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El Baassiri MG, Raouf Z, Badin S, Escobosa A, Sodhi CP, Nasr IW. Dysregulated brain-gut axis in the setting of traumatic brain injury: review of mechanisms and anti-inflammatory pharmacotherapies. J Neuroinflammation 2024; 21:124. [PMID: 38730498 PMCID: PMC11083845 DOI: 10.1186/s12974-024-03118-3] [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: 02/29/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients.
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Affiliation(s)
- Mahmoud G El Baassiri
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Zachariah Raouf
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Sarah Badin
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Alejandro Escobosa
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Chhinder P Sodhi
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Isam W Nasr
- Pediatric Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
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Khalaji A, Babajani N, Amirsardari Z, Saeedian B, Peiman S, Berger NA, Behnoush AH. Unveiling the Ghrelin and Obestatin Roles in Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis Assessing Their Pathogenic Implications and Biomarker Utility. Inflamm Bowel Dis 2024; 30:629-640. [PMID: 37669127 DOI: 10.1093/ibd/izad202] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Inflammatory bowel disease (IBD), pathologically known as chronic inflammation of the gastrointestinal tract, is among the diseases with a high burden worldwide. Ghrelin and obestatin, as adipocytokines mainly in adipose tissues, are involved in immune responses and inflammatory pathways. Studies have assessed the circulatory ghrelin levels in patients with IBD. Herein, we aim to pool these studies through systematic review and meta-analysis. METHODS Four international databases, PubMed, Embase, Scopus, and the Web of Science were systematically searched for studies assessing ghrelin or obestatin levels in patients with IBD (either Crohn's disease [CD] or ulcerative colitis [UC]) in active phase or in remission. Random-effects meta-analysis was conducted in order to calculate the pooled estimate using the standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS Nineteen studies were included in our systematic review, comprising 1064 patients with IBD (476 UC and 588 CD). A meta-analysis of 11 studies for comparison of active and quiescent disease showed that patients with active IBD had significantly higher levels of ghrelin (SMD, 0.70; 95% CI, 0.06 to 1.34; P = .03). However, in separate analyses for UC or CD, no such difference was observed (SMD, 1.30; 95% CI, -0.28 to 2.88, P = .11; and SMD, 0.80; 95% CI, -0.41 to 2.01; P = .20, respectively). No significant difference was also observed in ghrelin levels between patients with active IBD and healthy control subjects. Obestatin levels also were not different between patients with active disease and those in remission (SMD, 0.31; 95% CI, -0.05 to 0.68; P = .09). On the other hand, the obestatin/ghrelin ratio was significantly lower in patients with active IBD (SMD, -1.90; 95% CI, -2.45 to -1.35; P < .01). CONCLUSIONS Our results demonstrate that IBD patients with active disease have higher levels of ghrelin, which needs to be confirmed in future studies. Also, the obestatin/ghrelin ratio might be a promising biomarker for the assessment of disease activity.
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Affiliation(s)
| | - Nastaran Babajani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Amirsardari
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Behrad Saeedian
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheil Peiman
- Department of Internal Medicine, AdventHealth Orlando Hospital, Orlando, FL, USA
| | - Nathan A Berger
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
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Wang Z, Zhu D, Zhu X, Liu D, Cao Q, Pan T, Zhang Q, Gu X, Li L, Teng G. Interventional metabology: A review of bariatric arterial embolization and endovascular denervation for treating metabolic disorders. J Diabetes 2023; 15:665-673. [PMID: 37438984 PMCID: PMC10415876 DOI: 10.1111/1753-0407.13437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 05/12/2023] [Accepted: 06/06/2023] [Indexed: 07/14/2023] Open
Abstract
The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin-producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called "Interventional Metabology" to encompass these and other interventional approaches to treating metabolic disorders.
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Affiliation(s)
- Zhi Wang
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Dan‐Qi Zhu
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Xiang‐Yun Zhu
- Department of Endocrinology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
- Institute of PancreasSoutheast UniversityNanjingChina
| | - De‐Chen Liu
- Department of Endocrinology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
- Institute of PancreasSoutheast UniversityNanjingChina
| | - Qing‐Yue Cao
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Tao Pan
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Qi Zhang
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Xiao‐Chun Gu
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
- Institute of PancreasSoutheast UniversityNanjingChina
| | - Gao‐Jun Teng
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
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Huang J, Zhang K, Wang F, Tang X. The Associations between Helicobacter Pylori immunoglobulin G seropositivity and body mass index in adults. BMC Infect Dis 2023; 23:485. [PMID: 37474887 PMCID: PMC10360307 DOI: 10.1186/s12879-023-08427-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/26/2023] [Indexed: 07/22/2023] Open
Abstract
OBJECTIVES Inconsistent evidence currently exists regarding the associations between Helicobacter Pylori (H. pylori) infection and body mass index (BMI). The goal of the current study was to examine independent associations of H. pylori immunoglobulin G (IgG) seropositivity and BMI in a U.S.-based population sample. METHODS The US National Health and Nutrition Examination Survey (NHANES) with 2,576 subjects from 1999 to 2000 were analyzed. Using multivariate logistic regression models, associations between H. pylori IgG seropositivity and BMI were calculated after potential confounders were taken into account. Subgroup analyses were conducted furtherly stratified by sex, age, and race. RESULTS H. pylori IgG seropositivity was not associated with BMI in the general population (OR = 0.998; 95% CI = 0.977-1.019; P = 0.842). In the subgroup analyses stratified by race, a negative correction was found between the H. pylori IgG seropositivity and BMI among other races (OR = 0.873; 95% CI = 0.795-0.959; P = 0.004) except non-Hispanic white (OR = 1.006, 95% CI 0.966 to 1.048, P = 0.762), non-Hispanic black (OR = 1.021, 95% CI 0.979 to 1.065, P = 0.335), and Mexican American (OR = 1.010, 95% CI 0.966 to 1.055, P = 0.665). CONCLUSIONS In the general population, H. pylori IgG seropositivity is not associated with increased BMI, which provides a new perspective on obesity management.
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Affiliation(s)
- Jinke Huang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Kunli Zhang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengyun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xudong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
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Kono H, Hosomura N, Amemiya H, Shoda K, Furuya S, Akaike H, Kawaguchi Y, Kawaida H, Ichikawa D. Rikkunshito increases appetite by enhancing gastrointestinal and incretin hormone levels in patients who underwent pylorus-preserving pancreaticoduodenectomy: A retrospective study. World J Gastrointest Surg 2023; 15:871-881. [PMID: 37342846 PMCID: PMC10277958 DOI: 10.4240/wjgs.v15.i5.871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/22/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Rikkunshito (TJ-43) relieves gastrointestinal disturbance by increases in the levels of acylated ghrelin.
AIM To investigate the effects of TJ-43 in patients undergoing pancreatic surgery.
METHODS Forty-one patients undergoing pylorus-preserving pancreaticoduodenectomy (PpPD) were divided into two groups; patients took daily doses of TJ-43 after surgery or after postoperative day (POD) 21. The plasma levels of acylated and desacylated ghrelin, cholecystokinin (CCK), peptide YY (PYY), gastric inhibitory peptide (GIP), and active glucagon-like peptide (GLP)-1 were evaluated. Oral calorie intake was assessed at POD 21 in both groups. The primary endpoint of this study was the total food intake after PpPD.
RESULTS The levels of acylated ghrelin were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration at POD 21, and oral intake was significantly increased in patients treated with TJ-43. The CCK and PYY levels were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 treatment. Furthermore, the GIP and active GLP-1 levels increased and values at POD 21 were significantly greater in patients treated with TJ-43 than those in patients without TJ-43 administration. Insulin secretion tended to increase in patients treated with TJ-43.
CONCLUSION TJ-43 may have advantages for oral food intake in patients in the early phase after pancreatic surgery. Further investigation is needed to clarify the effects of TJ-43 on incretin hormones.
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Affiliation(s)
- Hiroshi Kono
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Naohiro Hosomura
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Hidetake Amemiya
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Katsutoshi Shoda
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Shinji Furuya
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Hidenori Akaike
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Yoshihiko Kawaguchi
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Hiromichi Kawaida
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
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Raghay K, Akki R, Bensaid D, Errami M. Ghrelin as an anti-inflammatory and protective agent in ischemia/reperfusion injury. Peptides 2020; 124:170226. [PMID: 31786283 DOI: 10.1016/j.peptides.2019.170226] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 11/27/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023]
Abstract
Ischemia/reperfusion (I/R) continue to be the most frequent cause of damaged tissues. Injured tissues resulted from the first ischemic insult, which is determined by the interruption in the blood supply, followed by subsequent impairment induced by reperfusion. In addition, ischemia-reperfusion injury is mediated by tumor necrosis factor (TNF) and other cytokines that activate complements and proteases responsible for free radical production. However, earlier studies have reported the protective roles of bioactive peptides during ischemia reperfusion injury. In fact, ghrelin is a peptide hormone discovered since 1999 as GH secretagogue and its production was identified in gastric X/A-like endocrine cells in rats and P/D1 type cells in humans. To date, this peptide receives growing attention due to its pleiotropic action in the organism and its role in maintaining energy homeostasis. Ghrelin is also involved in stress responses, assuming a modulatory action on immune pathways. Previous studies have identified many other functions related to an anti-inflammatory role in ischemia reperfusion injury. Under these challenging conditions, studies described acylated and unacylated ghrelin in activation and/or inhibition processes related to ischemia-reperfusion injury. The aim of this article is to provide a minireview about ghrelin mechanisms involved in the proinflammatory response of I/R injury. However, the regulatory processes of ghrelin in this pathologic event are still very limited and warrant further investigation.
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Affiliation(s)
- K Raghay
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - R Akki
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - D Bensaid
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
| | - M Errami
- Department of Biology, Faculty of Sciences, Abdelmalek Essaadi University, Tetouan, Morocco.
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Abstract
Purpose of Review Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. Recent Findings Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of “salt-induced obesity”; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. Summary SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.
