of des-acyl ghrelin with worksite blood pressure in overweight/obese male workers. Environ Health Prev Med 2015; 20:224-31. [PMID: 25753602 DOI: 10.1007/s12199-015-0454-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/23/2015] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Job strain, defined as a combination of high job demands and low job control, has been reported to elevate blood pressure (BP) during work. Meanwhile, a recent experimental study showed that ghrelin blunted the BP response to such mental stress. In the present study, we examined the hypothesis that des-acyl ghrelin may have some beneficial effects on worksite BP through modulating the BP response to work-related mental stress, i.e., job strain. METHODS Subjects were 34 overweight/obese male day-shift workers (mean age 41.7 ± 6.7 years). No subjects had received any anti-hypertensive medication. A 24-h ambulatory BP monitoring was recorded every 30 min on a regular working day. The average BP was calculated for Work BP, Morning BP, and Home BP. Job strain was assessed using the short version of the Japanese Job Content Questionnaire. RESULTS Des-acyl ghrelin showed significant inverse correlations with almost all BPs except Morning SBP, Morning DBP, and Home DBP. In multiple regression analysis, des-acyl ghrelin inversely correlated with Work SBP after adjusting for confounding factors. Des-acyl ghrelin was also negatively associated with BP changes from Sleep to Morning, Sleep to Work, and Sleep to Home. CONCLUSIONS Des-acyl ghrelin was inversely associated with Worksite BP, suggesting a unique beneficial effect of des-acyl ghrelin on Worksite BP in overweight/obese male day-shift workers.
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Effects of ghrelin administration on the early postoperative inflammatory response after esophagectomy. Surg Today 2014; 45:1025-31. [DOI: 10.1007/s00595-014-1076-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 10/06/2014] [Indexed: 12/20/2022]
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Plasma Ghrelin Concentrations Are Negatively Correlated With Urine Albumin-to-Creatinine Ratio in Newly Diagnosed Type 2 Diabetes. Am J Med Sci 2014; 348:382-6. [DOI: 10.1097/maj.0000000000000297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Hara M, Nishi Y, Yamashita Y, Hirata R, Takahashi S, Nagamitsu SI, Hosoda H, Kangawa K, Kojima M, Matsuishi T. Relation between circulating levels of GH, IGF-1, ghrelin and somatic growth in Rett syndrome. Brain Dev 2014; 36:794-800. [PMID: 24377437 DOI: 10.1016/j.braindev.2013.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 11/06/2013] [Accepted: 11/18/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Most cases of Rett syndrome (RTT) are caused by mutations in methyl CpG binding protein 2 (MECP2), and individuals with RTT have somatic growth failure, growth arrest of brain, epilepsy, and intellectual disability (ID). Ghrelin is a peptide hormone which stimulates growth hormone (GH) secretion from the pituitary gland. Ghrelin and GH regulate insulin-like growth factor-1 (IGF-1) synthesis, and this GH/IGF-1 axis is an endocrine axis involved in energy and sleep homeostasis and plays crucial roles in somatic and brain growth. This study aimed to determine whether circulating ghrelin, GH and IGF-1 reflect somatic and brain growth in RTT patients. METHODS We examined anthropometric data and circulating ghrelin, GH, and IGF-1 in 22 female RTT patients with epilepsy and ID (RTT-Ep/ID) and 14 age-matched females with epilepsy and ID (non-RTT-Ep/ID). RESULTS Body mass index (BMI) and height/length were significantly lower in RTT-Ep/ID than in non-RTT-Ep/ID in patients less than 20 years old. Plasma ghrelin in RTT-Ep/ID patients showed a significant inverse correlation with weight but had no significant correlations with BMI or height. Head circumference in both groups showed a significant positive correlation with circulating ghrelin and a significant negative correlation with circulating IGF-1. The ratio of octanoyl-ghrelin to total-ghrelin (O/T-ratio) is used as an indicator to estimate the biological activity of ghrelin. Among pre-adolescents, O/T-ratios were significantly higher in the RTT-Ep/ID group than in the non-RTT-Ep/ID group (P < 0.05). CONCLUSIONS Timing of growth-spurts differed between the RTT-Ep/ID and non-RTT-Ep/ID groups, possibly due to a common (but yet unknown) mechanism of growth failure. Ghrelin/GH/IGF-1 axis function was aberrant in both the RTT-Ep/ID and non-RTT-Ep/ID groups. The initial clinical course of Rett syndrome affects the development of the sleep-wake cycle and locomotion in early infancy, both of which may be based on the dysfunction of the aminergic neurons modulated by ghrelin/GH/IGF-1 axis. Further study with a larger sample size should help clarify the precise mechanisms controlling the somatic growth and hormonal features in Rett syndrome.
