Mechanisms Regulating Neurotensin Secretion and Function

摘要 我们的多学科研究团队一直在研究神经降压素(NT)的功能和影响，这是一种 十三肽定位于专门化的肠内分泌细胞，主要在小肠，几乎有三个 几十年。对NT释放最有效的刺激是摄入膳食脂肪。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，以及 有助于整体新陈代谢，尽管它在这些过程中的确切作用还没有被清楚地描绘出来。 最近的研究已经确定了空腹Pro-NT(一种稳定的NT前体)增加与显著相关 以等摩尔量产生的碎片相对于NT)水平随着糖尿病的发展而增加，风险增加 心血管疾病和死亡率、非酒精性脂肪性肝病(NAFLD)和乳房风险增加 女性患癌症。这些发现确定了NT在脂代谢中的可能作用，并将NT水平的升高联系起来 与各种代谢性疾病、某些癌症和增加的发病率和死亡率有关。信号转导通路 而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缺口。 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。我们已经证明NT缺乏症 (使用NT基因敲除小鼠模型)减少体重增加、胰岛素抵抗和NAFLD相关 对于高脂肪消耗量，我们进一步证明了NT减弱AMP激活蛋白的激活 并通过一种涉及NTR1和NTR3/sortilin的机制刺激FA的吸收。 重要的是，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分级 与体重指数和胰岛素抵抗无关，这表明NT可能提供了一种 是未来肥胖的预测标志，也是预防和治疗肥胖的潜在靶点。因此，要 延长在此授权期内的调查结果，此续期申请的中心假设是NT 促进肠道和肝脏甘油三酯合成和抑制FA氧化的可能机制 涉及AMPK抑制；此外，NT通过抑制参与高脂饮食干扰脂肪细胞的脂肪分解 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 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(如非酒精性脂肪肝和胰岛素抵抗)。审视我们更好的长期目标 定义肠道NT的功能，我们组建了一个高度协作的团队，具有明确的NT专业知识 生理和功能；信号转导、新陈代谢和系统生物化学；以及生物统计和 计算生物学。最终，我们的发现将：i)显著推进胃肠道领域 生理学、内分泌学和新陈代谢；ii)改变关于NT的全身影响的现有范式； 以及iii)彻底改变我们对肠道激素的概念及其在代谢性疾病中的作用。

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.