Mechanisms Regulating Neurotensin Secretion and Function

调节神经降压素分泌和功能的机制

• 批准号: 10651886
• 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/10651886
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Adipose tissue; Affinity; Amino Acids; 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; Hormone Activity Inhibition; Hormones; Human; Ingestion; Innovative Therapy; Insulin Resistance; Interdisciplinary Study; Intestinal Hormones; Intestinal Mucosa; Intestines; Knockout Mice; Knowledge; Laboratories; 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; Publishing; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Small Intestines; Stimulus; System; Technology; Time; Transgenic Organisms; Triglycerides; Weight Gain; Woman; absorption; 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; 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.

摘要 我们的多学科研究团队一直在研究神经降压素（NT）的功能和作用， 十三肽定位于专门的肠内分泌细胞，主要在小肠，几乎三个 几十年NT释放的最有力刺激是摄入膳食脂肪。NT促进脂肪酸（FA） 在肠中的吸收，刺激具有高亲和力NT受体1（NTR 1）的癌症的生长，和 虽然它在这些过程中的确切作用还没有明确界定。 最近的研究已经确定了空腹前NT（一种稳定的NT前体）增加与 相对于NT以等摩尔量产生的片段）水平随着糖尿病的发展而增加， 心血管疾病和死亡率，非酒精性脂肪肝（NAFLD）和乳腺癌风险增加 女性的癌症这些发现确定了NT在脂质代谢中的可能作用，并将NT水平的增加 各种代谢疾病、某些癌症以及发病率和死亡率的增加。的信号通路 NT在摄入脂肪的吸收和储存中的作用是我们目前知识中的一个主要空白。 流行病学证据清楚地表明营养过剩和肥胖之间有直接联系;然而， 肥胖与营养过剩之间的分子机制仍不清楚。我们已经证明NT缺乏 （使用NT敲除小鼠模型）降低体重增加、胰岛素抵抗和NAFLD相关性 我们进一步证明NT减弱AMP激活蛋白的激活， 蛋白激酶（AMPK），并通过涉及NTR 1和NTR 3/分拣蛋白的机制刺激FA吸收。 重要的是，在人类中，我们发现，在一个分级的肥胖模型中，前NT水平的增加强烈预测新发肥胖。 的方式，这是独立的体重指数和胰岛素抵抗，这表明NT可能提供了一个 预测未来肥胖的标志物和肥胖预防和治疗的潜在靶点。因此 延长在此赠款期间所作的调查结果，本续期申请的中心假设是，NT 促进甘油三酯的合成，并可能通过一种机制抑制肠道和肝脏中的FA氧化 此外，NT通过抑制高脂饮食破坏的脂肪细胞脂解， 激素敏感脂肪酶（HSL）和脂肪甘油三酯脂肪酶（ATGL）的活性。我们推测 饮食中脂肪的过度消耗，导致NT分泌过多，导致肥胖（由于持续的脂肪 储存）和代谢紊乱（例如，NAFLD和胰岛素抵抗）。审视我们的长远目标， 定义肠道NT功能，我们已经组建了一个高度合作的团队，具有NT方面的专业知识， 生理学和功能;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，我们的研究结果将：i）显著推进胃肠道领域 生理学、内分泌学和代谢学; ii）改变关于NT的全身效应的现有范例; 和iii）彻底改变我们对肠道激素及其在代谢疾病中的作用的概念。