Mechanisms for the Ghrelin Response to Caloric Restriction and Gastric Bypass

胃饥饿素对热量限制和胃绕道的反应机制

• 批准号: 8827170
• 负责人: Aki Uchida
• 金额: $ 3.81万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827170
• 关键词: Adrenergic Receptor; Applications Grants; Blood Glucose; Body Weight; Body Weight decreased; Bypass; Caloric Restriction; Catecholamines; Cell physiology; Cells; Cellular Morphology; Chronic; Comorbidity; Diet; Eating; Endocrine; Endocrinology; Enteroendocrine Cell; Epinephrine; Funding; Gastric Bypass; Gastrointestinal Hormones; Gastrointestinal tract structure; Glucagon; Glucose; Homeostasis; Hormones; Human; Hypoglycemia; Individual; Link; Measures; Mediating; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; Norepinephrine; Obesity; Operative Surgical Procedures; Physiology; Plasma; Play; Rattus; Relative (related person); Reporter; Reporting; Research; Research Personnel; Research Training; Rodent; Secretory Vesicles; Signal Transduction; Somatotropin; Stomach; Sympathetic Nervous System; Testing; Time; Training; Weight Gain; career; cell type; diabetic; feeding; ghrelin; glycemic control; human subject; improved; insight; insulin secretion; insulin sensitivity; interest; mortality; novel strategies; obesity treatment; peptide hormone; prevent; public health relevance; research study; response; sham surgery; skills

DESCRIPTION (provided by applicant): Ghrelin is a peptide hormone secreted mainly from cells of the gastrointestinal tract. It plays key roles in regulating food intake, energy homeostass and blood glucose. Circulating ghrelin rises during times of relative energy insufficiency, for example prior to set meals or upon more prolonged caloric restriction (CR), thus stimulating food intake and replenishment of energy stores. Low glucose levels also stimulate ghrelin release, initiating changes in insulin sensitivity and the secretion of insulin, glucagon and growt hormone, thus restoring normal blood glucose levels. The compensatory rise in ghrelin has been postulated to contribute to the rebound weight gain that often occurs in the setting of weight loss as achieved by dietary CR, and is required to prevent marked hypoglycemia when the CR is severe. Roux-en-Y gastric bypass (RYGB) represents a much more effective means of weight loss than CR, resulting in both a greater and more prolonged reduction of body weight, lowered mortality and amelioration of several comorbidities, including a rapid improvement in blood glucose levels of obese diabetic individuals. In contrast to most other forms of weight loss, including CR, most studies have shown an atypical ghrelin response (either decrease or lack of increase) following RYGB. Thus the differential ghrelin secretory response in the settings of CR (compensatory) vs. RYGB (atypical) may contribute to the differential efficacies of these two weight loss methods. However, the mechanisms controlling ghrelin secretion in general, including in the specific situations of chronic CR and RYGB, remain undetermined. The central theme of this proposal is to identify mechanisms mediating the differential ghrelin secretory responses to severe CR and RYGB. In this application, we will compare changes observed in calorically restricted vs. ad libitum-fed mice (Specific Aim 1) and in RYGB- manipulated vs. sham surgery-treated mice (Specific Aim 2). We will assess changes to the number of and ultra-structural organization of secretory granules within ghrelin cells and their distribution in relatin to other enter endocrine cells. We will assess changes in the sensitivity of ghrelin cells to sympathetic signaling and glucose. The findings from this proposal should provide important insights regarding the enteroendocrine contribution to both surgical and non-surgical weight loss. Our long-term objective is to uncover novel approaches to augment surgical weight loss or even to replace operative treatment for obesity and other metabolic diseases. Moreover, this research plan and its accompanying training plan will provide me with the opportunity to acquire research and analytical skills necessary to develop my own specific research interests and to pursue a career as a productive, independently-funded investigator in endocrinology and metabolism.

描述（由申请人提供）：Ghrelin是一种主要由胃肠道细胞分泌的肽激素。它在调节食物摄入、能量稳态和血糖方面起着关键作用。循环饥饿素在相对能量不足的时间期间升高，例如在固定膳食之前或在更长时间的热量限制（CR）时，从而刺激食物摄入和能量储存的补充。低葡萄糖水平也刺激生长素释放，引发胰岛素敏感性和胰岛素、胰高血糖素和生长激素分泌的变化，从而恢复正常的血糖水平。胃饥饿素的代偿性升高被认为有助于体重反弹，这通常发生在通过饮食CR实现的体重减轻的情况下，并且当CR严重时，需要防止明显的低血糖。Roux-en-Y胃旁路术（RYGB）是一种比CR更有效的减肥方法，可使体重减轻幅度更大、时间更长，死亡率降低，并改善多种合并症，包括快速改善肥胖糖尿病患者的血糖水平。与大多数其他形式的减肥相比， 包括CR在内，大多数研究显示RYGB后的非典型生长素释放肽应答（减少或不增加）。因此，在CR（代偿性）与RYGB（非典型）的设置中的差异生长激素释放肽分泌反应可能有助于这两种减肥方法的差异功效。然而，一般控制生长素释放肽分泌的机制，包括在慢性CR和RYGB的特定情况下，仍然不确定。该建议的中心主题是确定介导严重CR和RYGB的不同ghrelin分泌反应的机制。在本申请中，我们将比较热量限制与自由进食小鼠（特定目标1）和RYGB操作与假手术处理小鼠（特定目标2）中观察到的变化。我们将评估生长素释放肽细胞内分泌颗粒的数量和超微结构组织的变化及其与其他内分泌细胞的关系。我们将评估生长激素释放肽细胞对交感神经信号和葡萄糖的敏感性的变化。这项建议的发现应该提供关于肠内分泌对手术和非手术减肥的贡献的重要见解。我们的长期目标是发现新的方法来增加手术减肥，甚至取代肥胖和其他代谢性疾病的手术治疗。此外，这个研究计划及其附带的培训计划将为我提供机会，获得必要的研究和分析技能，以发展我自己的特定研究兴趣，并追求作为一个富有成效的，独立资助的内分泌学和代谢研究者的职业生涯。