Control of Energy Balance by ApoJ Signaling

通过 ApoJ 信号传导控制能量平衡

• 批准号: 9234692
• 负责人: YOUNG-BUM KIM
• 金额: $ 43.63万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234692
• 关键词: Anorexia; Area; Astrocytes; Biological Process; Body Weight; Body Weight decreased; Cell membrane; Complex; Coupled; Data; Diabetes Mellitus; Eating; Endocytosis; Energy Metabolism; Feeding behaviors; Genes; Goals; Grant; Homeostasis; Human; Hyperphagia; Hypothalamic structure; Impairment; Injection of therapeutic agent; Knowledge; LDL-Receptor Related Protein 1; Lead; Leptin; Link; LoxP-flanked allele; Maintenance; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiology; Play; Receptor Signaling; Risk Factors; Role; SF1; Signal Pathway; Signal Transduction; System; Technology; Testing; Tyrosine; Weight Gain; db/db mouse; energy balance; experimental study; feeding; genetic variant; human disease; in vivo; leptin receptor; new therapeutic target; novel; obesity treatment; receptor

Hypothalamic feeding circuits are essential for the maintenance of energy balance. Impairments in this feeding regulatory system cause hyperphagia, which then promotes adiposity and weight gain. However, knowledge of the critical anorexigenic signaling cascade involved in the hypothalamus remains incomplete. ApolipoproteinJ (ApoJ) was not previously suspected to be involved in hypothalamic control of feeding behavior and energy balance. We now have provided the preliminary data that ApoJ functions as such an anorexigenic molecule, targeting leptin signaling and energy balance in the hypothalamus, which could be mediated via the LRP1 (low- density lipoprotein receptor-related protein-1) signaling cascade. We found that centrally administered ApoJ in mice lead to anorexia and weight loss, whereas deletion of hypothalamic ApoJ results in hyperphagia and sever obesity. Specifically, deficiency of ApoJ in astrocytes, but not in AgRP, POMC, and SF-1 neurons, leads to obesity, suggesting that astrocytic ApoJ is important in regulating normal body-weight homeostasis. Like leptin, ApoJ activated Stat3 in leptin receptor (LepR)-expressing neurons but this effect was abolished in LepR- deficient db/db mice, indicating the necessity of LepR signaling for ApoJ's effect. Importantly, ApoJ or leptin- induced food intake was significantly impaired in mice lacking LRP1 in AgRP neurons. Moreover, we found that genetic variant in ApoJ and LRP1 gene is associated with human obesity, suggesting the important link between human disease and ApoJ/LRP1. We thus hypothesize that the ApoJ → LRP1 axis, coupled with the LepR system, is a novel anorexigenic signaling pathway that is central for the maintenance of normal body- weight homeostasis and energy balance. In this grant, Aim1 will establish the functional importance of ApoJ in astrocytes in the control of energy balance. Aim2 will determine the biological function of LRP1 in regulating energy balance. Aim 3 will elucidate the cellular mechanism(s) underlying the effect of ApoJ on leptin signaling. To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ and LRP1 model to clarify the specific role of ApoJ/LRP1 action and neuron-specific gene manipulation to test cellular mechanisms of ApoJ's anorexigenic action in an in vivo context. These studies provide a unique opportunity to establish a new paradigm in which ApoJ and LRP1 are key determinants of energy balance, and may offer a novel target for the treatment of obesity and diabetes.

下丘脑喂养电路对于维持能量平衡至关重要。此喂养的损害 调节系统会导致肥大，然后促进肥胖和体重增加。但是，知道 与下丘脑有关的关键厌食信号传导级联反应仍然不完整。 apoleipoproteinj （apoj）以前没有怀疑与喂养行为和能量的下丘脑控制有关 平衡。现在，我们提供了APOJ作为这种厌食分子的初步数据， 靶向下丘脑中的瘦素信号传导和能量平衡，可以通过LRP1介导（低 - 密度脂蛋白受体相关的蛋白质1）信号传导级联反应。我们发现在中心管理的Apoj 小鼠导致厌食症和体重减轻，而下丘脑apoj的缺失导致倍感和 肥胖。具体而言，星形胶质细胞中APOJ的缺乏，但不是AGRP，POMC和SF-1神经元的铅 对于肥胖症，表明星形胶质细胞APOJ对于调节正常的体重体内稳态很重要。喜欢 瘦素，APOJ激活的STAT3表达神经元（LEPR）中的STAT3，但在LEPR-中消除了这种作用 DB/DB小鼠缺陷，表明LEPR信号对APOJ效果的必要性。重要的是，apoj或瘦素 - 在AGRP神经元缺乏LRP1的小鼠中，诱导的食物摄入量显着受损。而且，我们发现 APOJ和LRP1基因中的基因变异与人类肥胖有关，这表明了重要的联系 在人类疾病和APOJ/LRP1之间。因此，我们假设APOJ→LRP1轴与 LEPR系统是一种新型的厌食性信号通路，是维持正常身体的核心 体重稳态和能量平衡。在这笔赠款中，AIM1将确定Apoj在 能量平衡控制的星形胶质细胞。 AIM2将确定LRP1在调节中的生物学功能 能量平衡。 AIM 3将阐明APOJ对瘦素信号传导影响的基础机制。 为了实现这些目标，我们将使用最先进的技术，包括有条件的apoj和 LRP1模型阐明APOJ/LRP1作用和神经特异性基因操纵的特定作用 在体内环境中，Apoj的厌食症作用的细胞机制。这些研究提供了独特的 建立一个新范式的机会，其中apoj和lrp1是能量平衡的关键决定者，并且 可以为治疗肥胖和糖尿病的治疗提供新的目标。