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Affiliation(s)
- Munetsugu Hara
- Department of Neonatology, Medical Center for Maternal and Child Health, St. Mary's Hospital, Kurume, Fukuoka 830-8543, Japan
| | - Yoshihiro Nishi
- Department of Physiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Rumiko Hirata
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Satoru Takahashi
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan
| | - Shin-Ichiro Nagamitsu
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
| | - Hiroshi Hosoda
- Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Kenji Kangawa
- Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Masayasu Kojima
- Institute of Life Science, Kurume University, Hyakunenkohen, Kurume, Fukuoka 839-0864, Japan
| | - Toyojiro Matsuishi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan.
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Yano Y, Nakazato M, Toshinai K, Inokuchi T, Matsuda S, Hidaka T, Hayakawa M, Kangawa K, Shimada K, Kario K. Circulating des-acyl ghrelin improves cardiovascular risk prediction in older hypertensive patients. Am J Hypertens 2014; 27:727-33. [PMID: 24363280 DOI: 10.1093/ajh/hpt232] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND We aimed to assess the predictive value of circulating levels of des-acyl ghrelin, an abundant form of ghrelin in humans, for the risk of cardiovascular disease (CVD) in older hypertensive patients. We simultaneously evaluated other biomarkers, such as high-molecular-weight (HMW) adiponectin, high-sensitivity C-reactive protein (hs-CRP), and plasminogen activator inhibitor 1 (PAI-1), for their usefulness in risk prediction. METHODS We enrolled 590 older hypertensive patients (mean age = 72.9 years; 41.0% men). The incidences of CVD, including coronary artery disease, stroke, congestive heart failure, and sudden death, were prospectively ascertained. RESULTS During an average duration of 2.8 (SD = 0.7) years (1,653 person-years), there were 42 CVD events. Patients with CVD events had lower levels of des-acyl ghrelin at baseline than those without CVD events (median = 78.2 vs. 114.7 fmol/ml; P < 0.001). No difference was found among other biomarkers between the patients with CVD events and those without such events. The Cox proportional hazards model adjusted by covariables revealed that the hazard ratio for CVD events in patients with a 1-SD decrease of log des-acyl ghrelin was 1.8 (95% confidence interval = 1.3-2.4). Incorporation of des-acyl ghrelin in the risk model (including age, current smoking, 24-hour systolic blood pressure, preexisting CVD, and carotid intima-media thickness) improved the C statistics (from 0.683 to 0.721; P = 0.22) and resulted in a net reclassification improvement of 20.5% (P = 0.02). In contrast, HMW adiponectin, hs-CRP, and PAI-1 provided no improvement in risk prediction. CONCLUSIONS Des-acyl ghrelin improved the prediction of CVD events in older hypertensive patients.
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Affiliation(s)
- Yuichiro Yano
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
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Han G, Ko SJ, Park JW, Kim J, Yeo I, Lee H, Kim SY, Lee H. Acupuncture for functional dyspepsia: study protocol for a two-center, randomized controlled trial. Trials 2014; 15:89. [PMID: 24655542 PMCID: PMC3994398 DOI: 10.1186/1745-6215-15-89] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 03/04/2014] [Indexed: 12/13/2022] Open
Abstract
Background Functional dyspepsia (FD) is a common health problem currently without any optimal treatments. Acupuncture has been traditionally sought as a treatment for FD. The aim of this study is to investigate whether acupuncture treatment helps improve symptoms of FD. Methods/design A two-center, randomized, waitlist-controlled trial will be carried out to evaluate whether acupuncture treatment improves FD symptoms. Seventy six participants aged 18 to 75 years with FD as diagnosed by Rome III criteria will be recruited from August 2013 to January 2014 at two Korean Medicine hospitals. They will be randomly allocated either into eight sessions of partially individualized acupuncture treatment over 4 weeks or a waitlist group. The acupuncture group will then be followed-up for 3 weeks with six telephone visits and a final visit will be paid at 8 weeks. The waitlist group will receive the identical acupuncture treatment after a 4-week waiting period. The primary outcome is the proportion of responders with adequate symptom relief and the secondary outcomes include Nepean dyspepsia index, EQ-5D, FD-related quality of life, Beck’s depression inventory, state-trait anxiety inventory questionnaire, and level of ghrelin hormone. The protocol was approved by the participating centers’ Institutional Review Boards. Discussion Results of this trial will help clarify not only whether the acupuncture treatment is beneficial for symptom improvement in FD patients but also to elucidate the related mechanisms of how acupuncture might work. Trial registration ClinicalTrials.gov Identifier: NCT01921504.
