Mechanisms Regulating Neurotensin Secretion and Function

调节神经降压素分泌和功能的机制

• 批准号: 10536470
• 负责人: Bernard Mark Evers
• 金额: $ 66.97万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536470
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Adipose tissue; Affinity; Amino Acids; Assimilations; Attenuated; Biochemistry; Biological Models; Biometry; Body Weight decreased; Body mass index; Breast Cancer Risk Factor; Cells; Clinical; Computational Biology; Consumption; Development; Diabetes Mellitus; Dietary Fats; Digestion; Disease; Disease Resistance; Distant; Drosophila genus; Endocrinology; Enteroendocrine Cell; Epidemiology; Epigenetic Process; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Gastrointestinal Hormones; Gastrointestinal Physiology; Genes; Genetic; Goals; Grant; Growth; Hepatic; High Fat Diet; Homeostasis; Hormones; Human; Ingestion; Innovative Therapy; Insulin Resistance; Interdisciplinary Study; Intestinal Hormones; Intestinal Mucosa; Intestines; Knockout Mice; Knowledge; Laboratories; Lead; Length; Link; Lipase; Lipids; Lipolysis; Liver; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolic Diseases; Metabolism; Molecular; Morbidity - disease rate; Mus; Neurotensin; Neurotensin Receptors; Nutrient; Obesity; Organ; Overnutrition; Physiological; Physiology; Play; Prevention; Process; Prognostic Marker; Protein Kinase; Publishing; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Small Intestines; Stimulus; System; Technology; Time; Transgenic Organisms; Triglycerides; Weight Gain; Woman; absorption; base; blood glucose regulation; cardiovascular disorder risk; diet-induced obesity; drug development; experimental study; fatty acid oxidation; insight; lipid biosynthesis; lipid metabolism; metabolomics; mortality; mouse model; multidisciplinary; non-alcoholic fatty liver disease; novel; obesity prevention; obesity treatment; receptor; response; sortilin; sterol esterase; uptake

ABSTRACT Our multidisciplinary research team has been studying the function and effects of neurotensin (NT), a tridecapeptide localized to specialized enteroendocrine cells predominantly in the small bowel, for almost three decades. The most potent stimulus for NT release is ingestion of dietary fats. NT facilitates fatty acid (FA) absorption in the intestine, stimulates growth of cancers that have the high affinity NT receptor 1 (NTR1), and contributes to overall metabolism although its precise role in these processes has not been clearly delineated. Recent studies have identified a significant association of increased fasting pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) levels with the development of diabetes, increased risk of cardiovascular disease and mortality, non-alcoholic fatty liver disease (NAFLD), and increased risk of breast cancer in women. These findings identify a possible role for NT in lipid metabolism and link increased NT levels to various metabolic diseases, certain cancers and increased morbidity and mortality. The signaling pathways and role for NT in the absorption and storage of ingested fats represents a major gap in our current knowledge. Epidemiological evidence clearly shows a direct linkage between overnutrition and obesity; however, the molecular mechanisms linking adiposity to overnutrition remain unknown. We have shown that NT deficiency (using an NT knockout mouse model) decreases body weight gain, insulin resistance and NAFLD associated with high fat consumption; we further demonstrated that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption through a mechanism involving NTR1 and NTR3/sortilin. Importantly, in humans, we show that increased levels of pro-NT strongly predict new onset obesity in a graded manner, which is independent of body mass index and insulin resistance, suggesting that NT may provide a prognostic marker of future obesity and a potential target for obesity prevention and treatment. Therefore, to extend the findings made during this grant period, the central hypothesis for this renewal application is that NT promotes triglyceride synthesis and suppresses FA oxidation in the intestine and liver likely through a mechanism involving AMPK inhibition; moreover, NT contributes to high-fat diet-disrupted adipocyte lipolysis via inhibiting activity of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). We speculate that overconsumption of dietary fats, which leads to excess NT secretion, results in obesity (from continued fat storage) and metabolic disorders (e.g., NAFLD and insulin resistance). To examine our long-term goal of better defining intestinal NT function, we have assembled a highly collaborative team with defined expertise in NT physiology and function; signal transduction, metabolism and systems biochemistry; and biostatistics and computational biology. Ultimately, our findings will: i) significantly advance the fields of gastrointestinal physiology, endocrinology and metabolism; ii) change existing paradigms regarding the systemic effects of NT; and iii) revolutionize our concept of gut hormones and their role in metabolic diseases.

抽象的 我们的多学科研究团队一直在研究神经素（NT）的功能和影响， 三肽肽本地定位于专业的肠内分泌细胞，主要是在小肠中，近三个 几十年。 NT释放最有效的刺激是摄入饮食脂肪。 NT促进脂肪酸（FA） 肠道吸收，刺激具有高亲和力NT受体1（NTR1）的癌症的生长，并且 尽管尚未清楚地描绘出其在这些过程中的精确作用，但促进了整体代谢。 最近的研究已经确定了空腹促进率增加的显着关联（稳定的NT前体 与糖尿病的发展相对于NT的水平，以等效量产生的碎片，风险增加 心血管疾病和死亡率，非酒精性脂肪肝疾病（NAFLD）和乳房风险增加 女性的癌症。这些发现确定了NT在脂质代谢中的可能作用，并联系了NT水平提高 对于各种代谢疾病，某些癌症以及发病率和死亡率提高。信号通路 NT在吸收和存储摄入的脂肪中的作用是我们当前知识的主要差距。 流行病学证据清楚地表明了营养和肥胖之间的直接联系。但是， 将肥胖与营养不良联系起来的分子机制尚不清楚。我们已经证明了NT缺乏症 （使用NT敲除鼠标模型）减少体重增加，胰岛素抵抗和NAFLD相关 高脂消耗；我们进一步证明了NT减弱了AMP激活蛋白的激活 激酶（AMPK）并通过涉及NTR1和NTR3/Tortilin的机制刺激FA吸收。 重要的是，在人类中，我们表明，提高的Pro-NT水平强烈预测了分级的新发作肥胖 与体重指数和胰岛素抵抗无关的方式，表明NT可以提供 未来肥胖症的预后标志和预防肥胖症和治疗的潜在靶标。因此，要 扩展了在此赠款期间提出的发现，此续签申请的中心假设是 促进甘油三酸酯的合成并抑制可能通过机制的肠和肝脏中的FA氧化 涉及AMPK抑制；此外，新约通过抑制有助于高脂饮食脂肪细胞脂肪分解 激素敏感脂肪酶（HSL）和脂肪甘油三酸酯脂肪酶（ATGL）的活性。我们推测 饮食脂肪的过度消费会导致NT分泌过多，导致肥胖症（来自持续脂肪 储存）和代谢性疾病（例如NAFLD和胰岛素抵抗）。检查我们的长期目标 定义NT NT功能，我们组建了一个高度协作的团队，在NT中具有明确的专业知识 生理和功能；信号转导，代谢和系统生物化学；和生物统计学和 计算生物学。最终，我们的发现将：i）大大提高胃肠道的领域 生理学，内分泌学和代谢； ii）更改有关NT系统影响的现有范例； iii）彻底改变了我们对肠道激素的概念及其在代谢疾病中的作用。