Astrocytic TrkB in diet-induced obesity

星形胶质细胞 TrkB 在饮食引起的肥胖中的作用

• 批准号: 9144463
• 负责人: BAOJI XU
• 金额: $ 28.8万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144463
• 关键词: Ablation; Animals; Astrocytes; Body Weight; Brain-Derived Neurotrophic Factor; Calories; Carbon Dioxide; Consumption; Diet; Dominant-Negative Mutation; Down-Regulation; Eating; Encephalitis; Epidemic; Excision; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Future; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Gliosis; Health; High Fat Diet; Homeostasis; Human; Hypothalamic structure; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Intervention; Knockout Mice; Lead; Length; Leptin; Ligands; Measurement; Measures; Melanocortin 4 Receptor; Microglia; Modeling; Morbid Obesity; Motor Activity; Mus; Mutant Strains Mice; Nerve Degeneration; Neuraxis; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Pathogenesis; Peripheral; Phase; Play; Production; Protein Tyrosine Kinase; Recruitment Activity; Regulation; Research Project Grants; Resistance; Rodent; Role; Saturated Fatty Acids; Secondary to; Signal Transduction; TNF gene; Testing; Time; Tissues; Tyrosine Kinase Domain; Up-Regulation; alpha-Melanocyte stimulating hormone; astrogliosis; common treatment; cytokine; energy balance; feeding; genome wide association study; leptin receptor; neuron loss; novel; promoter; receptor; response

 DESCRIPTION (provided by applicant): In rodent diet-induced obesity (DIO) models, long-term exposure to high-fat diets (HFD) increases the expression of proinflammatory genes, such as the genes encoding IL-1β, IL-6, TNFα, SOCS3 and IKKβ, in the hypothalamus. HFD feeding also induces reactive gliosis, as evidenced by an increase in both number and size of microglia and astrocytes, and neuronal loss in the mediobasal hypothalamus (MBH). The inflammatory response and gliosis in the MBH occur within 3 days of HFD exposure, which is much faster than the inflammatory response in peripheral tissues that takes more than 4 weeks of HFD feeding. Some studies suggest that saturated fatty acids derived from a HFD recruits and activates microglia in the MBH, which in turn orchestrate hypothalamic inflammation by releasing cytokines such as TNFα. However, it remains unknown whether hypothalamic microgliosis is sufficient to cause obesity and whether astrogliosis also play any role in the pathogenesis of DIO. Brain-derived neurotrophic factor (BDNF) is among the 18 genes that have been associated with human obesity in genome-wide association studies. Furthermore, BDNF and its receptor TrkB, along with leptin/leptin receptor and alpha melanocyte-stimulating hormone/melanocortin-4 receptor, are among a few ligand-receptor pairs whose signaling deficiencies lead to severe obesity in human individuals. In addition to the full-length TrkB receptor tyrosine kinase (TrkB-FL), the TrkB gene also produces truncated TrkB (TrkB-T) that misses the tyrosine kinase domain. We propose to test the hypothesis that HFD induces astrocytic TrkB-T expression, which leads to astrogliosis, down-regulation of neuronal BDNF-to-TrkB-FL signaling, and subsequent obesity. We will test this hypothesis by examining energy balance, hypothalamic inflammation, and hypothalamic gliosis in astrocyte-specific TrkB-T knockout mice fed a high-fat diet. If this exploratory research project demonstrates that this hypothesis is correct, we will provide evidence to indicate an important role for astrogliosis and TrkB-T in the pathogenesis of DIO. Future studies on the regulation of TrkB-T gene expression could provide targets for developing treatments for the common form of obesity.

 描述（由申请方提供）：在啮齿动物饮食诱导的肥胖（DIO）模型中，长期暴露于高脂饮食（HFD）增加了下丘脑中促炎基因的表达，例如编码IL-1β、IL-6、TNFα、SOCS 3和IKKβ的基因。HFD喂养还诱导反应性神经胶质增生，如通过小胶质细胞和星形胶质细胞的数量和大小的增加以及下丘脑内侧基底部（MBH）中的神经元损失所证明的。MBH中的炎症反应和神经胶质增生发生在HFD暴露的3天内，这比外周组织中的炎症反应快得多，外周组织中的炎症反应需要超过4周的HFD喂养。一些研究表明，来自HFD的饱和脂肪酸招募并激活MBH中的小胶质细胞，这反过来又通过释放细胞因子如TNFα来协调下丘脑炎症。然而，下丘脑小胶质细胞增生是否足以引起肥胖以及星形胶质细胞增生是否在DIO的发病机制中也起作用仍然是未知的。脑源性神经营养因子（BDNF）是全基因组关联研究中与人类肥胖相关的18个基因之一。此外，BDNF及其受体TrkB，沿着瘦素/瘦素受体和α促黑素细胞激素/黑皮质素-4受体，是少数配体-受体对中的一种，其信号传导缺陷导致人类个体的严重肥胖。除了全长TrkB受体酪氨酸激酶（TrkB-FL）之外，TrkB基因还产生缺失酪氨酸激酶结构域的截短的TrkB（TrkB-T）。我们建议检验HFD诱导星形胶质细胞TrkB-T表达的假设，这导致星形胶质细胞增生，神经元BDNF-至-TrkB-FL信号转导的下调，以及随后的肥胖。我们将通过检查高脂饮食喂养的星形胶质细胞特异性TrkB-T基因敲除小鼠的能量平衡、下丘脑炎症和下丘脑胶质增生来验证这一假设。如果这项探索性研究项目证明这一假设是正确的，我们将提供证据表明星形胶质细胞增生和TrkB-T在DIO发病机制中的重要作用。未来对TrkB-T基因表达调控的研究可以为开发常见肥胖症的治疗方法提供靶点。