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Wanyama R, Obai G, Odongo P, Kagawa M, Baingana R. Effect of maternal Helicobacter Pylori infection on gestational weight gain in an urban community of Uganda. Pan Afr Med J 2017. [PMID: 29541293 PMCID: PMC5847056 DOI: 10.11604/pamj.2017.28.145.9989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Introduction Maternal Helicobacter pylori (H. pylori) infection has been associated with undesirable effects during pregnancy such as; hyperemesis gravidarum, anemia, intrauterine fetal growth restriction and miscarriage. Our aim was to document the effect of H. pylori infection on gestational weight gain (GWG) in a low-income urban setting in Uganda. Methods This was a prospective cohort study conducted in Kampala between May 2012 and May 2013. The participants were HIV negative, H. pylori positive and H. pylori negative primigravidae and secundigravidae. Recruitment was at gestation age of eighteen or less weeks and follow up assessments were carried out at 26 and 36 weeks gestation age. H. pylori infection was determined using H. pylori stool antigen test. Maternal weight and height were measured, and body mass index (BMI) and rates of GWG were calculated. Results The participants’ mean±standard deviation (sd) age was 20.9±2.7 years. Primigravidae were 68.8% (n = 132) and 57.3% (n = 110) of the participants were positive for H. pylori infection. Low pre-women pregnancy BMI (< 18.5 kg/m2) was recorded in 14.6% (n = 28). The mean±sd rate of GWG during second and third trimesters was 300.5±79.7 grams/week. The mean±sd weight gained by 36 weeks of gestation was 9.6±2.2 kg while gestation age at delivery was 39.4±1.0 weeks. Factors independently associated with the rates of GWG during the second and third trimesters were parity (P=0.023), H. pylori infection (P = 0.006), pre-pregnancy BMI (P = 0.037), height (P = 0.022) and household income (P = 0.003). Conclusion H. pylori infection is associated with low rates of GWG among primigravidae and secundigravidae.
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Affiliation(s)
- Ronald Wanyama
- Department of Biochemistry, Faculty of Medicine, Gulu University, Gulu, Uganda
| | - Gerald Obai
- Department of Physiology, Faculty of Medicine, Gulu University, Gulu, Uganda
| | - Pancras Odongo
- Department of Internal Medicine, Faculty of Medicine, Gulu University, Gulu, Uganda
| | - Michael Kagawa
- Department of Obstetrics & Gynecology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Rhona Baingana
- Department of Biochemistry and Sports Science, School of Biolsciences, Makerere University, Kampala, Uganda
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9
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Abstract
The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for metabolic diseases. The present overview connects various metabolic research lines into an integrative physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement of the gut in the metabolic syndrome derives from the powerful effects of weight-reducing (bariatric) gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment option for type 2 diabetes in obesity. Several gut-related mechanisms that potentially contribute to the metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety-signalling gut hormones, reduced meal-associated energy expenditure and microbiota-assisted harvest of energy from nondigestible food ingredients. Adiposity per se is a well-established risk factor for hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state. The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride-rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the future, the metabolic syndrome will be treated according to novel pharmacological principles interfering with gastrointestinal functionality.
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Affiliation(s)
- L Fändriks
- Department of Gastrosurgical Research and Education, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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10
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Kipshidze N, Prakash A, Kipshidze N, Chakhunashvili D, Kakabadze Z. A Novel Endoscopic Bariatric Procedure: Results of an Experimental Study. Obes Surg 2016; 26:3058-3065. [PMID: 27718177 DOI: 10.1007/s11695-016-2389-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Surgical treatment of obesity is characterized by both early and late complications, and thus, there is a need to develop safe and non-invasive techniques. Ghrelin is an orexigenic hormone produced by the fundus of the stomach, which may represent a novel target for obesity management. Unfortunately, numerous attempts to alter ghrelin levels have failed to present significant clinical results. We describe a novel procedure that involves modifying arterial blood flow to the gastric fundus for limiting plasma ghrelin levels. METHODS A gastroscope was advanced into the gastric fundus of 13 healthy Yorkshire swine, and the fundus was clipped under direct visualization to restrict left gastric artery blood flow. Body weights and ghrelin levels were recorded before and once a week for 4 weeks after the procedure. RESULTS Compared to controls, gastroscopic clipping of the fundus decreased plasma ghrelin levels and prevented further weight gain in the 4 weeks of follow-up. Immunohistochemistry and histomorphometry revealed reduced numbers of ghrelin-positive cells in the fundus of experimental animals. We also observed thrombosis in submucosal arteries and submucosal fibrosis. Histological studies demonstrated minimal gastric mucosal injury. CONCLUSION Gastroscopic clipping of the fundus in an experimental porcine model resulted in sustained weight loss and a reduction in plasma ghrelin levels at 1 month post-procedure, with no adverse events. Further experimental studies in human patients are needed to examine the clinical utility of this procedure and to optimize a technique, which can facilitate adequate weight loss while minimizing the risk of mucosal injury.
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Affiliation(s)
- Nickolas Kipshidze
- New York Cardiovascular Research, 1726 2nd Ave., Suite 4S, New York, NY, 10028, USA. .,N. Kipshidze Central University Hospital, 29 Vazha Pshavela Ave, Tbilisi, Georgia.
| | - Anaka Prakash
- NJ Medical Health Associates, 1 Journal Square Plz. Ste. 2, Jersey City, NJ, USA
| | - Nodar Kipshidze
- New York Cardiovascular Research, 1726 2nd Ave., Suite 4S, New York, NY, 10028, USA.,College of Global Public Health, New York University, New York, NY, USA
| | | | - Zurab Kakabadze
- Tbilisi State Medical University, 7 Mikheli Asatianti St, Tbilisi, Georgia
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11
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Emmanuel A. Current management of the gastrointestinal complications of systemic sclerosis. Nat Rev Gastroenterol Hepatol 2016; 13:461-72. [PMID: 27381075 DOI: 10.1038/nrgastro.2016.99] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic sclerosis is a multisystem autoimmune disorder that involves the gastrointestinal tract in more than 90% of patients. This involvement can extend from the mouth to the anus, with the oesophagus and anorectum most frequently affected. Gut complications result in a plethora of presentations that impair oral intake and faecal continence and, consequently, have an adverse effect on patient quality of life, resulting in referral to gastroenterologists. The cornerstones of gastrointestinal symptom management are to optimize symptom relief and monitor for complications, in particular anaemia and malabsorption. Early intervention in patients who develop these complications is critical to minimize disease progression and improve prognosis. In the future, enhanced therapeutic strategies should be developed, based on an ever-improving understanding of the intestinal pathophysiology of systemic sclerosis. This Review describes the most commonly occurring clinical scenarios of gastrointestinal involvement in patients with systemic sclerosis as they present to the gastroenterologist, with recommendations for the suggested assessment protocol and therapy in each situation.
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Affiliation(s)
- Anton Emmanuel
- Gastrointestinal Physiology Unit, University College Hospital, 235 Euston Road, London NW1 2BU, UK
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12
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Affiliation(s)
| | - William Snape
- California Pacific Medical Center, San Francisco, California
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13
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Weiss CR, Gunn AJ, Kim CY, Paxton BE, Kraitchman DL, Arepally A. Bariatric embolization of the gastric arteries for the treatment of obesity. J Vasc Interv Radiol 2015; 26:613-24. [PMID: 25777177 DOI: 10.1016/j.jvir.2015.01.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 01/13/2015] [Accepted: 01/13/2015] [Indexed: 12/31/2022] Open
Abstract
Obesity is a public health epidemic in the United States that results in significant morbidity, mortality, and cost to the health care system. Despite advancements in therapeutic options for patients receiving bariatric procedures, the number of overweight and obese individuals continues to increase. Therefore, complementary or alternative treatments to lifestyle changes and surgery are urgently needed. Embolization of the left gastric artery, or bariatric arterial embolization (BAE), has been shown to modulate body weight in animal models and early clinical studies. If successful, BAE represents a potential minimally invasive approach offered by interventional radiologists to treat obesity. The purpose of the present review is to introduce the interventional radiologist to BAE by presenting its physiologic and anatomic bases, reviewing the preclinical and clinical data, and discussing current and future investigations.
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Affiliation(s)
- Clifford R Weiss
- Vascular and Interventional Radiology Center, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital/The Johns Hopkins University, Baltimore, Maryland.
| | - Andrew J Gunn
- Vascular and Interventional Radiology Center, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital/The Johns Hopkins University, Baltimore, Maryland
| | - Charles Y Kim
- Department of Vascular and Interventional Radiology, Duke University Medical Center, Durham, North Carolina
| | - Ben E Paxton
- Department of Interventional Radiology, Yavapai Regional Medical Center, Prescott, Arizona
| | - Dara L Kraitchman
- Division of MR Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital/The Johns Hopkins University, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, Maryland
| | - Aravind Arepally
- Division of Interventional Radiology, Piedmont Radiology, Atlanta, Georgia
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Paxton BE, Alley CL, Crow JH, Burchette J, Weiss CR, Kraitchman DL, Arepally A, Kim CY. Histopathologic and immunohistochemical sequelae of bariatric embolization in a porcine model. J Vasc Interv Radiol 2014; 25:455-61. [PMID: 24462005 DOI: 10.1016/j.jvir.2013.09.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 09/24/2013] [Accepted: 09/25/2013] [Indexed: 02/07/2023] Open
Abstract
PURPOSE To evaluate the histopathologic sequelae of bariatric embolization on the gastric mucosa and to correlate with immunohistochemical evaluation of the gastric fundus, antrum, and duodenum. MATERIALS AND METHODS This study was performed on 12 swine stomach and duodenum specimens after necropsy. Of the 12 swine, 6 had previously undergone bariatric embolization of the gastric fundus, and the 6 control swine had undergone a sham procedure with saline. Gross pathologic, histopathologic, and immunohistochemical examinations of the stomach and duodenum were performed. Specifically, mucosal integrity, fibrosis, ghrelin-expressing cells, and gastrin-expressing cells were assessed. RESULTS Gross and histopathologic evaluation of treatment animals showed healing or healed mucosal ulcers in 50% of animals, with gastritis in 100% of treatment animals and in five of six control animals. The ghrelin-immunoreactive mean cell density was significantly lower in the gastric fundus in the treated animals compared with control animals (15.3 vs 22.0, P < .01) but similar in the gastric antrum (9.3 vs 14.3, P = .08) and duodenum (8.5 vs 8.6, P = .89). The gastrin-expressing cell density was significantly lower in the antrum of treated animals compared with control animals (82.2 vs 126.4, P = .03). A trend toward increased fibrosis was suggested in the gastric fundus of treated animals compared with controls (P = .07). CONCLUSIONS Bariatric embolization resulted in a significant reduction in ghrelin-expressing cells in the gastric fundus without evidence of upregulation of ghrelin-expressing cells in the duodenum. Healing ulcerations in half of treated animals underscores the need for additional refinement of this procedure.
