The gastric X/A-like (ghrelin) cell: A peripheral regulator of food intake

胃 X/A 样（生长素释放肽）细胞：食物摄入的外周调节因子

• 批准号: 7795604
• 负责人: Nils WG Lambrecht
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795604
• 关键词: Acute; Acyltransferase; Address; Affect; Anatomy; Behavior; Blood Circulation; Body Weight; Brain; Cachexia; Cells; Characteristics; Cholecystokinin; Chronic; Circadian Rhythms; Clinical; Clinical Treatment; Complication; Confocal Microscopy; D Cells; Data; Desire for food; Detection; Doctor of Medicine; Dose; Down-Regulation; Eating; Endocrine; Energy Metabolism; Enterochromaffin-like Cells; Enteroglucagon; Enzymes; Esthesia; Expenditure; Fasting; Feedback; Food; Food Intake Regulation; Food deprivation (experimental); Functional disorder; Gastric Emptying; Gastrointestinal Hormones; Gastrointestinal tract structure; Gland; Health; Health Hazards; Healthcare; Histamine; Homeostasis; Hunger; Incidence; Indomethacin; Infection; Inflammation; Injection of therapeutic agent; Intake; Interleukin-1 beta; Interleukins; Lipopolysaccharides; Location; Maintenance; Malignant Neoplasms; MeSH Thesaurus; Mediating; Medical; Modeling; Modification; Molecular; Morbid Obesity; Morbidity - disease rate; Mucous Membrane; Nutrient; Obesity; Patient Care; Patients; Peptides; Peripheral; Peritoneal; Phase; Physiological; Plasma; Play; Population; Prevention; Principal Investigator; Program Description; Prostaglandins; Protein Isoforms; Proteins; Public Health; Quality of life; Rattus; Regulation; Research; Resources; Role; Satiation; Savings; Secretory Vesicles; Serum; Signal Transduction; Site; Somatostatin; Stimulus; Stomach; Transferase; United States; Veterans; care systems; des-n-octanoyl ghrelin; detection of nutrient; energy balance; feeding; food restriction; gastrointestinal; ghrelin; glucagon-like peptide 1; improved; in vivo; mRNA Expression; medical complication; mortality; peptide hormone; prevent; programs; protein expression; psychological stressor; research and development; response; treatment strategy; wasting

DESCRIPTION (provided by applicant): Department of Veterans Affairs SUMMARY DESCRIPTION OF PROGRAM SUMMARY DESCRIPTION OF PROJECT RESEARCH AND DEVELOPMENT PROGRAM PRINCIPAL INVESTIGATOR(S) Lambrecht, Nils, M.D. TITLE OF PROGRAM PROJECT (Not to exceed 72 character spaces) The gastric X/A (ghrelin) cell: A peripheral regulator of food intake KEYWORDS (MeSH terms only; minimum three) ghrelin, nucleobindin2 (NUCB2), nesfatin-1, MBOAT4, ghrelin-O-acyl transferase (GOAT), food intake, peripheral regulation, gastric mucosal X/A cell, obesity, cachexia, LPS BRIEF STATEMENT OF RESEARCH OBJECTIVES (Do not use continuation sheets) Chronic changes in body weight result in significant health problems. Appetite control is vital in body weight regulation and is controlled centrally and peripherally. Chronically increased food intake contributes to morbid obesity, chronically decreased food intake contributes to cachectic wasting as severe complication in overwhelming infections and cancer. To target those conditions a deep understanding of food intake regulation is necessary. While many food intake inhibitory peptides are released in the gastrointestinal tract, only one peptide, ghrelin, elicits feed-forward characteristics. It is the only known peripheral orexigenic peptide hormone which rises in concentration in the circulation before the central phase of food intake. We have recently begun to sub-classify the endocrine cell population of the rat gastric oxyntic mucosa and found that in addition to ECL and D cells, most of the endocrine cells in the upper and mid portion of the glands contain ghrelin. These cells appear to represent the gastric endocrine X/A-like cells. Octanoylation of ghrelin by an octanoyl transferase (GOAT) seems to be essential for its orexigenic activity while non-octanoylated ghrelin appears to have an anorexigenic effect. The cellular site of GOAT expression in gastric oxyntic mucosa has not been shown. We have also shown, that the X/A-like cell also expresses the anorexigenic protein nesfatin-1/NUCB2. This enables the X/A-like cell to signal both hunger and satiety. The release of ghrelin and nesfatin-1/NUCB2 must be independently controlled. However, specific physiological or pathological conditions to regulate the differential release of