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Affiliation(s)
| | | | | | | | | | | | | | - Hyangsook Lee
- Acupuncture and Meridian Science Research Center, College of Korean Medicine, Kyung Hee University, Kyung Hee dae-ro 26, Dongdaemun-gu, Seoul 130-701, South Korea.
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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: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [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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Clinical Significance of Ghrelin Expression in the Gastric Mucosa of Morbidly Obese Patients. World J Surg 2013; 37:2883-90. [DOI: 10.1007/s00268-013-2209-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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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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Takiguchi S, Hiura Y, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Mori M, Hosoda H, Kangawa K, Doki Y. Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy. Gastric Cancer 2013; 16:167-74. [PMID: 22895614 DOI: 10.1007/s10120-012-0164-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 05/11/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer patients who undergo gastrectomy suffer from a post-gastrectomy syndrome that includes weight loss, dumping syndrome, reflux esophagitis, alkaline gastritis, and finally malnutrition. It is important to ameliorate the post-gastrectomy symptoms to restore postoperative quality of life (QoL). The aim of this study was to investigate the effect of rikkunshito, a Japanese herbal medicine, on postoperative symptoms and ghrelin levels in gastric cancer patients after gastrectomy. METHODS Twenty-five patients who had undergone gastrectomy received 2.5 g of rikkunshito before every meal for 4 weeks, and a drug withdrawal period was established for the next 4 weeks. Changes in gastrointestinal hormones, including ghrelin, and appetite visual analog scale scores were measured, and QoL was estimated by using the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30. The Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS) scoring system was used to evaluate gastrointestinal symptoms after gastrectomy. RESULTS Sixteen men and nine women (mean age 61.9 years) were enrolled in the study. All patients had either stage I (n = 24) or II (n = 1) disease and had undergone either distal gastrectomy (n = 17) or total gastrectomy (n = 8) by a laparoscopy-assisted approach. The mean ratio of the acyl-/total ghrelin concentration increased significantly after rikkunshito administration (Pre: 7.8 ± 2.1, 4 weeks: 10.5 ± 1.7 %, p = 0.0026). The total DAUGS score, as well as the scores reflecting limited activity due to decreased food consumption, reflux symptoms, dumping symptoms, and nausea and vomiting significantly improved after rikkunshito administration. CONCLUSIONS The present study demonstrated a significant attenuation of gastrointestinal symptoms after gastrectomy by treatment with rikkunshito. Rikkunshito is potentially useful to minimize gastrointestinal symptoms after gastrectomy.
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Affiliation(s)
- Shuji Takiguchi
- Division of Gastroenterological Surgery, Department of Surgery, Graduate School of Medicine, Osaka University, 2-2, E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Chopin LK, Seim I, Walpole CM, Herington AC. The ghrelin axis--does it have an appetite for cancer progression? Endocr Rev 2012; 33:849-91. [PMID: 22826465 DOI: 10.1210/er.2011-1007] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHSR), is a peptide hormone with diverse physiological roles. Ghrelin regulates GH release, appetite and feeding, gut motility, and energy balance and also has roles in the cardiovascular, immune, and reproductive systems. Ghrelin and the GHSR are expressed in a wide range of normal and tumor tissues, and a fluorescein-labeled, truncated form of ghrelin is showing promise as a biomarker for prostate cancer. Plasma ghrelin levels are generally inversely related to body mass index and are unlikely to be useful as a biomarker for cancer, but may be useful as a marker for cancer cachexia. Some single nucleotide polymorphisms in the ghrelin and GHSR genes have shown associations with cancer risk; however, larger studies are required. Ghrelin regulates processes associated with cancer, including cell proliferation, apoptosis, cell migration, cell invasion, inflammation, and angiogenesis; however, the role of ghrelin in cancer is currently unclear. Ghrelin has predominantly antiinflammatory effects and may play a role in protecting against cancer-related inflammation. Ghrelin and its analogs show promise as treatments for cancer-related cachexia. Further studies using in vivo models are required to determine whether ghrelin has a role in cancer progression.