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Affiliation(s)
- Ben E Paxton
- Division of Vascular and Interventional Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710.
| | - Christopher L Alley
- Department of Pathology, Duke University Medical Center, Box 3808, Durham, NC 27710
| | - Jennifer H Crow
- Department of Pathology, Duke University Medical Center, Box 3808, Durham, NC 27710
| | - James Burchette
- Department of Pathology, Duke University Medical Center, Box 3808, Durham, NC 27710
| | - Clifford R Weiss
- The Russell H. Morgan Department of Radiology and Radiologic Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Dara L Kraitchman
- The Russell H. Morgan Department of Radiology and Radiologic Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Charles Y Kim
- Division of Vascular and Interventional Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710
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15
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Paxton BE, Kim CY, Alley CL, Crow JH, Balmadrid B, Keith CG, Kankotia RJ, Stinnett S, Arepally A. Bariatric embolization for suppression of the hunger hormone ghrelin in a porcine model. Radiology 2012. [PMID: 23204538 DOI: 10.1148/radiol.12120242] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To prospectively test in a porcine model the hypothesis that bariatric embolization with commercially available calibrated microspheres can result in substantial suppression of systemic ghrelin levels and affect weight gain over an 8-week period. MATERIALS AND METHODS The institutional animal care and use committee approved this study. Twelve healthy growing swine (mean weight, 38.4 kg; weight range, 30.3-47.0 kg) were evaluated. Bariatric embolization was performed by infusion of 40-μm calibrated microspheres selectively into the gastric arteries that supply the fundus. Six swine underwent bariatric embolization, while six control animals underwent a sham procedure with saline. Weight and fasting plasma ghrelin and glucose levels were obtained in animals at baseline and at weeks 1-8. Statistical testing for differences in serum ghrelin levels and weight at each time point was performed with the Wilcoxon signed rank test for intragroup differences and the Wilcoxon rank sum test for intergroup differences. RESULTS The pattern of change in ghrelin levels over time was significantly different between control and experimental animals. Weekly ghrelin levels were measured in control and experimental animals as a change from baseline ghrelin values. Average postprocedure ghrelin values increased by 328.9 pg/dL ± 129.0 (standard deviation) in control animals and decreased by 537.9 pg/dL ± 209.6 in experimental animals (P = .004). The pattern of change in weight over time was significantly different between control and experimental animals. The average postprocedure weight gain in experimental animals was significantly lower than that in control animals (3.6 kg ± 3.8 vs 9.4 kg ± 2.8, respectively; P = .025). CONCLUSION Bariatric embolization can significantly suppress ghrelin and significantly affect weight gain. Further study is warranted before this technique can be used routinely in humans.
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Affiliation(s)
- Ben E Paxton
- Department of Vascular, Duke University, Durham, NC, USA
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16
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Nikolic M, Boban M, Ljubicic N, Supanc V, Mirosevic G, Pezo Nikolic B, Krpan R, Posavec L, Zjacic-Rotkvic V, Bekavac-Beslin M, Gacina P. Morbidly obese are ghrelin and leptin hyporesponders with lesser intragastric balloon treatment efficiency : ghrelin and leptin changes in relation to obesity treatment. Obes Surg 2012; 21:1597-604. [PMID: 21494811 DOI: 10.1007/s11695-011-0414-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Ghrelin and leptin recently emerged as the most influential neuroendocrine factors in the pathophysiology of obesity. The said peptides act in reciprocity and are responsible for regulation of appetite and energy metabolism. Intragastric balloons acquired worldwide popularity for obesity treatment. However, the roles of ghrelin and leptin in intragastric balloon treatment were still not systematically studied. METHODS A prospective single-center study included 43 Caucasians treated with BioEnterics intragastric balloon, with age range of 18-60, and divided to non-morbid (body mass index cutoff 40 kg/m(2)) or morbid type of obesity, with 12 months follow-up. Serum hormonal samples were taken from fasting patients and kept frozen until analyses. RESULTS Significant differences were observed in anthropometrics and there were no differences between genders or comorbidities. The baseline weight for non-morbid vs. morbid was 104 kg (90-135) vs. 128.5 kg (104-197). Weight loss was statistically different between the studied groups during the study course with a median control weight at 6 months of 92 kg (72-121) vs. 107 kg (84-163), p < 0.001. Treatment was successful for 18 (94.7%) vs. 16 (66.7%) patients, p = 0.026. Ghrelin varied from 333.3 to 3,416.8 pg/ml and leptin from 1.7 to 61.2 ng/ml, with a statistically significant time-dependent relationship. A significant difference (p = 0.04) with emphasized ghrelin peak was found in the 3rd month of treatment for non-morbidly obese subjects. CONCLUSIONS The importance of ghrelin and leptin in treatment-induced changes was reaffirmed. Ghrelin hyper-response in non-morbidly obese subjects characterized greater short-term treatment efficiency and landmarked an inclination to weight regain. The results suggest a potential pattern of individualization between obese patients according to body mass index towards intragastric balloon or bariatric surgery. Further studies are needed in order to get better insights in the pathophysiologic mechanisms of obesity.
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Affiliation(s)
- Marko Nikolic
- Interventional Gastroenterology Unit, Department of Internal Medicine, University Hospital Centre "Sestre Milosrdnice", Vinogradska 29, Zagreb, 10000, Croatia.
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17
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Kizaki T, Maegawa T, Sakurai T, Ogasawara JE, Ookawara T, Oh-ishi S, Izawa T, Haga S, Ohno H. Voluntary exercise attenuates obesity-associated inflammation through ghrelin expressed in macrophages. Biochem Biophys Res Commun 2011; 413:454-9. [PMID: 21907183 DOI: 10.1016/j.bbrc.2011.08.117] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 08/25/2011] [Indexed: 12/21/2022]
Abstract
Chronic low-level inflammation is associated with obesity and a sedentary lifestyle, causing metabolic disturbances such as insulin resistance. Exercise training has been shown to decrease chronic low-level systemic inflammation in high-fat diet (HFD)-induced obesity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Ghrelin is a peptide hormone predominantly produced in the stomach that stimulates appetite and induces growth hormone release. In addition to these well-known functions, recent studies suggest that ghrelin localizes to immune cells and exerts an anti-inflammatory effect. The purpose of the current study was to investigate the role of ghrelin expressed in macrophages in the anti-inflammatory effects of voluntary exercise training. Expression of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP)-1 and F4/80 was increased in adipose tissue from mice fed a HFD (HFD mice) compared with mice fed a standard diet (SD mice), whereas the expression of these inflammatory cytokines was markedly decreased in mice performing voluntary wheel running during the feeding of a HFD (HFEx mice). The expression of TNF-α was also increased in peritoneal macrophages by a HFD and exercise training inhibited the increase of TNF-α expression. Interestingly, expression of ghrelin in peritoneal macrophages was decreased by a HFD and recovered by exercise training. Suppression of ghrelin expression by siRNA increased TNF-α expression and LPS-stimulated NF-κB activation in RAW264 cells, which is a macrophage cell line. TNF-α expression by stimulation with LPS was significantly suppressed in RAW264 cells cultured in the presence of ghrelin. These results suggest that ghrelin exerts potent anti-inflammatory effects in macrophages and functions as a mediator of the beneficial effects of exercise training.
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Affiliation(s)
- Takako Kizaki
- Department of Molecular Predictive Medicine and Sport Science, Kyorin University, School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
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18
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He J, David IM, Zhang Y. Gene duplication plays a major role in gene co-option: Studies into the evolution of the motilin/ghrelin family and their receptors. ACTA ACUST UNITED AC 2011. [DOI: 10.1007/s11434-011-4614-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Ghoshal UC, Singh R, Chang FY, Hou X, Wong BCY, Kachintorn U, Functional Dyspepsia Consensus Team of the Asian Neurogastroenterology and Motility Association and the Asian Pacific Association of Gastroenterology. Epidemiology of uninvestigated and functional dyspepsia in Asia: facts and fiction. J Neurogastroenterol Motil 2011; 17:235-244. [PMID: 21860815 PMCID: PMC3155059 DOI: 10.5056/jnm.2011.17.3.235] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2011] [Revised: 06/15/2011] [Accepted: 06/15/2011] [Indexed: 01/06/2023] Open
Abstract
Dyspepsia is a syndrome consisting of epigastric pain, burning, fullness, discomfort, early satiety, nausea, vomiting and belching. Functional dyspepsia (FD) is diagnosed if upper gastrointestinal endoscopy does not show structural abnormality explaining these symptoms. 8%-30% and 8%-23% of Asian people suffer from of uninvestigated dyspepsia and FD, respectively. Most patients with uninvestigated dyspepsia are found to have FD. Patients with FD are usually young and there is no predilection to any gender. Overlap of FD with other functional bowel diseases such as irritable bowel syndrome and gastroesophageal reflux disease is common in Asia. Cultural difference in reporting of symptoms of dyspepsia is well-known. Moreover, dietary factors, socio-cultural and psychological issues, gastrointestinal infection including that caused by Helicobacter pylori, frequency of organic diseases such as peptic ulcer and gastric cancer responsible for dyspeptic symptoms in the study population may also influence epidemiology of dyspepsia. There is considerable heterogeneity in the above issues among different Asian countries. More studies on epidemiology of FD are needed in Asia.
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Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rajan Singh
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Full-Young Chang
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Udom Kachintorn
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Afsar B, Elsurer R, Huddam B, Erden C. Helicobacter pylori Infection: Protective Against Increased Interdialytic Weight Gain in Asymptomatic Hemodialysis Patients? J Ren Nutr 2011; 21:322-8. [DOI: 10.1053/j.jrn.2010.06.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 06/14/2010] [Accepted: 06/29/2010] [Indexed: 01/17/2023] Open
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Suzuki H, Matsuzaki J, Hibi T. Ghrelin and oxidative stress in gastrointestinal tract. J Clin Biochem Nutr 2011; 48:122-5. [PMID: 21373264 PMCID: PMC3045684 DOI: 10.3164/jcbn.10-16gfr] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 02/23/2010] [Indexed: 12/22/2022] Open
Abstract
Oxidative stress is a major cause of the gastrointestinal damage under physical or psychological stress. Ghrelin exhibits gastroprotective effects and they are supposed to be derived from antioxidant effects. In gastroduodenal mucosal injury, the plasma ghrelin levels increase in response to the demand for gastroduodenal cytoprotection. However, in the condition of Helicobacter pylori-induced gastric mucosal severe atrophy, the plasma ghrelin concentration shifted to lower levels. In diabetic gastroparesis, the regulation of ghrelin secretion is impaired with vagal nerve dysfunction. Selective ghrelin agonist is expected to represent a new class of prokinetic agent. In addition, the plasma ghrelin levels are also enhanced by systemic oxidative stress, and ghrelin exhibits antioxidant effects in many organs, such as heart, pancreas, and lung. This suggests that ghrelin would be an important player as a sensor of systemic oxidative stress.
