Apo AIV-Induced Satiety and HF Diet-Induced Obesity

在本供资周期内，我们取得了重大进展，并提出了几点重要意见。首先，我们 证实载脂蛋白AIV是在下丘脑的弓状核合成的，在那里肥胖信号 采取行动影响能量动态平衡。此外，外源性载脂蛋白AIV外周或 中枢进入大脑可以减少食物摄入量和体重，并减少apo-aIV抗体的使用。 集中增加食物摄入量。其次，肥胖大鼠以高脂肪饱和饮食(HF-SAT，黄油)维持 脂肪)大大降低了下丘脑载脂蛋白AIV基因和蛋白的表达。第三。HF-SAT肥胖大鼠也 肠道和下丘脑apo AIV基因和蛋白对空腹和脂肪的反应减弱 与低脂(LF-SAT)饮食或食物喂养的大鼠相比。最后，我们发现， Apo AIV基因敲除(KO)小鼠更容易受到高脂(HF)饮食诱导的肥胖的影响。这些观察结果 这意味着正常的载脂蛋白AIV活动对于预防肥胖是必要的。来自我们的动物的初步证据 CORE建议，饮食中总脂肪含量相匹配，但使用橄榄油(富含油酸，一种单不饱和脂肪酸)的大鼠 脂肪，缩写为HF-Mono)比那些在HF-SAT饮食中肥胖的人更少。此外， 与喂食HF-SAT的大鼠不同，HF-Mono大鼠的下丘脑apo ATV基因表达没有降低。 我们假设载脂蛋白AIV能保护动物免受慢性禽流感引起的肥胖。 HF-SAT饮食的喂养和饮食中脂肪酸的类型调节下丘脑 Apo AIV基因和蛋白表达(饱和FA apo AIV表达，油酸 中性)。为了检验这些假设，我们提出了4个具体目标。特定目标1.2。(项目I、 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在饮食诱导中的作用 维持HF-SAT或HF-Mono饮食导致的肥胖。特定目标1.2。我们会 确定载脂蛋白AIV和CCK对食物摄入量的交互作用以及这种交互作用是否受 HF-SAT或HF-Mono的维护。特定目标1.3。我们将测试肠多肽的假说 会因饮食脂肪的不同而有所改变。特定目标1.4。这一特定目的利用载脂蛋白AIV 基因敲除(KO)鼠标作为补充其他特定目标和具体解决问题的工具 载脂蛋白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.