Apo AIV-Induced Satiety and HF Diet-Induced Obesity

Apo AIV 引起的饱腹感和高频饮食引起的肥胖

• 批准号: 7425075
• 负责人: PATRICK TSO
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425075
• 关键词: Address; Animals; Antibodies; Attenuated; Biology; Body Weight; Brain; Butter; Cholecystokinin; Chronic; Chylomicrons; Complement; Diet; Dietary Fats; Dose; Eating; Fasting; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Fistula; Funding; Gene Expression; Gene Proteins; Genetic Transcription; Goals; Homeostasis; Hypothalamic structure; Infusion procedures; Intake; Intestines; Knock-out; Knockout Mice; Laboratories; Lead; Lipids; Lymph; Maintenance; Modeling; Mono-S; NBS1 gene; Nuclear; Obesity; Oils; Oleic Acid; Oleic Acids; Olive oil preparation; Peptides; Plasma; Positioning Attribute; Principal Investigator; Progress Reports; Rate; Rattus; Relative (related person); Research Personnel; Role; Run-On Assays; Satiation; Saturated Fatty Acids; Series; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Unsaturated Fats; Unsaturated Fatty Acids; Wild Type Mouse; Wood material; absorption; apolipoprotein A-IV; cholecystokinin 8; feeding; interest; novel; prevent; protein expression; research study; response; saturated fat; size; tool

During the current funding cycle, we made significant progress and made several key observations. First, we demonstrated that apo AIV is synthesized in the arcuate nucleus of the hypothalamus where adiposity signals act to influence energy homeostasis. Also, the administration of exogenous apo AIV either peripherally or centrally into the brain reduces food intake and body weight, and the administration of apo AIV antibodies centrally increases food intake. Second, obese rats maintained on a high fat saturated diet (HF-SAT, butter fat) have greatly reduced hypothalamic apo AIV gene and protein expression. Third. HF-SAT obese rats also have an attenuated intestinal and hypothalamic apo AIV gene and protein response to fasting and lipid feeding when compared to rats maintained on a low-fat (LF-SAT) diet or chow. Finally, we found that apo AIV knockout (KO) mice are more susceptible to high-fat (HF) diet-induced obesity. These observations imply that normal apo AIV activity is necessary to prevent obesity. Preliminary evidence from our Animal Core suggest that rats maintained on a diet matched in total fat but using olive oil (rich in oleic acid, a monounsaturated fat, abbreviated as HF-MONO) had less obesity than those on the HF-SAT diet. Furthermore, unlike the HF-SAT fed rats, the HF-MONO rats did not have reduced hypothalamic apo ATV gene expression. We hypothesize that apo AIV protects the animal against obesity caused by the chronic feeding of a HF-SAT diet and that the type of fatty acid in the diet regulates hypothalamic apo AIV gene and protein expression (saturated FA apo AIV expression while oleic acid is neutral). To test these hypotheses, we have proposed 4 specific aims. SPECIFIC AIM 1.2. (Project i, Specific Aim i) We will determine the role of intestinal apo AIV and hypothalamic apo AIV in diet-induced obesity caused by maintenance on a HF-SAT or a HF-MONO diet. SPECIFIC AIM 1.2. We will determine the interaction of apo AIV and CCKonfood intake and whether this interaction is influenced by maintenance on HF-SAT or HF-MONO. SPECIFIC AIM 1.3. We will test the hypothesis that gut peptides are differentially modified by dietary fats. SPECIFIC AIM 1.4. This specific aim utilizes the apo AIV knockout (KO) mouse as a tool to complement the other specific aims and to specifically address the question of whether apo AIV protects the animal against diet-induced obesity.

在当前的融资周期中，我们取得了重大进展并提出了一些关键观察结果。首先，我们 证明 apo AIV 在下丘脑的弓状核中合成，其中肥胖信号 影响能量稳态。此外，外源性apo AIV的给药可以是外周给药，也可以是外源性apo AIV给药。 集中进入大脑可减少食物摄入量和体重，并且apo AIV抗体的施用 集中增加食物摄入量。其次，肥胖大鼠维持高脂肪饱和饮食（HF-SAT、黄油 脂肪）大大降低了下丘脑apo AIV基因和蛋白质的表达。第三。 HF-SAT 肥胖大鼠也 肠道和下丘脑 apo AIV 基因和蛋白质对禁食和脂质的反应减弱 与维持低脂（LF-SAT）饮食或食物的大鼠相比。最后，我们发现 apo AIV 基因敲除 (KO) 小鼠更容易受到高脂肪 (HF) 饮食引起的肥胖的影响。这些观察 表明正常的 apo AIV 活性对于预防肥胖是必要的。来自我们动物的初步证据 核心建议，老鼠维持与总脂肪相匹配的饮食，但使用橄榄油（富含油酸，一种单不饱和脂肪酸） 脂肪（缩写为 HF-MONO）的肥胖率比那些采用 HF-SAT 饮食的人要少。此外， 与 HF-SAT 喂养的大鼠不同，HF-MONO 大鼠的下丘脑 apo ATV 基因表达没有减少。 我们假设 apo AIV 可以保护动物免受慢性肥胖症引起的肥胖的影响。 喂养 HF-SAT 饮食以及饮食中的脂肪酸类型调节下丘脑 apo AIV 基因和蛋白质表达（饱和 FA apo AIV 表达，而油酸为 中性的）。为了检验这些假设，我们提出了 4 个具体目标。具体目标 1.2。 （项目一， 具体目标 i) 我们将确定肠道载脂蛋白 AIV 和下丘脑载脂蛋白 AIV 在饮食诱导的中的作用 因维持 HF-SAT 或 HF-MONO 饮食而导致的肥胖。具体目标 1.2。我们将 确定 apo AIV 和 CCKonfood 摄入量的相互作用以及这种相互作用是否受到 HF-SAT 或 HF-MONO 的维护。具体目标 1.3。我们将检验肠道肽的假设 受膳食脂肪的不同改变。具体目标 1.4。这一特定目标利用了 apo AIV 敲除（KO）小鼠作为补充其他特定目标并专门解决问题的工具 apo AIV 是否可以保护动物免受饮食引起的肥胖。