Role of the foregut in nutrient metabolism in lean and obese humans

前肠在瘦人和肥胖人营养代谢中的作用

• 批准号: 9259965
• 负责人: Naji N Abumrad
• 金额: $ 34.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2020-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259965
• 关键词: Affect; Animals; Attention; Attenuated; Benzocaine; Biopsy; Body Weight decreased; Bypass; Carbohydrates; Comorbidity; Consumption; Data; Defect; Distal; Duodenum; Eating; Effectiveness; Endoscopy; Enteral; Fatty acid glycerol esters; Food; Future; Gastric Bypass; Gastrointestinal tract structure; Glucose; Health; Hepatic; High Fat Diet; Hindgut; Homeostasis; Hormonal; Human; Impairment; In Vitro; Infusion procedures; Intake; Intestines; Lipids; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Methodology; Molecular; Morbid Obesity; Neurosecretory Systems; Nonesterified Fatty Acids; Nutrient; Nutritional; Obesity; Operative Surgical Procedures; Pathway interactions; Pharmacologic Substance; Physiological; Plasma; Play; Population; Prevalence; Primitive foregut structure; Regulation; Rodent; Role; Sampling; Satiation; Signal Pathway; Taste Buds; Thinness; Tissues; Tracer; Translations; Triglycerides; Work; absorption; bariatric surgery; base; detection of nutrient; glucose production; glucose tolerance; glucose uptake; improved; in vivo; interest; jejunum; lipid mediator; metabolic rate; neurotransmission; nutrient absorption; nutrient metabolism; obesity treatment; oxidation; public health relevance; response; therapeutic target; trend; uptake

DESCRIPTION (provided by applicant): Obesity is highly related to excess nutrient intake, and particularly consumption of a high-fat diet. The prevalence of severe obesity (BMI e 35 kg/m2) is increasing more rapidly than general obesity trends, and is estimated to affect 6% of the population. This degree of obesity is a particularly significant health problem due to higher rates of metabolic co-morbidities. Gastric bypass surgery is the only effective means to achieve a meaningful and sustained weight loss and improve co-morbidities in people with a BMI e 35 kg/m2; however, this approach is not feasible to reverse global obesity rates. Work from our lab and others have described beneficial metabolic effects of gastric bypass that occur immediately after surgery and appear to be weight-loss independent. As a result, much attention has been placed on the gastrointestinal tract as a non-surgical therapeutic target for obesity and metabolic diseases. The intestines express numerous "taste" receptors that can sense the nutrient content of a meal and communicate this information to the body via hormonal and neuronal signals to control food intake, absorption, and metabolism. It has been shown that a high-fat diet can attenuate the ability of intestinal lipid to initiate neuroendocrine pathways tha promote satiety and reduce hepatic glucose production. Intestinal chemosensing is increasingly cited as a potential therapeutic target for obesity and metabolic diseases. Yet, much of the information related to nutrient sensing pathways has been derived from animal and in vitro studies, and it remains unknown whether foregut nutrient sensing mechanisms regulate food absorption and metabolism in humans. Given the prevalence of obesity and its significant health effects, the translation of intestinal chemosensing mechanisms in humans is extremely relevant. Our preliminary studies in humans suggest that the presence of a small amount of lipid in the duodenum, insufficient to increase circulating plasma free fatty acid and triglyceride levels, can decrease splanchnic glucose uptake and increase glucose oxidation and can also decrease hepatic glucose production. The overall hypothesis of this proposal is that lipid nutrient sensing in the foregut regulates glucose absorption and metabolism and these mechanisms might be defective in obesity. In this proposal, we will assess the effect of intestinal lipid infusions on splanchnic glucose absorption, oxidation, and metabolism in lean and obese humans. We will also examine the impact of obesity on the expression of molecular mediators of lipid nutrient sensing in duodenal biopsies obtained during upper endoscopy from obese and lean humans. The results of our studies will significantly advance the understanding of foregut nutrient sensing in humans and also determine if nutrient sensing is defective in obesity. Future studies will determine if foregut nutrient sensing contributes to the effectiveness of gastric bypass surgery to induce weight loss and improve nutrient metabolism. Foregut nutrient sensing may provide a therapeutic target for treatment of obesity alone or in conjunction with less invasive (but less effective) bariatric surgeries such as adjustable gastric banding.

描述(申请人提供)：肥胖与过量的营养摄入高度相关，特别是高脂肪饮食的消费。严重肥胖症(BMI为35公斤/平方米)的流行比一般肥胖症趋势增长得更快，估计影响到6%的人口。这种程度的肥胖是一个特别严重的健康问题，因为代谢合并症的发生率更高。胃旁路手术是实现有意义的、持续的体重减轻和改善体重指数为35公斤/平方米的人的合并症的唯一有效手段；然而，这种方法不能扭转全球肥胖率。我们实验室和其他实验室的工作已经描述了胃旁路手术的有益代谢效应，这种效应在手术后立即发生，似乎不依赖于减肥。因此，胃肠道作为肥胖和代谢性疾病的非手术治疗靶点而备受关注。肠道表达许多“味觉”感受器，这些感受器可以感知一顿饭的营养含量，并通过荷尔蒙和神经信号将这些信息传达给身体，以控制食物的摄取、吸收和代谢。已有研究表明，高脂饮食可以减弱肠道脂质启动神经内分泌通路的能力，从而促进饱腹感和减少肝脏葡萄糖的产生。肠道化学传感越来越多地被认为是肥胖和代谢性疾病的潜在治疗靶点。然而，许多与营养感知途径相关的信息都来自动物和体外研究，目前尚不清楚前肠营养感知机制是否调节人类对食物的吸收和代谢。鉴于肥胖症的流行及其对健康的重大影响，人类肠道化学感觉机制的翻译是非常相关的。我们对人类的初步研究表明，十二指肠中存在少量的脂肪，不足以增加循环中血浆游离脂肪酸和甘油三酯的水平，可以减少内脏葡萄糖摄取和增加葡萄糖氧化，也可以减少肝脏葡萄糖的产生。这一建议的总体假设是，前肠中的脂肪营养感应调节葡萄糖的吸收和代谢，而这些机制在肥胖中可能是有缺陷的。在这项建议中，我们将评估肠道脂肪输注对瘦人和肥胖者内脏葡萄糖吸收、氧化和代谢的影响。我们还将研究肥胖对肥胖者和瘦肉者十二指肠活检组织中脂质营养感知分子介体表达的影响。我们的研究结果将极大地促进对前肠营养传感的理解 还可以确定肥胖患者的营养感知是否存在缺陷。未来的研究将确定前肠营养感知是否有助于胃旁路手术的有效性 促进减肥，改善营养代谢。前肠营养感知可能为单独或与侵入性较小(但效果较差)的减肥手术(如可调胃束带术)联合治疗肥胖症提供治疗靶点。