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Affiliation(s)
- Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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22
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Ozen A, Furman A, Berber M, Karatepe HO, Mutlu N, Sarıçoban HE, Büyükgebiz B. The effect of Helicobacter pylori and economic status on growth parameters and leptin, ghrelin, and insulin-like growth factor (IGF)-I concentrations in children. Helicobacter 2011; 16:55-65. [PMID: 21241414 DOI: 10.1111/j.1523-5378.2010.00814.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND It was suggested that gastric colonization with Helicobacter pylori (H. pylori) was associated with suboptimal nutrition and growth in childhood. Furthermore, several studies indicated a relationship between H. pylori colonization and alterations in the circulating levels of growth-related molecules (GRM). Accordingly, in this study, we investigate the effect of H. pylori infection on GRMs and on the growth of healthy school children, taking into consideration the effect of their economic status (ES) and anthropometric indices of their parents. METHODS To acquire sociodemographic and anthropometric nutritional parameters and to detect H. pylori-specific serum IgG antibodies and growth-related molecules, we evaluated a total of 473 children attending four different primary and secondary schools in Istanbul. Subsequently, we assessed the effect of H. pylori on growth-related parameters (weight for age SDS, height for age SDS, BMI SDS, TSF, and waist-to-hip ratio) and on GRMs (leptin, ghrelin, and insulin-like growth factor-1 (IGF-1)), controlling for age, gender, family income, household crowding (HC), breastfeeding, maternal and paternal BMI SDS, and midparental height SDS with complex statistical models. RESULTS Of the 473 children (275 F/198 M, age 6-15 years; mean: 10.3 ± 0.1 years), 161 (34%) were H. pylori-positive. The prevalence of H. pylori was significantly higher in lower economic status (ES) groups, in children living in crowded houses, and in older age groups. Using simple statistical models, we did not find any significant associations between H. pylori infection and the growth parameters. However, in complex models for height for age SDS and for weight for age SDS, there was a significant interaction between H. pylori infection status and ES. Whereas in H. pylori-positive subjects, mid-income family children were both taller and heavier than the low-income group, there was no such an association in H. pylori-negative subjects. Among biochemical parameters, only ghrelin levels were associated with H. pylori infection in all models. Leptin levels were associated with HC in girls, whereas none of the parameters was significantly associated with leptin levels in boys. For IGF-1 levels, for boys, age and maternal BMI, and for girls, age and HC were significantly associated with IGF-1 levels. CONCLUSION We suggest that H. pylori may impair growth significantly only in susceptible children where unfavorable socioeconomic conditions facilitate its action, probably through mechanisms, at least in part, involving growth-related molecules.
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Affiliation(s)
- Ahmet Ozen
- Department of Pediatrics, Medical Faculty, Yeditepe University
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He J, Irwin MD, Zhang Y. Motilin and ghrelin gene experienced episodic evolution during primitive placental mammal evolution. SCIENCE CHINA. LIFE SCIENCES 2010; 53:677-82. [PMID: 20602270 DOI: 10.1007/s11427-010-3105-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2009] [Accepted: 12/02/2009] [Indexed: 11/28/2022]
Abstract
Motilin and ghrelin, members of a structure-function-related hormone family, play important roles in gastrointestinal function, regulation of energy homeostasis and growth hormone secretion. We observed episodic evolution in both of their prehormone gene sequences during primitive placental mammal evolution, during which most of the nonsynonymous changes result in radical substitution. Of note, a functional obestatin hormone might have only originated after this episodic evolution event. Early in placental mammal evolution, a series of biology complexities evolved. At the same time the motilin and ghrelin prehormone genes, which play important roles in several of these processes, experienced episodic evolution with dramatic changes in their coding sequences. These observations suggest that some of the lineage-specific physiological adaptations are due to episodic evolution of the motilin and ghrelin genes.
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Affiliation(s)
- Jing He
- State Key Laboratory of Genetic Resource and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
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24
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The activity of gastric ghrelin positive cells in obese patients treated surgically. Folia Histochem Cytobiol 2010; 47:307-13. [PMID: 19995718 DOI: 10.2478/v10042-009-0033-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ghrelin is a 28 amino acid peptide hormone regulating food intake and stimulating releasement of growth hormone. It is produced in a distinct endocrine call known as X/A - like cells. The most abundant source of this very important factor in energy homeostasis is gastric fundus. Regulatory mechanisms of ghrelin synthesis and secretion in physiological and pathological states are not discovered completely. The aim of our study was evaluation of the activity of gastric X/A-like cells in obese patients before and after the most popular surgical bariatric procedures - Roux - Y Gastric Bypass (RYGB) and Laparoscopic Adjustable Gastric Banding (LAGB). Obese patients in number 18 took part in the study. LAGB was performed in 7 patients and RYGB in 11 patients. Peripheral blood was taken from each patient before operation and first day, seventh day, one month and three months after surgery. Ghrelin level was determined by RIA technique. The specimen of stomach was taken from circular stapler after gastrojejunostomy during RYGB and immunohistochemical study of gastric mucosa, using the EnVision method and specific monoclonal antybodies against ghrelin was performed. The intensity of ghrelin-immunoreactivity in X/A-like cells was analyzed using Olympus Cell D image analysis system. Efficiency of bariatric procedures was estimated by EWL- excess weight loss. We observed very strong immunohistochemical reactions of gastric X/A-like cells, accompanied by lower ghrelin plasma concentration, in comparison to the control group. LAGB procedure induced increase of ghrelin plasma level while RYGB procedure induced decrease of this hormone. The main finding of the present study is the hypoactivity of gastric X/A-like cells in obese patients in comparison to the control group.
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Kellokoski E, Kummu O, Serpi R, Lehenkari P, Ukkola O, Kesäniemi YA, Hörkkö S. Ghrelin vaccination decreases plasma MCP-1 level in LDLR(-/-)-mice. Peptides 2009; 30:2292-300. [PMID: 19751783 DOI: 10.1016/j.peptides.2009.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Revised: 08/28/2009] [Accepted: 09/04/2009] [Indexed: 12/11/2022]
Abstract
Ghrelin is a novel peptide hormone having growth hormone releasing activity and many endocrine and metabolic functions. In rats and pigs, ghrelin immunizations have recently been shown to induce an antibody response against ghrelin simultaneously with a decrease in body weight gain. Our aim was to test the role of ghrelin immunization on atherosclerosis and weight gain in mice. LDLR(-/-)-mice (n=36) were immunized with ghrelin-PADRE, PADRE alone and PBS and then placed on a high fat diet for 22 weeks. Weight gain and food intake were followed throughout the study. Acylated and total ghrelin, cytokines and MCP-1 were analyzed from plasma using commercial kits. Stomach ghrelin was assessed using qRT-PCR and immunohistochemistry. Atherosclerosis was determined from aorta and cross-sections at the end of study. Mice immunized with ghrelin-PADRE developed high plasma IgG titers to ghrelin simultaneously with a significant increase in plasma acylated and total ghrelin levels. Plasma MCP-1 levels decreased in mice immunized with ghrelin-PADRE compared to mice immunized with PADRE and PBS. There were no differences in atherosclerosis determined from aorta and cross-sections as well as in body weights and food intake in LDLR(-/-)-mice between the different immunization groups. Our data indicates that ghrelin-PADRE vaccination induces a strong exclusive IgG response to ghrelin and increases plasma acylated and total ghrelin levels in mice. Ghrelin vaccination decreases plasma MCP-1 levels even though no effects on developing signs of atherosclerosis or weight gain in mice were observed.
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Affiliation(s)
- Eija Kellokoski
- Department of Internal Medicine, Institute of Clinical Medicine, Biocenter Oulu, Finland.
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Nikolopoulos D, Theocharis S, Kouraklis G. Ghrelin's role on gastrointestinal tract cancer. Surg Oncol 2009; 19:e2-e10. [PMID: 19328680 DOI: 10.1016/j.suronc.2009.02.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2008] [Revised: 01/10/2009] [Accepted: 02/14/2009] [Indexed: 12/15/2022]
Abstract
Ghrelin is a recently identified 28-amino-acid peptide, with pituitary growth hormone releasing activities in humans and other mammals. In mammals, ghrelin plays a variety of roles, including influence on food intake, gastric motility, and acid secretion of the gastrointestinal tract. It is mainly secreted from the stomach mucosa, but it is also expressed widely in other tissues - in normal and malignant conditions - and, therefore, ghrelin may exert such variable endocrine and paracrine effects, as autocrine and/or paracrine function in cancer. Ghrelin's actions are mediated via its receptor, known as growth hormone secretagogue receptor (GHS-R), type 1a and 1b. Several endocrine and non-endocrine cancers, such as gastro-entero-pancreatic carcinoids, colorectal neoplasms, pituitary adenomas, pulmonary and thyroid tumours, as well as lung, breast, and pancreatic carcinomas express ghrelin at both mRNA and protein levels. In the current review, we summarise the available so far data with regard to: (a) the structure of the ghrelin molecule and its receptor; (b) its tissue contribution in physiologic and neoplasmatic conditions; and (c) ghrelin's possible role in carcinogenesis; specifically, in the area of gastrointestinal tract cancer. The aim of the present study is to determine whether or not ghrelin promotes the proliferation rate of the gastrointestinal tract (GIT) tumours.
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Affiliation(s)
- Dimitrios Nikolopoulos
- 2nd Department of Propedeutic Surgery, University of Athens, Medical School, Laiko General Hospital, Athens, Greece.
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Jang EJ, Park SW, Park JS, Park SJ, Hahm KB, Paik SY, Sin MK, Lee ES, Oh SW, Park CY, Baik HW. The influence of the eradication of Helicobacter pylori on gastric ghrelin, appetite, and body mass index in patients with peptic ulcer disease. J Gastroenterol Hepatol 2008; 23 Suppl 2:S278-85. [PMID: 19120912 DOI: 10.1111/j.1440-1746.2008.05415.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Helicobacter pylori (H. pylori) infection has been known to influence the gastric leptin and ghrelin secretion, for which the exact pathogenic role has not been documented yet. This study was designed to investigate the influence of H. pylori eradication on plasma or gastric levels of ghrelin, body mass index (BMI), and resultant levels of appetite in patients with peptic ulcer disease. METHODS Twenty-two patients with H. pylori-associated active duodenal or gastric ulcer were treated with 7 weeks of antisecretory medication followed with 7 days of eradication regimen. The plasma and tissue ghrelin levels, tumor necrosis factor-alpha (TNF-alpha) mRNA, BMI, and appetite scale were checked before and after treatment. An additional endoscopic examination was conducted in 10 patients taking both ulcer treatment and H. pylori eradication. RESULTS Gastric ghrelin mRNA expression was significantly increased after either ulcer healing or H. pylori eradication, whereas gastric TNF-alpha mRNA expression was decreased after ulcer treatment and H. pylori eradication. In parallel with these changes, the visual analog scales for hunger and prospective food consumption were significantly increased after ulcer healing and H. pylori eradication. An increase in BMI was not statistically related to ulcer healing and H. pylori eradication therapy. In the subgroup analysis of 10 patients performed with additional endoscopic examination, ulcer treatment was associated with increased plasma ghrelin level and tissue ghrelin expression irrelevant to H. pylori eradication. CONCLUSION Restored tissue levels of ghrelin and improved status of appetite was achieved with gastric ulcer healing and H. pylori eradication.
