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: 8456185
• 负责人: ABBA J KASTIN
• 金额: $ 31.63万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456185
• 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(申请人提供)：这项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。肥胖和神经损伤一样，会导致区域性星形胶质细胞增多症。我们观察到，星形胶质细胞中的OBR基因敲除导致小鼠对饮食诱导的肥胖产生部分抵抗，这一发现与在神经元中OBR基因敲除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团星形细胞OBR的强烈上调。这些OBR是有功能的，因为瘦素治疗激活了原代星形胶质细胞中的多个信号通路。因此，我们假设OBR(+)星形胶质细胞通过两种主要方式提供促进肥胖的负性调节：(A)通过加速瘦素的更新来减少神经元对瘦素的可获得性；(B)通过改变释放的胶质递质的轮廓来调节神经元的功能。星形胶质细胞的这种作用提供了一种将神经炎症过程和体重控制联系起来的直接机制。我们将在三个具体目标上检验这些假设。(1)为了证明反应性星形胶质细胞促进瘦素的周转并减弱神经元中的瘦素信号，Aim 1将使用已建立的反应性星形胶质细胞增生性肥胖模型来确定侧脑室注射瘦素后荧光结合的瘦素和pSTAT3信号的分布。结果将与星形胶质细胞特异性瘦素受体基因敲除小鼠的结果进行比较，并在星形胶质细胞抑制剂氟柠檬酸预处理后进行比较。(2)在目标2中，我们将检验瘦素调节神经胶质递质产生的假设，包括急性期的谷氨酸和三磷酸腺苷，以及稍后的细胞因子。原代星形胶质细胞和神经元将用于钙成像，并将测试星形胶质细胞条件培养液和神经元-神经胶质混合培养的效果。(3)目的3将确定星形胶质细胞特异性瘦素受体基因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，这些结果将证明OBR(+)星形胶质细胞在调节神经元瘦素信号方面发挥着重要作用。由于星形胶质细胞在神经损伤中起关键作用，也是神经免疫轴的组成部分，这些研究将提供神经炎症调节体重的切实机制。