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（由申请人提供）：肥胖与营养摄入过多，特别是高脂肪饮食的摄入密切相关。严重肥胖患病率（BMI为35 kg/m2）的增长速度超过一般肥胖趋势，估计影响6%的人口。由于代谢并发症的发生率较高，这种程度的肥胖是一个特别重要的健康问题。胃旁路手术是实现有意义和持续的体重减轻和改善BMI为35 kg/m2的人的合并症的唯一有效手段；然而，这种方法在扭转全球肥胖率方面并不可行。我们的实验室和其他人的工作已经描述了胃旁路术在手术后立即发生的有益代谢作用，并且似乎与减肥无关。因此，胃肠道作为肥胖和代谢性疾病的非手术治疗靶点受到了广泛的关注。肠道表达了许多“味觉”受体，它们可以感知食物中的营养成分，并通过激素和神经元信号将这些信息传递给身体，以控制食物的摄入、吸收和新陈代谢。研究表明，高脂肪饮食可以减弱肠道脂质启动神经内分泌通路的能力，从而促进饱腹感并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，大部分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的食物吸收和代谢。鉴于肥胖的普遍存在及其对健康的重大影响，肠道化学感应机制的翻译在人类中是非常相关的。我们对人类的初步研究表明，十二指肠中存在少量脂质，不足以增加循环血浆游离脂肪酸和甘油三酯水平，可以减少内脏葡萄糖摄取，增加葡萄糖氧化，也可以减少肝脏葡萄糖生成。该建议的总体假设是，前肠的脂质营养感知调节葡萄糖的吸收和代谢，而这些机制可能在肥胖中存在缺陷。在这个提议中，我们将评估肠道脂质输注对瘦人和肥胖人内脏葡萄糖吸收、氧化和代谢的影响。我们还将研究肥胖对脂质营养感知分子介质表达的影响，这些介质是在肥胖和瘦人的上内窥镜检查中获得的十二指肠活检结果。我们的研究结果将显著促进对前肠营养感知的理解