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Affiliation(s)
- Eun Jeong Jang
- Digestive Disease Center, Daejin Medical Center Jesaeng Hospital at Bundang, Bundang-gu, Seongnam, Korea
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Hou Y, An J, Hu XR, Sun BB, Lin J, Xu D, Wang T, Wen FQ. Ghrelin inhibits interleukin-8 production induced by hydrogen peroxide in A549 cells via NF-kappaB pathway. Int Immunopharmacol 2008; 9:120-6. [PMID: 19038366 DOI: 10.1016/j.intimp.2008.10.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2008] [Revised: 10/03/2008] [Accepted: 10/21/2008] [Indexed: 02/05/2023]
Abstract
Ghrelin, a novel growth hormone-releasing peptide, can influence appetite and induce positive energy balances. Previous studies have reported that ghrelin ameliorated inflammatory responses of the heart, liver and pancreas. We examined whether ghrelin inhibits the proinflammatory cytokine interleukin-8 production induced by hydrogen peroxide (H2O2) in human lung epithelia cell line A549 and which mechanism is related with this effect of ghrelin. A549 cells were preincubated with vehicle or ghrelin (0.1 to 1000 ng/mL) in a concentration-dependent manner and then H2O2 (0 to 50 microM) was added. The interleukin-8 released by A549 in the medium was determined by ELISA, the mRNA expressions of interleukin-8 and ghrelin receptor were detected by RT-PCR. We also examined the phosphorylation of NF-kappaB/p65 protein and the degradation of inhibitory protein-kappaB (I-kappaB) in A549 by western blot analysis, the NF-kappaB DNA-binding activity by electrophoretic mobility shift assay, and then detected the generation of reactive oxygen species (ROS) in A549 by nitroblue tetrazolium reduction assay. Cells treated with H2O2 (50 microM) exhibited significantly higher interleukin-8 production and ghrelin receptor mRNA expression compared with cells treated with vehicle alone (P < 0.05). Ghrelin inhibited H2O2-induced interleukin-8 production by A549 at both mRNA and protein levels in a concentration-dependent manner (P < 0.05). Moreover, ghrelin attenuated H2O2-triggered NF-kappaB activation dependent on I-kappaB degradation dose-dependently in A549, but the intracellular ROS level after application of H2O2 was not affected by ghrelin (1000 ng/mL). Together, these results suggest that ghrelin inhibits H2O2-induced interleukin-8 production in A549 cells by targeting on NF-kappaB pathway, but not by directly scavenging intracellular ROS.
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Affiliation(s)
- Yan Hou
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China
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Arepally A, Barnett BP, Patel TH, Patel TT, Howland V, Boston RC, Kraitchman DL, Malayeri AA. Catheter-directed gastric artery chemical embolization suppresses systemic ghrelin levels in porcine model. Radiology 2008; 249:127-33. [PMID: 18796671 DOI: 10.1148/radiol.2491071232] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE To prospectively test, in a porcine model, the hypothesis that catheter-directed gastric artery chemical embolization (GACE) can result in suppression of systemic ghrelin levels and affect weight gain. MATERIALS AND METHODS This study, which had Animal Care and Use Committee approval, was performed in healthy, growing swine (weight range, 40-45 kg; n = 10). GACE was performed in five swine with the infusion of sodium morrhuate (125 mug) selectively into the gastric arteries that supply the fundus. Five control animals underwent a sham procedure with 5 mL of saline. Weight and fasting plasma ghrelin levels were obtained in animals at baseline and in weeks 1-4. Statistical testing for substantial differences in ghrelin blood levels over time and between treated and untreated animals was performed by using a cross-sectional time-series linear model with feasibility generalized least squares. RESULTS The pattern of the change in ghrelin levels over time was significantly different between control and treated animals (P < .004). In treated animals, ghrelin levels were significantly reduced at week 1 (mean, 664.1 pg/mL +/- 103.1 [standard error of the mean], P < .02), week 2 (mean, 618.1 pg/mL +/- 180.4, P < .001), week 3 (mean, 578.4 pg/mL +/- 214.9, P < .001), and week 4 (mean, 876.6 pg/mL +/- 228.6, P < .03) relative to baseline (mean, 1006.3 pg/mL +/- 190.1). The percentage change in serum ghrelin values in swine treated with GACE decreased from baseline to -34%, -38.6%, -42.5%, and -12.9% during weeks 1-4, respectively. In control swine, percentage change in serum ghrelin was -1.7%, -9.7%, +2.6%, and +18.2% during weeks 1-4, respectively. At the end of 4 weeks, control swine continued to gain weight, with a 15.1% increase from their original weight, while the weight in swine treated with GACE plateaued at an increase of 7.8% from the original weight. CONCLUSION Catheter-directed GACE can suppress the appetite hormone ghrelin and affect weight gain.
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Affiliation(s)
- Aravind Arepally
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, 600 N Wolfe St, Blalock 544, Baltimore, MD 21287, USA.
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Gao XY, Kuang HY, Liu XM, Ma ZB, Nie HJ, Guo H. Plasma obestatin levels in men with chronic atrophic gastritis. Peptides 2008; 29:1749-54. [PMID: 18588931 DOI: 10.1016/j.peptides.2008.05.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2008] [Revised: 05/25/2008] [Accepted: 05/28/2008] [Indexed: 11/28/2022]
Abstract
Obestatin is a recently discovered active peptide isolated from the stomach. The purpose of the present study was to investigate the modification of plasma obestatin levels in men with chronic atrophic gastritis. Men older than 65 years undergoing upper gastrointestinal endoscopy were included. All patients with chronic atrophic gastritis underwent multiple biopsies. Fasting plasma obestatin and ghrelin levels were examined in 50 men with chronic atrophic gastritis and 50 healthy men. Plasma obestatin levels were significantly lower in patients with chronic atrophic gastritis than in healthy subjects. Plasma ghrelin levels and ghrelin to obestatin ratio was decreased in men with chronic atrophic gastritis. There was a significant relationship between atrophy and decreased obestatin. A negative correlation was found between circulating obestatin levels and body mass index (BMI) in healthy subjects, but not in patients with chronic atrophic gastritis. The data indicated that chronic atrophic gastritis influenced plasma obestatin levels as well as ghrelin to obestatin ratio in elderly men.
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Affiliation(s)
- Xin-Yuan Gao
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin 150001, China
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31
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Serum ghrelin levels in inflammatory bowel disease with relation to disease activity and nutritional status. Dig Dis Sci 2008; 53:2215-21. [PMID: 18080768 DOI: 10.1007/s10620-007-0113-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2006] [Accepted: 11/05/2007] [Indexed: 01/04/2023]
Abstract
Ghrelin possesses various biological activities -- it stimulates growth hormone (GH) release, plays a major role in energy metabolism, and is one of the hormones that affects body composition. It also plays a role in modulating immune response and inflammatory processes. In this study we aimed to determine whether serum ghrelin levels had correlation with markers associated with disease activation. We also investigated any probable relationship between serum ghrelin level and nutritional status. Serum levels of ghrelin and its relationship with disease activity and nutritional status were evaluated in 34 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 30 healthy controls. Serum ghrelin levels, serum IGF-1 and GH levels, and markers of disease activity (sedimentation, C-reactive protein, and fibrinogen) were measured in all subjects. Body composition and nutritional status was assessed by both direct (by anthropometry) and indirect (by bioimpedance) methods. Serum ghrelin levels were significantly higher in patients with active UC and CD than in those in remission (108 +/- 11 pg/ml vs. 71 +/- 13 pg/ml for UC patients, P < 0.001; 110 +/- 10 pg/ml vs. 75 +/- 15 pg/ml for CD patients, P < 0.001). Circulating ghrelin levels in UC and CD patients were positively correlated with sedimentation, fibrinogen and CRP and was negatively correlated with IGF-1, BMI, TSFT, MAC, fat mass (%), and fat free mass (%). This study demonstrates that patients with active IBD have higher serum ghrelin levels than patients in remission and high levels of circulating ghrelin correlate with the severity of disease and the activity markers. Ghrelin levels in inflammatory bowel disease (IBD) patients show an appositive correlation with IGF-1 and bioelectrical impedance analysis, body composition, and anthropometric assessments. Finally, we arrived at the conclusion that ghrelin level may be important in determination of the activity in IBD patients and evaluation of nutritional status.
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Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 2008; 143:334-42. [PMID: 18291254 PMCID: PMC2278045 DOI: 10.1016/j.surg.2007.09.039] [Citation(s) in RCA: 187] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2007] [Revised: 09/20/2007] [Accepted: 09/27/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ghrelin, an orexigenic 28-amino-acid peptide, has been studied primarily in relation to the control of appetite and fat metabolism. In addition to these well-known functions, ghrelin, and its target receptors, growth hormone secretagogue receptors (GHS-Rs), have been localized to neutrophils, lymphocytes, and macrophages, which suggests that ghrelin may be involved in immune modulation. METHODS To assess the therapeutic role of ghrelin in production of pro-inflammatory and anti-inflammatory cytokines, the effects of exogenous ghrelin administration on the regulation of cytokine release in lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages were analyzed. RESULTS Ghrelin and GHS-Rs are expressed in murine macrophages. In addition, exogenous ghrelin inhibited the production of pro-inflammatory cytokines IL-1beta and TNF-alpha in LPS-stimulated murine macrophages in a dose dependent and time-dependent fashion. Exogenous ghrelin pretreatment resulted in a decrease in LPS-induced NFkappaB activation and was presumably the reason for this ghrelin-mediated effect. In contrast to these findings, exogenous ghrelin significantly augmented the release of the anti-inflammatory cytokine IL-10 in a dose-dependent and time-dependent fashion from LPS-stimulated murine macrophages. Ghrelin administration enhanced activation of p38 MAPK, which is known to control the release of IL-10 in macrophages independent of the NFkappaB pathway. These effects of ghrelin on both pro-inflammatory and anti-inflammatory cytokines were offset when a specific GHS-R receptor antagonist was added to the culture media. CONCLUSIONS These data suggest that ghrelin has potent anti-inflammatory properties through modulation of secretion of both pro-inflammatory and anti-inflammatory cytokines from LPS-stimulated macrophages through distinct signaling cascades. Therapeutic utility of ghrelin to control, modulate, or treat pathologic inflammatory conditions like endotoxemic shock and ulcerative colitis requires additional investigation.
