Apo AIV-Induced Satiety and HF Diet-Induced Obesity

在本供资周期，我们取得了重大进展，并提出了几项重要意见。一是 表明apoAIV是在下丘脑的弓状核合成的，在那里肥胖信号 影响能量平衡。此外，外源性apo AIV的外周或外周给药也是有效的。 中枢进入大脑减少了食物摄入和体重， 中枢增加食物摄入。第二，肥胖大鼠维持高脂肪饱和饮食（HF-SAT，黄油 脂肪）大大降低了下丘脑载脂蛋白AIV基因和蛋白的表达。三分之HF-SAT肥胖大鼠也 肠道和下丘脑apo AIV基因和蛋白对禁食和脂质的反应减弱 当与维持低脂肪（LF-SAT）饮食或食物的大鼠相比时，最后，我们发现， apo AIV敲除（KO）小鼠更易患高脂肪（HF）饮食诱导的肥胖症。这些观察结果 这意味着正常载脂蛋白AIV活性是预防肥胖所必需的。动物的初步证据 Core的研究表明，大鼠维持在总脂肪相匹配的饮食中，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）比HF-SAT饮食的肥胖率低。此外，委员会认为， 与喂食HF-SAT的大鼠不同，HF-MONO大鼠的下丘脑apoATV基因表达没有降低。 我们假设载脂蛋白AIV保护动物免受由慢性炎症引起的肥胖。 喂食HF-SAT饮食，饮食中的脂肪酸类型调节下丘脑 apo AIV基因和蛋白表达（饱和FA apo AIV表达，而油酸是 中性）。为了验证这些假设，我们提出了四个具体目标。具体目标1.2.（项目i， 具体目的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 由维持HF-SAT或HF-MONO饮食引起的肥胖。具体目标1.2.我们将 确定载脂蛋白AIV和CCKon食物摄入的相互作用，以及这种相互作用是否受到以下因素的影响： 维护HF-SAT或HF-MONO。具体目标1.3.我们将检验肠道肽 都被膳食脂肪改变了具体目标1.4.这一具体目标利用载脂蛋白AIV 敲除（KO）小鼠作为补充其他特定目标并具体解决问题的工具 apo AIV是否保护动物免受饮食诱导的肥胖。

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.