Mechanisms regulating neurotensin secretion and function

调节神经降压素分泌和功能的机制

• 批准号: 9219942
• 负责人: Bernard Mark Evers
• 金额: $ 44.02万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219942
• 关键词: 5' -AMP-activated protein kinase; Adipose tissue; Affinity; Amino Acids; Assimilations; Attenuated; Biochemistry; Biometry; Body mass index; Cells; Clinical; Colorectal Cancer; Complex; Computational Biology; Consumption; Development; Diabetes Mellitus; Diet therapy; Dietary Fats; Digestion; Distant; Drosophila genus; Endocrinology; Enterocytes; Enteroendocrine Cell; Epidemiology; Epigenetic Process; FRAP1 gene; Fasting; Fat Body; Fatty Liver; Fatty acid glycerol esters; Food; Future; Gastrointestinal Physiology; Genes; Genetic; Goals; Growth; Hepatocyte; High Fat Diet; Homeostasis; Hormones; Human; Ingestion; Innovative Therapy; Insulin Resistance; Intestinal Absorption; Intestinal Mucosa; Intestines; Knockout Mice; Laboratories; Lead; Length; Link; Lipids; Liver; MAPK3 gene; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Mediating; Metabolic Diseases; Metabolism; Midgut; Molecular; Morbidity - disease rate; Mus; Neurotensin; Neurotensin Receptors; Nonesterified Fatty Acids; Nutrient; Obesity; Overnutrition; Peptides; Physiology; Play; Population Study; Process; Protein Kinase; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Site; Small Intestines; Stimulus; Stomach; System; Time; Transgenic Organisms; Woman; absorption; base; blood glucose regulation; cardiovascular disorder risk; cell motility; disorder risk; epidemiology study; lipid metabolism; mTOR inhibition; malignant breast neoplasm; mortality; mouse model; multidisciplinary; non-alcoholic fatty liver; novel; overexpression; receptor; response; sortilin; uptake

ABSTRACT Neurotensin (NT) is a tridecapeptide localized to specialized enteroendocrine (EE) cells predominantly in the small bowel. The most potent stimulus for NT release is the ingestion of dietary fats. NT facilitates free fatty acid (FFA) absorption in the proximal intestine, stimulates growth of colorectal, pancreatic and breast cancers that have the high affinity NT receptor 1 (NTR1), and contributes to lipid metabolism and glucose control although its precise role in these processes has not been delineated. Recently, a large population study 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, and increased risk of breast cancer in women. Together, these findings identify an important role for NT in lipid metabolism and, moreover, links increased NT levels to various metabolic diseases and increased morbidity and mortality. Epidemiological evidence clearly shows direct linkage between overnutrition and obesity; however, the molecular mechanisms linking adiposity to overnutrition remain unknown. In exciting recent findings, we demonstrate that NT deficiency (using an NT knockout mouse model) protects against obesity, insulin resistance and non-alcoholic fatty liver disease (NAFLD) associated with high fat consumption; we further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FFA absorption through a mechanism involving NTR1 and NTR3/sortilin. Conversely, the overexpression of NT in Drosophila midgut EE cells increases lipid accumulation in the midgut, fat body and oenocytes (hepatocyte-like cells). Remarkably, 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 (BMI) and insulin resistance. Therefore, the central hypothesis for our current proposal is that FFA-mediated NT release by EE cells, through a cross-talk mechanism involving AMPK activation, mTOR inhibition, and ERK1/2 activation, promotes intestinal absorption of FFAs acting through NTR1 and/or NTR3 and the inhibition of intestinal AMPK. Moreover, we speculate that the overconsumption of dietary fats, which leads to excess NT secretion, results in obesity (from continued fat storage) and metabolic disorders (e.g., hepatic steatosis and insulin resistance). To examine our long-term goal of better defining intestinal NT secretion and function, we have assembled a multidisciplinary and highly collaborative team with defined expertise in NT physiology and function; metabolism and systems biochemistry; Drosophila genetics; and, biostatistics/computational biology. Ultimately, our findings will: i) significantly advance the fields of GI 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 obesity and metabolic diseases.

摘要 神经降压素(NT)是一种定位于专门的肠内分泌(EE)细胞的十三肽 在小肠里。对NT释放最有效的刺激是摄入膳食脂肪。NT提供免费服务 脂肪酸(FFA)在近端肠道的吸收，促进结直肠、胰腺和乳房的生长 具有高亲和力NT受体1(NTR1)并对脂肪代谢和葡萄糖有贡献的癌症 控制，尽管它在这些进程中的确切作用还没有被描述。最近，一大批人 研究发现，空腹蛋白-NT(一种稳定的NT前体片段)的增加与显著相关 等摩尔量相对于NT)水平随着糖尿病的发展，心血管风险增加 疾病和死亡率，以及妇女患乳腺癌的风险增加。总而言之，这些发现确定了一个 NT在脂类代谢中的重要作用，此外，NT水平的升高与各种代谢有关 疾病和发病率和死亡率的增加。 流行病学证据清楚地表明营养过剩和肥胖之间存在直接联系；然而， 将肥胖与营养过剩联系起来的分子机制仍不清楚。在最近令人兴奋的发现中，我们 证明NT缺乏(使用NT基因敲除的小鼠模型)可以预防肥胖、胰岛素 与高脂肪摄入量相关的抵抗力和非酒精性脂肪性肝病；我们进一步 证明NT可减弱AMP激活的蛋白激酶(AMPK)的激活并刺激FFA 通过NTR1和NTR3/sortilin的机制吸收。反之，NT在 果蝇中肠EE细胞增加中肠、脂肪体和卵母细胞(肝细胞样细胞)中的脂肪积聚 单元格)。值得注意的是，在人类中，我们表明Pro-NT水平的增加强烈地预测了新发肥胖的发生。 分级方式，不受体重指数(BMI)和胰岛素抵抗的影响。因此， 我们目前提议的中心假设是FFA通过串扰由EE细胞介导的NT释放 AMPK激活、mTOR抑制和ERK1/2激活的机制促进肠道吸收 通过NTR1和/或NTR3作用的游离脂肪酸以及对肠道AMPK的抑制。此外，我们推测， 过度摄入膳食脂肪，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，肝脏脂肪变性和胰岛素抵抗)。来审视我们的长期 为了更好地定义肠道NT的分泌和功能，我们已经组装了一个多学科的高度 在NT生理和功能、新陈代谢和系统方面具有明确专业知识的协作团队 生物化学；果蝇遗传学；以及生物统计学/计算生物学。最终，我们的发现将：i) 显著推进胃肠道生理学、内分泌学和新陈代谢领域；二)改变现有范式 关于NT的全身性影响；以及，iii)彻底改变我们对胃肠激素的概念及其在 肥胖和代谢性疾病。