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Affiliation(s)
- Talat Waseem
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA
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33
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Anderwald-Stadler M, Krebs M, Promintzer M, Mandl M, Bischof MG, Nowotny P, Kästenbauer T, Luger A, Prager R, Anderwald C. Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans. Am J Physiol Endocrinol Metab 2007; 293:E1393-8. [PMID: 17785502 DOI: 10.1152/ajpendo.00330.2007] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Obestatin, a recently discovered 23-amino acid peptide, is involved in the regulation of appetite and body weight in antagonistic fashion to ghrelin, both deriving from a common precursor peptide. Ghrelin was shown to be associated with insulin resistance, which may also affect obestatin. We investigated the association between insulin resistance and plasma concentrations of obestatin and ghrelin in nondiabetic individuals with high (IS; n = 18, 13 females and 5 males, age 47 +/- 2 yr, BMI = 25.5 +/- 0.9 kg/m(2)) and low (IR; n = 18, 12 females and 6 males, age 45 +/- 2 yr, P = 0.49, BMI = 27.5 +/- 1.1 kg/m(2), P = 0.17) insulin-stimulated glucose disposal (M), measured by 2-h hyperinsulinemic (40 mU.min(-1).m(-2)) isoglycemic clamp tests. M(100-120 min) was higher in IS (10.7 +/- 0.7) than in IR (4.4 +/- 0.2 mg.min(-1).kg(-1), P < 10(-9)), whereas insulin-dependent suppression of free fatty acids (FFA) in plasma was reduced in IR (71 +/- 6% vs. IS: 82 +/- 5%, P < 0.02). In both groups, plasma ghrelin concentrations were comparable at fasting and similarly reduced by 24-28% during insulin infusion. IR had lower fasting plasma obestatin levels (383 +/- 26 pg/ml vs. IS: 469 +/- 23 pg/ml, P < 0.02). Clamp insulin infusion reduced plasma obestatin to approximately 81% of basal values in IS (P < 0.00002), but not in IR. Fasting plasma obestatin was correlated positively with M (r = 0.34, P = 0.04), HDL cholesterol (r = 0.45, P = 0.01), and plasma ghrelin concentrations (r = 0.80, P < 0.000001) and negatively with measures of adiposity, plasma FFA during clamp (r = -0.42, P < 0.01), and systolic blood pressure (r = -0.33, P < 0.05). In conclusion, fasting plasma concentrations of obestatin, but not of ghrelin, are reduced in insulin resistance and are positively associated with whole body insulin sensitivity in nondiabetic humans. Furthermore, plasma obestatin is reduced by insulin in insulin-sensitive but not in insulin-resistant persons.
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Affiliation(s)
- Marietta Anderwald-Stadler
- Third Medical Department of Metabolic Diseases and Nephrology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
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Checchi S, Montanaro A, Pasqui L, Ciuoli C, Cevenini G, Sestini F, Fioravanti C, Pacini F. Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies. J Clin Endocrinol Metab 2007; 92:4346-4351. [PMID: 17711921 DOI: 10.1210/jc.2007-0988] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Autoimmune gastritis is frequently associated with autoimmune thyroiditis and other organ-specific autoimmune diseases, and may lead to atrophic body gastritis (ABG). We studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of ABG in patients with autoimmune gastritis. METHODS We studied 233 patients with autoimmune gastritis and 211 control subjects. All patients and control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin, pepsinogen I and II, and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy. RESULTS In PCA/positive patients, mean (+/-sd) serum ghrelin levels were significantly lower (238 +/- 107 pmol/liter), and mean (+/-sd) serum gastrin levels were significantly higher (81.2 +/- 128.3 ng/ml), with respect to PCA/negative patients (282 +/- 104 pmol/liter and 20.7 +/- 13.3 ng/ml, respectively; P < 0.0001). Serum ghrelin and gastrin levels were inversely correlated (P = 0.004). A total of 40 patients had ABG documented by the gastric biopsy (90% in PCA/positive patients and 10% in PCA/negative patients). The receiver operating characteristic curve analysis revealed that a cutoff value for serum ghrelin of 188 pmol/liter was associated with the highest sensitivity and specificity (97.3 and 100%, respectively) in detecting gastric atrophy and was superior to gastrin (P = 0.012), PCA (P = 0.002), and the pepsinogen I/II ratio (P = 0.016) measurements. CONCLUSIONS Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG.
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Affiliation(s)
- Serenella Checchi
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Viale Bracci 1, 53100 Siena, Italy
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M'Koma AE, Wise PE, Muldoon RL, Schwartz DA, Washington MK, Herline AJ. Evolution of the restorative proctocolectomy and its effects on gastrointestinal hormones. Int J Colorectal Dis 2007; 22:1143-1163. [PMID: 17576578 PMCID: PMC10497984 DOI: 10.1007/s00384-007-0331-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2006] [Accepted: 05/02/2007] [Indexed: 02/08/2023]
Abstract
Gastrointestinal (GI) peptide hormones are chemical messengers that regulate secretory, mechanical, metabolic, and trophic functions of the gut. Restorative proctocolectomy (RPC) or resection of the colon and rectum with maintenance of intestinal continuity through the construction of an ileal pouch reservoir and preservation of the anal sphincters has become the standard of care for the surgical treatment of ulcerative colitis and familial adenomatous polyposis. The manipulation of the digestive system to create the ileal pouch involves altering gut-associated lymphoid tissue among other anatomic changes that lead to changes in GI peptides. In addition, the ileal pouch epithelium responds to a wide variety of stimuli by adjusting its cellularity and function. These adaptive mechanisms involve systemic factors, such as humoral and neural stimuli, as well as local factors, such as changes in intestinal peristalsis and intraluminal nutrients. There have been conflicting reports as to whether the alterations in GI hormones after RPC have actual clinical implications. What the studies on alterations of GI peptides' response and behavior after RPC have contributed, however, is a window into the possible etiology of complications after pouch surgery, such as pouchitis and malabsorption. Given the possibility of pharmacologically modifying GI peptides or select components of adaptation as a therapeutic strategy for patients with ileal pouch dysfunction or pouchitis, a clear understanding of human pouch mucosal adaptation is of paramount importance. In this review, we summarize the evolution of the RPC and its effects on the GI hormones as well as their possible clinical implications.
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Affiliation(s)
- Amosy E M'Koma
- Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232-2765, USA.
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36
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Jun DW, Lee OY, Lee YY, Choi HS, Kim TH, Yoon BC. Correlation between gastrointestinal symptoms and gastric leptin and ghrelin expression in patients with gastritis. Dig Dis Sci 2007; 52:2866-72. [PMID: 17436104 DOI: 10.1007/s10620-006-9651-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2006] [Accepted: 10/15/2006] [Indexed: 01/28/2023]
Abstract
The purpose of this study was to examine the changes in gastric ghrelin and leptin with respect to Helicobacter pylori infection and whether such changes affect the plasma levels of leptin and ghrelin. In addition, we examined the relationship between changes in gastric mucosal ghrelin and leptin levels and gastrointestinal symptoms. Sixty-three patients diagnosed with chronic gastritis were enrolled in the study. Twenty-nine patients were Helicobacter pylori negative and 34 were Helicobacter pylori positive. Expression of ghrelin and leptin mRNA in the gastric mucosa was measured using endoscopic biopsies from the fundus. Plasma levels of ghrelin and leptin were measured by radioimmunoassay. Expression of leptin mRNA in the gastric mucosa was significantly higher in Helicobacter pylori-positive patients than in negative patients (0.38 +/- 0.17 vs. 0.24 +/- 0.12, p = 0.039). The expression of ghrelin was lower in positive patients than in the negative group, although this difference was not significant (p = 0.07). However, there was no significant difference in plasma leptin and ghrelin levels. Gastric mucosal ghrelin mRNA expression was significantly lower in patients with dyspepsia than in those without (0.15 +/- 0.11 vs. 0.23 +/- 0.20, p = 0.05). Helicobacter pylori infection and gastrointestinal symptoms could be associated with leptin and ghrelin expression in the gastric mucosa.
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Affiliation(s)
- Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Seoul, 133-792, Republic of Korea
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Arepally A, Barnett BP, Montgomery E, Patel TH. Catheter-directed gastric artery chemical embolization for modulation of systemic ghrelin levels in a porcine model: initial experience. Radiology 2007; 244:138-43. [PMID: 17581899 DOI: 10.1148/radiol.2441060790] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
PURPOSE To prospectively test, in a porcine model, the hypothesis that use of catheter-directed gastric artery chemical embolization (GACE) can result in substantial suppression of systemic ghrelin levels. MATERIALS AND METHODS The institutional animal care and use committee approved this study. Adult healthy swine (40-45 kg, n=8) were tested. GACE was performed by infusing morrhuate sodium selectively into the left gastric artery. Six swine (animals A-F) underwent left GACE by using a dose-escalating regimen of morrhuate sodium, whereas two control swine underwent a sham procedure. Weight and fasting plasma ghrelin levels were compared in swine at baseline and at weeks 1-4. At week 4, stomachs were excised and analyzed. Analysis of the change in ghrelin values and weight was performed with both paired t test and unpaired Student t test. RESULTS In control swine (n=2), there was no significant difference in ghrelin values before (844.8 pg/mL +/- 40 [standard deviation]) and after (997 pg/mL +/- 93) the procedure (P=.5). Swine that received a low dose of morrhuate sodium (animals A-D) showed a significant increase in serum ghrelin values from 683.7 pg/mL +/- 241 to 1555.9 pg/mL +/- 312 (P=.002). At a higher dose, the mean baseline ghrelin values decreased from 466 pg/mL to 187 pg/mL +/- 162. Weight changes of +1.4% and +8.6% were seen in swine that underwent GACE and control swine, respectively. Histochemical staining showed preservation of overall tissue architecture and parietal cells. CONCLUSION Use of GACE can result in increased or suppressed ghrelin levels.
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Affiliation(s)
- Aravind Arepally
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutes, Johns Hopkins Hospital, Blalock 545, 600 N Wolfe St, Baltimore, MD 21287, USA.
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Janas-Kozik M, Krupka-Matuszczyk I, Malinowska-Kolodziej I, Lewin-Kowalik J. Total ghrelin plasma level in patients with the restrictive type of anorexia nervosa. ACTA ACUST UNITED AC 2007; 140:43-6. [PMID: 17187877 DOI: 10.1016/j.regpep.2006.11.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Revised: 11/06/2006] [Accepted: 11/10/2006] [Indexed: 11/17/2022]
Abstract
Ghrelin is produced mainly in the stomach and is an essential link of the brain-gut axis. Ghrelin stimulates hunger centers in hypothalamus controlling food intake and body mass gain. The aim of the study is to analyze the total ghrelin plasma level in patients suffering from restrictive type of anorexia nervosa (AN-R). According to DSM-IV classification a group of 30 AN-R patients was investigated before and after 3 and 6 months of therapy. Therapy included normocaloric diet and cognitive-behavioral psychotherapy (CBT). The control group consisted of 20 girls without any eating disorders. Before the therapy the total ghrelin plasma level in AN-R patients was significantly higher than in the control group. After 3 and 6 months of treatment the total ghrelin plasma level in AN-R patients was significantly lower than in the control group. In AN-R patients, the total ghrelin plasma level is connected with the pathological feeding behavior.
