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.

下丘脑摄食回路对于维持能量平衡至关重要。这种进食的障碍 调节系统引起食欲过盛，然后促进肥胖和体重增加。然而，知识 下丘脑中涉及的关键性促肾上腺皮质激素信号级联仍然不完整。载脂蛋白J ApoJ蛋白以前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作为这样一种促凋亡分子发挥作用的初步数据， 针对下丘脑中的瘦素信号传导和能量平衡，这可以通过LRP 1（低- 密度脂蛋白受体相关蛋白-1）信号级联。我们发现，集中给药的ApoJ 小鼠导致厌食和体重减轻，而下丘脑ApoJ的缺失导致食欲过盛， 严重肥胖。具体地说，星形胶质细胞中ApoJ缺乏，而AgRP、POMC和SF-1神经元中ApoJ缺乏， 肥胖，表明星形胶质细胞ApoJ是重要的，在调节正常体重的稳态。像 瘦素、ApoJ激活了表达瘦素受体（LepR）的神经元中的Stat 3，但这种作用在LepR- 缺陷型db/db小鼠，表明LepR信号传导对于ApoJ作用的必要性。重要的是，ApoJ或瘦素- 在AgRP神经元中缺乏LRP 1的小鼠中，诱导的食物摄入显著受损。此外，我们发现， ApoJ和LRP 1基因的遗传变异与人类肥胖相关，表明ApoJ和LRP 1基因的重要联系。 ApoJ/LRP 1与人类疾病的关系因此，我们假设ApoJ → LRP 1轴，与 LepR系统是一种新的促凋亡信号通路，是维持正常机体功能的核心。 体重平衡和能量平衡。在这项资助中，Aim 1将确定ApoJ在以下方面的功能重要性： 星形胶质细胞控制能量平衡。Aim 2将决定LRP 1在调节细胞凋亡中的生物学功能。 能量平衡。目的3将阐明ApoJ对瘦素信号转导的影响的细胞机制。 为了实现这些目标，我们将使用最先进的技术，包括条件floxed ApoJ和 LRP 1模型，以阐明ApoJ/LRP 1作用的特定作用和神经元特异性基因操作，以测试 ApoJ在体内环境中的促凋亡作用的细胞机制。这些研究提供了一个独特的 有机会建立一个新的范式，其中ApoJ和LRP 1是能量平衡的关键决定因素， 可能为肥胖症和糖尿病的治疗提供新的靶点。