MODULATION OF INTESTINAL OBESITY SIGNALS

肠道肥胖信号的调节

• 批准号: 6198963
• 负责人: PATRICK TSO
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198963
• 关键词: apolipoproteins; biological signal transduction; blood lipoprotein biosynthesis; chylomicrons; dietary lipid; gastrointestinal nutrient absorption; genetically modified animals; gluconeogenesis; glucose; laboratory mouse; laboratory rat; lipid metabolism; lymphatic system; nutrition related tag; obesity

Considerable evidence indicates that the ingestion of a high-fat (HF) diet predisposes humans and animals to obesity. The applicants hypothesize that: (1) apolipoprotein A-IV (apo A-IV) is an endogenous signal for fat absorption by gastrointestinal apo A-IV production and secretion in response to lipids in the gastrointestinal tract; (2) chronic high-fat diets alter the metabolism of chylomicron (CM) by altering its physiochemical nature; and (3) chronic consumption of a high-fat diet increases the secretion and/or action of intestinal factors that facilitate fat absorption and predispose the body to increase the storage of fat in adipose tissue. SPECIFIC AIM 1. The applicants will determine the dose-response relationship between the dose of lipid fed and the mRNA levels, synthesis and secretion of apo A-IV by the jejunum in animals fed chronically HF compared to low-fat (LF). They will also compare the A-IV response to lipid feeding in jejunum and in ileum and also the type of fat. In addition, they will determine if apo A-IV may be involved in the long-term regulation of food intake and body weight regulation. Specifically, they will use the apo A-IV knockout and transgenic mouse to address this question. SPECIFIC AIM 2. The applicants will test the hypothesis that chronic HF diets alter the metabolism of CM by studying the plasma removal of both the labeled triglyceride and cholesterol ester moieties of the chylomicron (CM) from the HF and LF animals. SPECIFIC AIM 3. The applicants recently discovered that the small intestine secretes glucose in response to a lipid meal and that the glucose concentration in lymph is directly proportional to the amount of lipid transported by the small intestine (r = +0.97). They will test the hypothesis that the gut secretes glucose during lipid absorption and that the gut and/or the lymphatic ducts detect this intestinally-derived de novo glucose. They further hypothesize that the amount of glucose acts as a signal indicating the amount of fat being transported by the small intestine. A corollary hypothesis is that the amount of glucose synthesized and released per unit of fat absorbed, or else the impact of this glucose signaling, is altered by high-fat feeding. In addition, the apo A-IV knockout and transgenic animals will be used to determine if there is interaction between the lymph glucose and lymph apo A-IV signals.

大量证据表明摄入高脂 （HF）饮食使人类和动物易于肥胖。申请人假设 那是：（1）载脂蛋白A-IV（Apo A-IV）是脂肪的内源信号 胃肠道APO A-IV产生和分泌的吸收 胃肠道中的脂质； （2）慢性高脂饮食改变 通过改变其生理化学性质的乳糜微粒（CM）代谢； （3） 长期消费高脂饮食会增加分泌和/或作用 促进脂肪吸收并使身体易于诱发的肠道因素 增加脂肪在脂肪组织中的储存。特定目标1。申请人 将确定脂质剂剂量和 空肠在动物中对Apo A-IV的MRNA水平，合成和分泌 与低脂（LF）相比，饲喂长期HF。他们还将比较A-IV 对空肠和回肠的脂质进食的反应以及脂肪的类型。在 此外，他们还将确定是否可能参与长期的APO A-IV 调节食物摄入和体重调节。具体来说，他们会的 使用APO A-IV敲除和转基因鼠标来解决此问题。 具体目的2。申请人将检验慢性HF饮食的假设 通过研究两个标记的血浆去除来改变CM的代谢 HF的酪蛋白（CM）的甘油三酸酯和胆固醇酯部分 和LF动物。特定目标3。申请人最近发现 小肠响应脂质餐，分泌葡萄糖， 淋巴中的葡萄糖浓度与脂质的量成正比 由小肠运输（r = +0.97）。他们将检验假设 肠道在脂质吸收过程中分泌葡萄糖，肠道和/或 淋巴管检测到这种衍生的从头葡萄糖。他们 进一步假设葡萄糖的量充当信号，表明 小肠传输的脂肪量。推论假设 是每单位脂肪合成并释放的葡萄糖量 吸收，否则该葡萄糖信号的影响会被高脂改变 进食。此外，将使用Apo A-IV敲除和转基因动物 确定淋巴葡萄糖和淋巴APO之间是否存在相互作用 A-IV信号。