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.

下丘脑喂养回路对于维持这种喂养的能量平衡至关重要。 调节系统会导致食欲亢进，从而促进肥胖和体重增加。 下丘脑中涉及的关键的厌食信号级联仍然不完整。 (ApoJ) 之前并未被怀疑参与下丘脑对进食行为和能量的控制 我们现在已经提供了 ApoJ 作为一种厌食分子的初步数据， 针对下丘脑中的瘦素信号传导和能量平衡，这可以通过 LRP1（低- 我们发现ApoJ在密度脂蛋白受体相关蛋白-1)信号级联中集中施用。 小鼠会导致厌食和体重减轻，而下丘脑 ApoJ 的缺失会导致食欲亢进和体重减轻。 具体而言，星形胶质细胞中的 ApoJ 缺陷会导致严重肥胖，但 AgRP、POMC 和 SF-1 神经元中的 ApoJ 缺陷则不会。 肥胖，表明星形细胞 ApoJ 在调节正常体重稳态中很重要。 瘦素、ApoJ 激活表达瘦素受体 (LepR) 的神经元中的 Stat3，但这种作用在 LepR 中被消除 db/db 缺陷小鼠，表明 LepR 信号对于 ApoJ 的作用是必要的，重要的是，ApoJ 或瘦素-。 AgRP 神经元中缺乏 LRP1 的小鼠诱导的食物摄入显着受损。 ApoJ 和 LRP1 基因的遗传变异与人类肥胖有关，表明两者之间存在重要联系 因此，我们得出 ApoJ → LRP1 轴与 ApoJ/LRP1 之间的关系。 LepR 系统是一种新型的厌食信号通路，对于维持正常的机体功能至关重要。 在这项资助中，Aim1 将确定 ApoJ 在体重稳态和能量平衡中的功能重要性。 星形胶质细胞在能量平衡中的控制将决定LRP1在调节中的生物学功能。 目标 3 将阐明 ApoJ 对瘦素信号传导影响的细胞机制。 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 LRP1模型阐明ApoJ/LRP1作用的具体作用和神经元特异性基因操作进行测试 这些研究提供了独特的体内 ApoJ 抑制食欲作用的细胞机制。 有机会建立一个新的范式，其中 ApoJ 和 LRP1 是能量平衡的关键决定因素，并且 可能为肥胖和糖尿病的治疗提供新的靶点。