ghrelin and nesfatin-1/NUCB2 in vivo have not been studied. We propose two model conditions to study changes in ghrelin and nesfatin- 1/NUCB2 cellular expression, peptide modification and release into the circulation: a) 24 h food deprivation compared to ad libitum feeding and b) acute inflammation compared to healthy rats (peritoneal injection of gram-negative bacteriallipopolysaccharides at non-toxic doses). Specific Aims: 1) Characterization of rat gastric endocrine X/A-like cells: Coexpression of ghrelin, nesfatin-1/NUCB2 and GOAT. 2) Effect of fasting (24 hr food restriction) and re-feeding on (a) nesfatin-1/NUCB2 concentration and ghrelin/desacyl ghrelin (DAG) ratios in rat blood plasma and on (b) mRNA and protein expression of ghrelin, GOAT, and nesfatin-1/NUCB2 in enriched rat oxyntic mucosal endocrine cells. 3) Effect of LPS and interleukin-1ss in the presence and absence of indomethacin on (a) nesfatin- 1/NUCB2 concentration and ghrelin/DAG ratios in rat blood plasma and on (b) mRNA and protein expression of ghrelin, GOAT, and nesfatin-1/NUCB2 in enriched rat oxynticmucosal endocrine cells. VAAPRFO19R9M0(R) 10-1313-2 Page 2 of VA Form 10-1313 package PUBLIC HEALTH RELEVANCE: Project narrative: Dysregulation of body weight is associated with significant mortality in the United States and world wide. Obesity-attributable medical expenditures are estimated at $75 billion in 2003. Cachexia is a significant contributor to the overall increased morbidity and mortality in patients with overwhelming infections, and in patients with chronic inflammation and cancer, affecting up to 85% of patients with gastrointestinal malignancies. The mechanisms leading to the sensation of appetite and the release of gastrointestinal hormones in response to meal stimuli play an important role in the regulation of body weight homeostasis. A complete understanding of this mechanism will improve the quality of life in our veteran patients by preventing serious medical complications. It appears to us, that acute control of food intake and long-term maintenance of body weight are regulated by a concerted action of sensing peripheral nutrient status and energy metabolism to the brain which integrates the signals with central inputs of circadian rhythm and psychological stressors. One of the peripheral regulators of food intake appears to be the X/A- like cell of the gastric oxyntic glands. The proposed studies aim to show, that this cell appears to have mechanisms in place to acutely stimulate or inhibit food intake by opposing actions of released ghrelin or nesfatin- 1/NUCB2. The cell is also in a perfect anatomic location, to sense acutely, when nutrients become available. Postprandial nutrient exposure of the X/A-like cell may result in a rapid down-regulation of ghrelin release and in down regulation of expression or enzymatic activity of the acylating enzyme of ghrelin, GOAT. This may result in a further decrease of n-octanoyl- ghrelin with concurrent increase in des-acyl ghrelin concentration leading to the central sensation of satiety. Another fail-safe mechanism of this cell to confer satiety is the increased release of the anorexic peptide NUCB2/nesfatin-1, a mechanism in concert with other anorexic peptide hormones of the gut. Acute dysregulation of these physiological endocrine responses may cause declining food intake in states of inflammation in the body caused by infections or cancer; chronic dysregulation may represent one of the changes occurring in the pathophysiology of obesity. The present proposal will attempt to elucidate the exact cellular and molecular mechanisms related to this effect and may result in clinical targets to control body weight. Given that the VA Medical Care System is the largest of its type in the USA, and that the 158 medical facilities include over 5 million patients, strategies to reduce the incidence of obesity and cachexia related morbidity and mortality are likely to have a beneficial impact not only on patient care through prevention but result in significant savings in resources that could be better spent on other aspects of veteran healthcare. The proposed studies will address important pathophysiological questions regarding the mechanisms regulating appetite and satiety as well as provide potentially important clinical treatment strategies.

