Consequences of Astrocytic Leptin Receptor Upregulation on Obesity

星形细胞瘦素受体上调对肥胖的影响

• 批准号: 8661763
• 负责人: ABBA J KASTIN
• 金额: $ 32.78万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-26 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661763
• 关键词: Acute; Address; Adult; Affect; Astrocytes; Attention; Attenuated; Binding; Biological Markers; Body Weight; Brain; Brain Injuries; Calcium; Calcium Signaling; Cardiovascular system; Cell Communication; Cell Nucleus; Cells; Conditioned Culture Media; Cultured Cells; Data; Diet; Eating; Endocytosis; Energy Metabolism; Fatty acid glycerol esters; Gliosis; Glutamates; Hormones; Hyperlipidemia; Hypothalamic structure; Image; Incidence; Insulin Resistance; Knock-out; Knockout Mice; Leptin; Link; Lipids; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Modeling; Molecular Weight; Mus; Neuroglia; Neurons; Neurosecretory Systems; Obesity; Phase; Phenotype; Play; Process; Production; Proteins; Regulation; Resistance; Role; Series; Serum; Signal Pathway; Signal Transduction; Sleep Apnea Syndromes; System; Testing; Time; Tissues; Up-Regulation; Weight; Weight maintenance regimen; astrogliosis; cancer complication; combat; cytokine; design; fluorocitrate; inhibitor/antagonist; leptin receptor; mouse model; nerve injury; neuroinflammation; new therapeutic target; novel; receptor upregulation; research study; response

DESCRIPTION (provided by applicant): The proposed study aims to determine how astrocytic leptin receptors (ObR, or LR) affect obesity regulation. Obesity, like neural injury, results in regional astrogliosis. We observed that knockout of ObR in astrocytes leads to partial resistance of the mice to diet-induced obesity, a finding opposite to the obesity found in mice with knockout of ObR in neurons. Moreover, mice with adult-onset obesity show both astrogliosis and robust upregulation of astrocytic ObR in selective nuclei of the hypothalamus. These ObR are functional, as leptin treatment activates multiple signaling pathways in primary astrocytes. We, therefore, hypothesize that the ObR (+) astrocytes provide negative regulation to facilitate obesity in two main ways: (a) reducing availability of leptin to neurons by accelerating leptin turnover; (b) modulating neuronal function by alterations of the profile of glial transmitters released. Such a role for astrocytes provides a direct mechanism linking neuroinflammatory processes and body weight control. We will test the hypotheses in three specific aims. (1) To show that reactive astrocytes facilitate the turnover of leptin and attenuate neuronal leptin signaling in the brain, Aim 1 will use an established model of reactive astrogliosis - adult-onset obesity - to determine the distribution of fluorescently conjugated leptin and pSTAT3 signaling after intracerebroventricular delivery of leptin. The results will be compared with those from astrocyte specific leptin receptor knockout mice, and after pretreatment with the astrocyte inhibitor fluorocitrate. (2) In Aim 2, we will test the hypothesis that leptin modulates the production profile of gliotransmitters, including glutamate and ATP in the acute phase and cytokines at a later time. Primary astrocytes and neurons will be used for calcium imaging, and the effects of astrocyte conditioned medium and mixed neuron-glial culture will be tested. (3) Aim 3 will identify functional consequences of astrocyte specific leptin receptor knockout on the metabolic phenotype and correlate this with serum biomarkers of neuroinflammation. Overall, the results will demonstrate an essential role of ObR(+) astrocytes in the regulation of neuronal leptin signaling. As astrocytes are crucially involved in neural injury and an integral part of the neuroimmune axis, these studies will provide tangible mechanisms by which neuroinflammation can regulate body weight.

描述（由申请人提供）：拟议的研究旨在确定星形细胞瘦素受体（ObR 或 LR）如何影响肥胖调节。肥胖与神经损伤一样，会导致局部星形胶质细胞增生。我们观察到，敲除星形胶质细胞中的 ObR 会导致小鼠对饮食诱导的肥胖产生部分抵抗力，这一发现与敲除神经元中 ObR 的小鼠中发现的肥胖相反。此外，成年肥胖小鼠表现出星形胶质细胞增生和下丘脑选择性核中星形胶质细胞 ObR 的强烈上调。这些 ObR 具有功能性，因为瘦素治疗可激活原代星形胶质细胞中的多种信号通路。因此，我们假设 ObR (+) 星形胶质细胞通过两种主要方式提供负调节以促进肥胖：(a) 通过加速瘦素周转来减少神经元对瘦素的利用； (b)通过改变释放的神经胶质递质的分布来调节神经元功能。星形胶质细胞的这种作用提供了连接神经炎症过程和体重控制的直接机制。我们将在三个具体目标中测试这些假设。 (1) 为了证明反应性星形胶质细胞促进瘦素的周转并减弱大脑中神经元瘦素信号传导，目标 1 将使用已建立的反应性星形胶质细胞增生模型（成人发病性肥胖）来确定荧光缀合瘦素和 pSTAT3 信号传导后的分布瘦素的脑室内输送。结果将与星形胶质细胞特异性瘦素受体敲除小鼠的结果以及星形胶质细胞抑制剂氟柠檬酸盐预处理后的结果进行比较。 (2) 在目标 2 中，我们将检验瘦素调节神经胶质递质的产生特征的假设，包括急性期的谷氨酸和 ATP 以及后期的细胞因子。原代星形胶质细胞和神经元将用于钙成像，并测试星形胶质细胞条件培养基和混合神经元-胶质细胞培养物的效果。 (3) 目标 3 将确定星形胶质细胞特异性瘦素受体敲除对代谢表型的功能影响，并将其与神经炎症的血清生物标志物相关联。总体而言，结果将证明 ObR(+) 星形胶质细胞在神经元瘦素信号传导调节中的重要作用。由于星形胶质细胞在神经损伤中至关重要，并且是神经免疫轴的组成部分，因此这些研究将提供神经炎症调节体重的切实机制。