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Affiliation(s)
- Malgorzata Janas-Kozik
- Department and Clinic of Psychiatry and Psychotherapy, Medical University of Silesia, Katowice, ul. Ziolowa 45/47, 40-635 Katowice, Poland.
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Cindoruk M, Yetkin I, Deger SM, Karakan T, Kan E, Unal S. Influence of H pylori on plasma ghrelin in patients without atrophic gastritis. World J Gastroenterol 2007; 13:1595-8. [PMID: 17461454 PMCID: PMC4146904 DOI: 10.3748/wjg.v13.i10.1595] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the association between H pylori infection and serum ghrelin levels in patients without atrophic gastritis.
METHODS: Fifty consecutive patients (24 males and 26 females) with either H pylori-positive gastritis (n = 34) or H pylori-negative gastritis (n = 16) with normal gastric acid secretion determined by 24-h pHmetry and without atrophic gastritis in histopathology were enrolled in this study. Thirty-four H pylori-infected patients were treated with triple therapy consisting of a daily regimen of 30 mg lansoprazole bid, 1 g amoxicillin bid and 500 mg clarithromycin bid for 14 d, followed by an additional 4 wk of 30 mg lansoprazol treatment. H pylori infection was eradicated in 23 of 34 (67.6%) patients. H pylori-positive patients were given eradication therapy. Gastric acidity was determined via intragastric pH catethers. Serum ghrelin was measured by radioimmunoassay (RIA).
RESULTS: There was no signifficant difference in plasma ghrelin levels between H pylori-positive and H pylori-negative groups (81.10 ± 162.66 ng/L vs 76.51 ± 122.94 ng/L). In addition, there was no significant difference in plasma ghrelin levels and gastric acidity levels measured before and 3 mo after the eradication therapy.
CONCLUSION: H pylori infection does not influence ghrelin secretion in patients with chronic gastritis without atrophic gastritis.
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Affiliation(s)
- Mehmet Cindoruk
- Gazi University, Department of Gastroenterology, Ankara, Turkey
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Abstract
The gastric emptying rate is a carefully regulated process consisting of different mathematically defined phases. The gastric metabolic load, as well as neural regulatory mechanisms and hormonal influences, cooperate in order to achieve a well-balanced emptying of contents from the stomach into the duodenum for absorption in the small intestine. This finely tuned regulation is primarily regulated by the release of gastrointestinal peptide hormones which serve to counteract the emptying process in the fed state and to stimulate sweeping contractions in the fasted state, most likely in order to prepare the stomach for another meal. We have found that the two peptide hormones ghrelin and glucagon-like peptide- I (GLP- I) have a great impact on the regulation of gastric emptying: ghrelin is a most potent stimulator of gastric contractions and emptying, and GLP- I profoundly inhibits this emptying process. These data suggest possibilities for governing the rate of gastric emptying as a natural step in achieving metabolic balance and control.
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Affiliation(s)
- Per M Hellström
- Department of Gastroenterology and Hepatology, Karolinska University Hospital, Solna, Sweden.
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Park WH, Oh YJ, Kim GY, Kim SE, Paik KH, Han SJ, Kim AH, Chu SH, Kwon EK, Kim SW, Jin DK. Obestatin is not elevated or correlated with insulin in children with Prader-Willi syndrome. J Clin Endocrinol Metab 2007; 92:229-34. [PMID: 17047025 DOI: 10.1210/jc.2006-0754] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
CONTEXT Obestatin is a peptide hormone derived from the proteolytic cleavage of ghrelin preprohormone. In Prader-Willi syndrome (PWS), the levels of total ghrelin (TG) and acylated ghrelin (AG) are increased, and these hormones are regulated by insulin. OBJECTIVE Our objective was to analyze the changes in the obestatin levels after glucose loading and to characterize the correlations of obestatin with TG, AG, and insulin. DESIGN Plasma obestatin, TG, AG, and insulin levels were measured in PWS children (n = 15) and controls (n = 18) during an oral glucose tolerance test. SETTING All subjects were admitted to the Samsung Medical Center. INTERVENTIONS An oral glucose tolerance test was performed after an overnight fast. MAIN OUTCOME MEASURES The plasma levels of obestatin, TG, AG, and serum insulin were measured at 0, 30, 60, 90, and 120 min after glucose challenge, and areas under the curves (AUCs) were calculated. RESULTS No significant difference in AUC of the plasma obestatin was found between the PWS children and normal obese controls (P = 0.885), although AUC of AG (P = 0.002) and TG (P = 0.003) were increased in the PWS children. Moreover, There was a negative correlation between the AUC of AG and AUC of insulin both in PWS (r = -0.432; P = 0.049) and in controls (r = -0.507; P = 0.016). However, AUC of obestatin was not significantly correlated with AUC of insulin (in PWS, r = 0.168 and P = 0.275; in controls, r = -0.331 and P = 0.09). CONCLUSIONS Our results indicate that plasma obestatin is not elevated in PWS children and is not regulated by insulin both in PWS children and in obese controls.
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Affiliation(s)
- Won Hah Park
- Department of Orthopedic Sports Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 135-710 Seoul, Korea
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42
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Lanzini A, Magni P, Petroni ML, Motta M, Lanzarotto F, Villanacci V, Amato M, Mora A, Bertolazzi S, Benini F, Ricci C. Circulating ghrelin level is increased in coeliac disease as in functional dyspepsia and reverts to normal during gluten-free diet. Aliment Pharmacol Ther 2006; 23:907-13. [PMID: 16573793 DOI: 10.1111/j.1365-2036.2006.02852.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND It is controversial whether serum ghrelin concentration is altered in coeliac disease and whether this alteration is related to nutritional impairment or to inflammatory changes of duodenal mucosa. AIM To investigate clinical and histopathological variables affecting circulating ghrelin in coeliac patients by comparison with dyspeptic patients and with healthy controls. METHODS We measured serum ghrelin and obtained gastric and duodenal biopsies in 44 coeliac patients before and after 1-year gluten-free diet, in 39 dyspeptic patients and 53 healthy controls. RESULTS Serum ghrelin concentration was significantly higher in coeliac (531 +/- 29 pg/mL, P < 0.05) and in dyspeptic patients (526 +/- 14 pg/mL, P < 0.01) than in healthy controls (451 +/- 8 pg/mL), and body mass index was significantly lower in coeliac (20 +/- 1) and in dyspeptic patients (20 +/- 1) than in healthy controls (22 +/- 1, P < 0.05). In coeliac patients serum ghrelin concentration was not related to the severity of duodenal lesions. Serum ghrelin reverted to normal (399 +/- 30 pg/mL) and body mass index increased significantly (0.6 +/- 0.1 kg/m(2) increase, P < 0.05) during gluten-free diet despite persistent duodenal lymphocytic infiltration. CONCLUSIONS Ghrelin concentration is increased and body mass index is decreased in coeliac and in dyspeptic patients irrespective of presence and severity of duodenal inflammation. Nutritional impairment is a key factor in elevating plasma ghrelin levels in coeliac disease.
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Affiliation(s)
- A Lanzini
- Gastroenterology Unit, University and Spedali Civili, Brescia, Italy.
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43
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Nishi Y, Isomoto H, Ueno H, Ohnita K, Wen CY, Takeshima F, Mishima R, Nakazato M, Kohno S. Plasma leptin and ghrelin concentrations in patients with Crohn's disease. World J Gastroenterol 2006; 11:7314-7. [PMID: 16437634 PMCID: PMC4725148 DOI: 10.3748/wjg.v11.i46.7314] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the concentrations of leptin and ghrelin, which have opposite effects on appetite, energy expenditure, and weight control, in the plasma of patients with Crohn's disease (CD), which is often associated with weight loss and malnutrition. METHODS Plasma leptin and ghrelin 'concentrations were determined in 28 outpatients with CD by radioimmunoassay. Age- and sex-matched controls with and without Helicobacter pylori (H pylori) infection (28 for each) were enrolled in the study. Circulating levels of these hormones were assessed with respect to CD activity, disease localization and medical treatment. RESULTS There were no significant differences in ghrelin levels between CD patients and H pylori-negative controls. However, circulating ghrelin levels were significantly lower in H pylori-infected subjects than in CD patients and uninfected controls. Plasma leptin levels were comparable among the groups. Localization and medication profile had no significant impact on circulating ghrelin and leptin levels. CONCLUSION Apart from H pylori infection, CD itself has no significant influence on circulating ghrelin and leptin levels in the outpatients who were mostly in inactive state.
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Affiliation(s)
- Yoshito Nishi
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA
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44
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De Smet B, Depoortere I, Moechars D, Swennen Q, Moreaux B, Cryns K, Tack J, Buyse J, Coulie B, Peeters TL. Energy homeostasis and gastric emptying in ghrelin knockout mice. J Pharmacol Exp Ther 2006; 316:431-9. [PMID: 16203827 DOI: 10.1124/jpet.105.091504] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin(-/-)) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying ((14)C breath test) were compared between ghrelin(+/+) and ghrelin(-/-) mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin(-/-) mice showed some subtle phenotypic changes. Body weight gain and 24-h food intake were not affected, but interruption of the normal light/dark cycle triggered additional food intake in old ghrelin(+/+) but not in ghrelin(-/-) mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin(-/-) mice. During the dark period, young ghrelin(-/-) mice had a lower respiratory quotient, whereas their heat production was higher than that of the wild-type littermates, inferring a leaner body composition of the ghrelin(-/-) mice. Absence of ghrelin did not affect gastric emptying, and the bell-shaped dose-response curves of the acceleration of gastric emptying by exogenous ghrelin were not shifted between both strains. In conclusion, ghrelin is not an essential regulator of food intake and gastric emptying, but its loss may be compensated by other redundant inputs. In old mice, meal initiation triggered by the light/dark cue may be related to ghrelin. In young animals, ghrelin seems to be involved in the selection of energy stores and in the partitioning of metabolizable energy between storage and dissipation as heat.
