Control of Energy Balance by ApoJ Signaling

通过 ApoJ 信号传导控制能量平衡

• 批准号: 9977165
• 负责人: YOUNG-BUM KIM
• 金额: $ 43.75万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977165
• 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; Injections; 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 manipulation; 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.

下丘脑的供血回路对于维持能量平衡是必不可少的。这种进食的损害 调节系统会导致过度吞噬，进而促进肥胖和体重增加。然而，了解 涉及下丘脑的关键厌食信号级联仍未完成。载脂蛋白J (ApoJ)此前并未被怀疑参与下丘脑对摄食行为和能量的控制 平衡。我们现在已经提供了ApoJ作为这样一个厌氧分子发挥作用的初步数据， 靶向瘦素信号和下丘脑的能量平衡，这可能是通过LRP1(低- 密度脂蛋白受体相关蛋白-1)信号级联反应。我们发现集中管理的ApoJ在 小鼠会导致厌食和体重减轻，而下丘脑ApoJ基因缺失会导致吞噬功能亢进和 严重的肥胖。具体地说，ApoJ在星形胶质细胞中的缺陷，而不是在AgRP、POMC和SF-1神经元中，导致 提示星形细胞载脂蛋白J在调节正常体重动态平衡中起重要作用。喜欢 瘦素、ApoJ激活表达瘦素受体(Lepr)的神经元中的STAT3，但这一作用在Lepr- 缺乏db/db小鼠，表明Lepr信号对ApoJ的影响是必要的。重要的是，ApoJ或瘦素- 在AgRP神经元中缺乏LRP1的小鼠，诱导的摄食量显著减少。此外，我们发现， ApoJ和LRP1基因的遗传变异与人类肥胖有关，提示这一重要联系 人类疾病与ApoJ/LRP1之间的关系。因此，我们假设ApoJ→LRP1轴，加上 Lepr系统，是一种新的厌氧信号通路，对维持正常的机体- 体重动态平衡和能量平衡。在这笔拨款中，Aim1将确立ApoJ在 星形胶质细胞在能量平衡中的控制。AIM2将决定LRP1在调节中的生物学功能 能量平衡。目的3将阐明载脂蛋白J影响瘦素信号转导的细胞机制(S)。 为了实现这些目标，我们将使用最先进的技术，包括有条件的浮动ApoJ和 用LRP1模型阐明ApoJ/LRP1的具体作用及神经元特异性基因操作来验证 载脂蛋白J体内厌氧作用的细胞机制。这些研究提供了一种独特的 有机会建立一种新的范式，其中ApoJ和LRP1是能量平衡的关键决定因素 可能为肥胖和糖尿病的治疗提供一个新的靶点。