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Affiliation(s)
- Lisa K Chopin
- Ghrelin Research Group, Institute of Health and Biomedical Innovation, Queensland University of Technology and Australian Prostate Cancer Research Centre-Queensland, Brisbane, Queensland 4001, Australia.
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Yamamoto K, Takiguchi S, Miyata H, Miyazaki Y, Hiura Y, Yamasaki M, Nakajima K, Fujiwara Y, Mori M, Kangawa K, Doki Y. Reduced plasma ghrelin levels on day 1 after esophagectomy: a new predictor of prolonged systemic inflammatory response syndrome. Surg Today 2012; 43:48-54. [PMID: 23001546 DOI: 10.1007/s00595-012-0342-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 10/19/2011] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND PURPOSE Ghrelin, a stomach-derived hormone, stimulates growth hormone secretion and appetite, and inhibits excessive inflammatory response. Plasma ghrelin might affect the inflammatory response to stressful surgical interventions. The aim of this study was to investigate the relationship between serial changes in plasma ghrelin concentrations and the postoperative clinical course after esophagectomy. METHODS The prospective cohort study subjects were 20 patients with esophageal cancer, who underwent esophagectomy with gastric tube reconstruction. Blood samples were taken six times perioperatively during the course of esophagectomy. RESULTS The plasma ghrelin level decreased to 33 % (range 15-90 %) on postoperative day (POD) 1, relative to the preoperative level, then recovered to about 50 % by POD 3-10. The duration of systemic inflammatory response syndrome (SIRS) was significantly longer in patients with a marked ghrelin reduction to <33 % on POD 1, than in those with less marked reduction of ≥ 33 % (6.1 ± 1.3 vs. 2.1 ± 0.6 days, P = 0.019). On POD 1, the only inflammatory marker that correlated with the duration of SIRS was the % ghrelin, whereas C-reactive protein, leukocyte count, and IL-6 did not. CONCLUSION An early postoperative drop in plasma ghrelin correlated with prolonged SIRS after esophagectomy. Thus, the supplementation of low plasma ghrelin may help minimize excess inflammatory response in these patients.
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Affiliation(s)
- Kazuyoshi Yamamoto
- Division of Gastroenterological Surgery, Department of Surgery, Graduate School of Medicine, Osaka University, 2-2, E2, Yamadaoka, Suita, Osaka 565-0871, Japan
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Kim YS, Lee JS, Lee TH, Cho JY, Kim JO, Kim WJ, Kim HG, Jeon SR, Jeong HS. Plasma levels of acylated ghrelin in patients with functional dyspepsia. World J Gastroenterol 2012; 18:2231-7. [PMID: 22611317 PMCID: PMC3351774 DOI: 10.3748/wjg.v18.i18.2231] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 09/20/2011] [Accepted: 03/10/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between plasma acylated ghrelin levels and the pathophysiology of functional dyspepsia.
METHODS: Twenty-two female patients with functional dyspepsia and twelve healthy volunteers were recruited for the study. The functional dyspepsia patients were each diagnosed based on the Rome III criteria. Eligible patients completed a questionnaire concerning the severity of 10 symptoms. Plasma acylated ghrelin levels before and after a meal were determined in the study participants using a commercial human acylated enzyme immunoassay kit; electrogastrograms were performed for 50 min before and after a standardized 10-min meal containing 265 kcal.
RESULTS: There were no significant differences in plasma acylated ghrelin levels between healthy volunteers and patients with functional dyspepsia. However, in patients with functional dyspepsia, there was a negative correlation between fasting plasma acylated ghrelin levels and the sum score of epigastric pain (r = -0.427, P = 0.047) and a positive correlation between the postprandial/fasting plasma acylated ghrelin ratio and the sum score of early satiety (r = 0.428, P =0.047). Additionally, there was a negative correlation between fasting acylated ghrelin plasma levels and fasting normogastria (%) (r = -0.522, P = 0.013). Interestingly, two functional dyspepsia patients showed paradoxically elevated plasma acylated ghrelin levels after the meal.