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Affiliation(s)
- B De Smet
- Centre for Gastroenterological Research, Catholic University of Leuven, Gasthuisberg, 3000 Leuven, Belgium
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45
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Ulukavak Ciftci T, Kokturk O, Bukan N, Bilgihan A. Leptin and ghrelin levels in patients with obstructive sleep apnea syndrome. Respiration 2005; 72:395-401. [PMID: 16088283 DOI: 10.1159/000086254] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2004] [Accepted: 12/02/2004] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Leptin is a hormone with well-investigated functions concerning body composition, energy homeostasis and feeding behavior in humans. The obstructive sleep apnea syndrome (OSAS) is strongly associated with obesity, which is known to be closely associated with hyperleptinemia. More recently, ghrelin, a hormone that also influences appetite and energy homeostasis, has been discovered. OBJECTIVES The aim of this study was to investigate serum leptin and ghrelin levels in obese patients with OSAS in comparison with equally obese controls without OSAS. METHODS Thirty untreated obese patients with moderate-severe OSAS (apnea-hypopnea index: AHI > or =15) and 22 obese controls (AHI <5) were studied. To confirm the diagnosis, all patients underwent standard polysomnography in our sleep disorders center. Serum samples were taken at 08:00 h in the morning after overnight fasting. RESULTS Significantly higher serum leptin levels were found in OSAS patients compared to controls (p = 0.012), but there was no significant difference in serum ghrelin levels between OSAS patients and controls. Serum leptin levels were significantly correlated with body mass index in both OSAS patients (r = 0.55, p = 0.002) and controls (r = 0.46, p = 0.028), but only in OSAS patients was the leptin level significantly correlated with AHI (r = 0.38, p = 0.036). CONCLUSION These data support findings suggesting that leptin is a hormonal factor affected by OSAS and not determined by obesity alone. Further studies are needed to investigate the relationship between serum ghrelin and OSAS.
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46
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Polidori C, Massi M, Guerrini R, Grandi D, Lupo D, Morini G. Peripheral mechanisms involved in gastric mucosal protection by intracerebroventricular and intraperitoneal nociceptin in rats. Endocrinology 2005; 146:3861-7. [PMID: 15919744 DOI: 10.1210/en.2005-0397] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Nociceptin (N/OFQ) exerts multiple effects in the gastrointestinal tract after central or peripheral administration. In the present study, we examined the possible peripheral mechanisms mediating gastric protection by N/OFQ in rats. Gastric mucosal lesions were induced by 50% ethanol (1 ml/rat intragastrically). N/OFQ, administered either intracerebroventricularly (3 microg/rat) or ip (10 microg/kg), significantly reduced macroscopic and histological damage. The protective effect of intracerebroventricular N/OFQ was blocked by atropine, subdiaphragmatic vagotomy, and bretylium. The effect of both central and peripheral N/OFQ was blocked by functional ablation of afferent nerves produced by capsaicin, by the antagonist of calcitonin gene-related peptide, CGRP(8-37), and by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results indicate that N/OFQ increases gastric mucosal resistance to ethanol by operating both in the central nervous system and in the periphery. Vagal cholinergic and sympathetic pathways mediate the central activity of N/OFQ, whereas vagal nonmuscarinic pathways mediate the peripheral activity of the peptide. The neuronal circuit involving extrinsic sensory neurons, calcitonin gene-related peptide, and nitric oxide is activated by central as well as peripheral N/OFQ. The study provides evidence that N/OFQ contributes to neurally mediated gastric mucosal protection.
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Affiliation(s)
- Carlo Polidori
- Department of Experimental Medicine and Public Health, University of Camerino, Italy
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Isomoto H, Ueno H, Saenko VA, Mondal MS, Nishi Y, Kawano N, Ohnita K, Mizuta Y, Ohtsuru A, Yamashita S, Nakazato M, Kohno S. Impact of Helicobacter pylori infection on gastric and plasma ghrelin dynamics in humans. Am J Gastroenterol 2005; 100:1711-20. [PMID: 16086706 DOI: 10.1111/j.1572-0241.2005.41492.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES There are contradictory reports on the relationship between Helicobacter pylori and circulating ghrelin. We sought to clarify the influence of H. pylori infection on gastric and plasma ghrelin dynamics in humans. METHODS Using endoscopic biopsies from the corpus of 56 H. pylori-infected patients and 25 uninfected subjects, ghrelin mRNA expression levels and gastric ghrelin peptide contents were measured by real-time polymerase chain reaction and radioimmunoassay, respectively. We also measured plasma ghrelin concentrations and analyzed the numbers of ghrelin immunoreactive cells in the fundic gland area. Fifty-one patients with H. pylori infection were treated with a 7-day triple therapy consisting of lansoprazole, clarithromycin, and amoxicillin. RESULTS The gastric ghrelin mRNA expression level of H. pylori-positive patients (1.64 +/- 1.27 in arbitrary units) was significantly lower than in H. pylori-negative subjects (4.87 +/- 4.1, p < 0.0001). A similar trend was noted for ghrelin peptide contents (31.2 +/- 27.5 vs 81.2 +/- 64.1 ng/mg protein, respectively, p < 0.0001). There was no significant difference in the number of ghrelin immunoreactive cells/mm(2) in terms of H. plyori status. Plasma ghrelin concentrations in H. pylori-infected patients (144.6 +/- 7.8.8 fmol/ml) were significantly lower than in uninfected subjects (196.1 +/- 97.2, p < 0.05) and increased following cure of the infection. Plasma ghrelin levels correlated positively with the expression levels of ghrelin mRNA (r = 0.583, p < 0.0001) and peptide products (r = 0.574, p < 0.0001). There was a significant stepwise decrease in gastric ghrelin mRNA expression (p < 0.05), peptide contents (p < 0.01) and density of ghrelin immunoreactive cells (p < 0.05) with progression of histological severity of glandular atrophy in the corpus. The histological severity of chronic inflammation also negatively influenced the ghrelin mRNA expression (p < 0.001) and peptide production (p < 0.005). CONCLUSIONS H. pylori infection has a negative impact on gastric and plasma ghrelin dynamics. Chronic inflammatory and atrophic changes associated with the infection may affect gastric ghrelin biosynthesis and contribute to the low circulating levels.
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Affiliation(s)
- Hajime Isomoto
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Sakamoto, Nagasaki, Japan
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Isomoto H, Nishi Y, Ohnita K, Mizuta Y, Kohno S, Ueno H, Nakazato M. The Relationship between Plasma and Gastric Ghrelin Levels and Strain Diversity in Helicobacter pylori Virulence. Am J Gastroenterol 2005; 100:1425-7. [PMID: 15929785 DOI: 10.1111/j.1572-0241.2005.41929_7.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Choe YH, Jin DK, Kim SE, Song SY, Paik KH, Park HY, Oh YJ, Kim AH, Kim JS, Kim CW, Chu SH, Kwon EK, Lee KH. Hyperghrelinemia does not accelerate gastric emptying in Prader-Willi syndrome patients. J Clin Endocrinol Metab 2005; 90:3367-70. [PMID: 15657368 DOI: 10.1210/jc.2004-1651] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Prader-Willi syndrome (PWS) is the most common form of syndromic obesity associated with hyperphagia. Because ghrelin stimulates gastric motility in rodents, and PWS patients have 3- to 4-fold higher fasting plasma ghrelin concentrations than normal subjects, we hypothesized that hyperphagia associated with PWS may be partly explained by rapid gastric emptying due to the increased gastric motility caused by ghrelin. We determined gastric emptying times (GETs) and measured ghrelin levels in 11 PWS children and 11 age-, sex-, and body mass index-matched controls using a standard meal containing [(99m)Tc]diaminetriaminepentacetate. Median plasma ghrelin levels before (precibum) and after the GET study were higher in PWS patients than in controls (P = 0.004 and P = 0.001, respectively). Median percent gastric retentions at 90 min after the standard meal were 57.1% (range, 34.0-83.2%) in PWS patients and 40.2% (range, 27.2-60.2%) in controls (P = 0.03). In particular, precibum ghrelin concentrations were not significantly correlated with the rate of gastric emptying in PWS patients (P = 0.153; r = 0.461) or controls (P = 0.911; r = 0.048). Our results show that gastric emptying in PWS is reduced despite higher ghrelin levels, and that the voracious appetite associated with PWS is related to another mechanism.
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Affiliation(s)
- Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Il-Won Dong, Gang-Nam Gu, Seoul 135-710, Korea
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Depoortere I, De Winter B, Thijs T, De Man J, Pelckmans P, Peeters T. Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro. Eur J Pharmacol 2005; 515:160-168. [PMID: 15890336 DOI: 10.1016/j.ejphar.2005.04.008] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2004] [Revised: 03/15/2005] [Accepted: 04/08/2005] [Indexed: 01/02/2023]
Abstract
UNLABELLED Ghrelin and motilin form a new family of structurally related peptides. We compared the gastroprokinetic effects of ghrelin, the ghrelin receptor agonist, growth hormone releasing peptide 6 (GHRP-6), and motilin in rats in vivo and in vitro. METHODS Ghrelin, GHRP-6 or motilin (10-150 microg/kg) were injected i.p. and the effects on gastric emptying and transit were measured after intragastric application of Evans blue. In antral and fundic strips the effect of motilin, ghrelin or GHRP-6 was studied during electrical field stimulation (EFS) in the absence and presence of N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME) (300 microM). RESULTS Ghrelin and GHRP-6 but not motilin accelerated gastric emptying and transit in rats. Ghrelin was more potent than GHRP-6 and the dose-response relationship for ghrelin but not for GHRP-6 was bell-shaped. In fundic or antral strips, neural responses to EFS consisted of an on-relaxation that was reversed into a cholinergically mediated contraction by addition of the nitric oxide (NO)-synthase blocker, l-NAME. The post-stimulus off-contraction was cholinergically mediated. Under normal conditions, the ghrelin agonists reduced the on-relaxations in fundic strips and increased the cholinergic off-contractions in antral and fundic strips. The concentration response curves in muscle strips of the fundus were bell-shaped with maximal effects for ghrelin at 1.2 microM (on-responses) and 0.66 microM (off-responses) and for GHRP-6 at 0.50 microM (on-responses) and 0.26 microM (off-responses). No effects were observed with motilin between 1 nM and 0.1 microM. Studies in the presence of l-NAME confirmed the effect of the ghrelin agonists on cholinergic excitatory motor responses. No effects were observed with motilin under the different experimental conditions. The presence of growth hormone secretagogue receptor 1a transcripts in the strip preparations was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). CONCLUSION Ghrelin and GHRP-6 but not motilin accelerate gastric emptying and transit by activating cholinergic excitatory pathways in the enteric nervous system in addition to the known vagal pathways.
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Affiliation(s)
- Inge Depoortere
- Centre for Gastroenterological Research, Department of Pathophysiology, University of Leuven, Gasthuisberg O & N, B-3000, Leuven, Belgium.
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