描述（由申请人提供）： 退伍军人事务部的计划计划研究和开发计划的总结说明主要研究者兰布雷希特，尼尔斯，医学博士计划项目的标题（不超过72个字符空间）胃X/A（ghrelin）单元格：一个食物摄入量的外围调节剂（Mesh Terme terk; Mine triens n eft; Minius 3）ghririn-nucbind-nucbin nucbind nucbind nucbind nucband n nucbind n nucbind n nucbind 2 MBOAT4，生长素蛋白-O-酰基转移酶（山羊），食物摄入量，外周调节，胃粘膜X/A细胞，肥胖，恶病质，LPS的研究目标简短声明（请勿使用持续性）慢性变化导致体重的重大健康问题。食欲控制在体重调节中至关重要，并且在中央和周边受到控制。长期增加的食物摄入有助于病态肥胖，长期降低的食物摄入量导致缓存浪费是压倒性感染和癌症的严重并发症。要针对这些条件，必须深入了解食物摄入调节。虽然许多食物摄入抑制性肽在胃肠道中释放出来，但只有一种肽，生长素蛋白，引起前喂养特征。它是唯一已知的周围外周肽激素，它在食物摄入中心阶段之前的循环中以浓度升高。我们最近开始将大鼠胃羟基粘膜的内分泌细胞群体分类，发现除了ECL和D细胞外，腺体上部和中部的大多数内分泌细胞都含有生长素蛋白。这些细胞似乎代表胃内分泌X/A类细胞。八烷酰转移酶（山羊）对生长素的八烯酰化似乎对于其骨髓活性至关重要，而非二十二酰化的生长素蛋白似乎具有厌食作用。尚未显示胃氧粘膜中山羊表达的细胞位点。我们还表明，X/A样细胞还表达厌食症蛋白Nesfatin-1/nucB2。这使X/A样细胞可以发出饥饿和饱腹感的信号。必须独立控制生长素蛋白和NESFATIN-1/nucB2的释放。然而，尚未研究特定的生理或病理条件，以调节生长素蛋白和NESFATIN-1/nucB2体内的差异释放。我们提出了两个模型条件，以研究生长素素和NESFATIN-1/nucB2细胞表达，肽修饰并释放到循环中：a）与额外的喂养和b）与健康的大鼠相比，急性炎症与健康的大鼠相比（与粒度维内尼尔氏pacialliallipialiallipialiallipopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopopomacachace consection a）相比24小时。具体目的：1）大鼠胃内分泌X/a样细胞的表征：生长素蛋白的共表达，Nesfatin-1/nucb2和山羊。 2）禁食（24小时食物限制）和重新喂养对大鼠血浆中的（a）Nesfatin-1/nucB2浓度和生长素蛋白/避免的生长素蛋白（DAG）比率在富含大鼠血浆中的mRNA和（b）ghrelin，goat和nesfatin-1/uncb2中的mRNA和蛋白质表达。 3) Effect of LPS and interleukin-1ss in the presence and absence of indomethacin on (a) nesfatin- 1/NUCB2 concentration and ghrelin/DAG ratios in rat blood plasma and on (b) mRNA and protein expression of ghrelin, GOAT, and nesfatin-1/NUCB2 in enriched rat oxynticmucosal endocrine cells. VAAPRFO19R9M0（R）10-1313-2 VA表格10-1313包装 公共卫生相关性： 项目叙述：体重失调与美国和世界范围的重大死亡率有关。 2003年估计肥胖症的医疗支出估计为750亿美元。卡希克西亚是压倒性感染患者的总体发病率和死亡率的重要贡献，以及慢性炎症和癌症患者的总体发病率和死亡率，影响了多达85％的胃肠道恶性患者。 导致食欲感和胃肠激素释放而响应饮食刺激的机制在调节体重体重稳态中起着重要作用。对这种机制的完整了解将通过预防严重的医疗并发症来改善退伍军人患者的生活质量。 在我们看来，急性控制食物摄入量和体重的长期维持受到传感外周营养状况和能量代谢的共同作用，将信号与昼夜节律的中心输入和心理压力源相结合。食物摄入的外围调节剂之一似乎是胃催产腺的X/a类细胞。 拟议的研究旨在表明，该细胞似乎具有适当的机制，可以通过释放的生长素释放蛋白或Nesfatin-1/nucb2的相反作用来急性刺激或抑制食物摄入。当营养可用时，该细胞也处于完美的解剖位置，可以敏锐地感知。 X/A样细胞的餐后营养暴露可能会导致生长素释放蛋白释放的快速下调，并下调山羊蛋白酶的酰化酶的表达或酶活性。这可能导致N-辛烯酰 - 生长素蛋白进一步降低，并同时增加DES-酰基酶素浓度，从而导致饱腹感中心感觉。该细胞赋予饱腹感的另一个故障安全机制是增加厌食症肽nucb2/nesfatin-1的释放，这是一种与肠道的其他厌食肽激素协同的机制。 这些生理内分泌反应的急性失调可能会导致体内炎症状态的食物摄入量的下降。慢性失调可能代表肥胖病理生理学中发生的变化之一。本提案将试图阐明与此作用相关的确切细胞和分子机制，并可能导致临床靶标以控制体重。 鉴于VA医疗保健系统是美国类型中最大的一种，并且158个医疗机构包括超过500万名患者，减少肥胖症和相关的发病率和死亡率的策略，不仅会通过预防对患者护理产生有益的影响，而且可以通过预防产生有益的影响，而且可以在Veteran Healthcare的其他方面得到更好的储蓄。拟议的研究将解决有关调节食欲和饱腹感的机制的重要病理生理问题，并提供潜在的重要临床治疗策略。