CONCLUSION: Abnormal plasma acylated ghrelin levels before or after a meal may be related to several of the dyspeptic symptoms seen in patients with functional dyspepsia.
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Akamizu T, Sakura N, Shigematsu Y, Tajima G, Ohtake A, Hosoda H, Iwakura H, Ariyasu H, Kangawa K. Analysis of plasma ghrelin in patients with medium-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type II. Eur J Endocrinol 2012; 166:235-40. [PMID: 22048973 DOI: 10.1530/eje-11-0785] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Ghrelin requires a fatty acid modification for binding to the GH secretagogue receptor. Acylation of the Ser3 residue of ghrelin is essential for its biological activities. We hypothesized that acyl-CoA is the fatty acid substrate for ghrelin acylation. Because serum octanoyl-CoA levels are altered by fatty acid oxidation disorders, we examined circulating ghrelin levels in affected patients. MATERIALS AND METHODS Blood levels of acyl (A) and des-acyl (D) forms of ghrelin and acylcarnitine of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and glutaric aciduria type II (GA2) were measured. RESULTS Plasma acyl ghrelin levels and A/D ratios increased in patients with MCAD deficiency or GA2 when compared with normal subjects. Reverse-phase HPLC confirmed that n-octanoylated ghrelin levels were elevated in these patients. CONCLUSION Changing serum medium-chain acylcarnitine levels may affect circulating acyl ghrelin levels, suggesting that acyl-CoA is the substrate for ghrelin acylation.
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Affiliation(s)
- Takashi Akamizu
- The First Department of Medicine, Wakayama Medical University, 811-1 Kimi-idera, Wakayama 641-8509, Japan.
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Hiura Y, Takiguchi S, Yamamoto K, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Fujiwara Y, Mori M, Kangawa K, Doki Y. Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients. Cancer 2012; 118:4785-94. [DOI: 10.1002/cncr.27430] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 12/20/2011] [Accepted: 12/28/2011] [Indexed: 12/22/2022]
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Cederberg H, Koivisto VM, Jokelainen J, Surcel HM, Keinänen-Kiukaanniemi S, Rajala U. Unacylated ghrelin is associated with changes in insulin sensitivity and lipid profile during an exercise intervention. Clin Endocrinol (Oxf) 2012; 76:39-45. [PMID: 21645020 DOI: 10.1111/j.1365-2265.2011.04135.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Ghrelin has been implicated in energy homeostasis, body weight regulation and glucose metabolism. Level of unacylated ghrelin (UAG), but not acylated ghrelin (AG), has been suggested to increase during long-term exercise. However, the association of the level of UAG with exercise-induced changes of insulin sensitivity and lipid metabolism has not been previously investigated. We hypothesized that an increase in UAG level in response to a long-term exercise programme improves insulin sensitivity and associated lipid profile, independently of weight loss. DESIGN, PATIENTS AND MEASUREMENTS A prospective study of 552 young men (mean age 19·3 and range 19-28 years) undergoing military service with structured 6-month exercise training programme. Exercise performance, clinical and biochemical measurements were obtained at baseline and follow-up. Association between UAG level and fasting glucose, insulin, insulin sensitivity and lipid levels were evaluated. RESULTS An overall increase in the level of UAG was observed during the 6-month follow-up (P < 0·001), which was largest among those with weight loss ≥ 2·5% or among those whose reduction in waist circumference was largest (P = 0·007 and P < 0·001, respectively). A change in UAG level correlated inversely with a change in fasting glucose and insulin levels, HOMA-IR, total cholesterol and total triglyceride levels (P < 0·001 for all). The association between change in the UAG level and the change in insulin sensitivity was independent of weight loss or reduction in waist circumference. CONCLUSIONS Increase in UAG level was associated with improved insulin sensitivity via mechanisms independent of weight loss during an intensive, long-term exercise intervention in young healthy men.
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Affiliation(s)
- Henna Cederberg
- Institute of Health Sciences, Faculty of Medicine, University of Oulu, Finland.
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