Mechanisms regulating neurotensin secretion and function

摘要 神经降压素（neurotensin，NT）是一种十三肽，主要定位于特化的肠内分泌（enteroendocrine，EE）细胞 在小肠里。NT释放的最有力刺激是摄入膳食脂肪。新界方便免费 脂肪酸（FFA）在近端肠道吸收，刺激结直肠、胰腺和乳腺的生长 具有高亲和力NT受体1（NTR 1）并有助于脂质代谢和葡萄糖代谢的癌症 控制，但其在这些过程中的确切作用尚未确定。最近，大量的人口 一项研究发现，空腹前NT（一种稳定的NT前体片段， 在相对于NT等摩尔量）水平与糖尿病的发展，心血管疾病的风险增加 疾病和死亡率，以及妇女患乳腺癌的风险增加。总之，这些发现确定了一个 NT在脂质代谢中的重要作用，此外，将增加的NT水平与各种代谢 疾病和发病率和死亡率增加。 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。在最近令人兴奋的发现中，我们 证明NT缺乏（使用NT敲除小鼠模型）可防止肥胖、胰岛素 抵抗和非酒精性脂肪性肝病（NAFLD）与高脂肪消费相关;我们进一步 表明NT减弱AMP活化蛋白激酶（AMPK）的活化并刺激FFA 通过涉及NTR 1和NTR 3/分拣蛋白的机制吸收。相反，NT的过度表达在 果蝇中肠EE细胞增加中肠、脂肪体和卵母细胞（肝细胞样）中的脂质积累 细胞）。值得注意的是，在人类中，我们表明，增加的pro-NT水平强烈预测新发肥胖， 分级方式，与体重指数（BMI）和胰岛素抵抗无关。因此 我们目前的建议的中心假设是FFA介导的NT释放EE细胞，通过一个串扰， 涉及AMPK激活、mTOR抑制和ERK 1/2激活的机制促进肠吸收 FFAs通过NTR 1和/或NTR 3起作用以及抑制肠AMPK。此外，我们推测， 饮食脂肪的过度消耗导致NT分泌过多，导致肥胖（来自持续的脂肪 储存）和代谢紊乱（例如，肝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分泌和功能，我们组装了一个多学科和高度 具有NT生理学和功能、代谢和系统方面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，我们的研究结果将：i） 显著推进胃肠道生理学、内分泌学和代谢领域; ii）改变现有范式 关于NT的全身效应;以及，iii）彻底改变我们对肠道激素及其在 肥胖和代谢性疾病。

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.