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: 9047998
• 负责人: BAOJI XU
• 金额: $ 24万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047998
• 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; Homeostasis; Human; Hypothalamic structure; Individual; Inflammation; Inflammatory; Inflammatory Response; 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; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; 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; public health relevance; 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(申请人提供)：在啮齿动物饮食诱导肥胖模型中，长期暴露于高脂饮食会增加下丘脑促炎基因的表达，如编码IL-1β、IL-6、肿瘤坏死因子α、SOCS3和IKKβ的基因。高脂饲料喂养也可引起反应性胶质增生，表现为小胶质细胞和星形胶质细胞的数量和大小增加，下丘脑内侧基底区(MBH)神经元丢失。MBH的炎症反应和胶质细胞增生发生在HFD暴露后3天内，比周围组织的炎症反应快得多，后者需要HFD喂养4周以上。一些研究表明，从高脂血症中提取的饱和脂肪酸招募并激活了MBH中的小胶质细胞，而MBH又通过释放细胞因子如肿瘤坏死因子α来协调下丘脑的炎症。然而，尚不清楚下丘脑小胶质细胞增多症是否足以导致肥胖，以及星形胶质细胞增多症是否也在DIO的发病机制中起到任何作用。在全基因组关联研究中，脑源性神经营养因子(BDNF)是与人类肥胖相关的18个基因之一。此外，BDNF及其受体TrkB，以及瘦素/瘦素受体和α-黑素细胞刺激素/黑素皮质素-4受体，是导致人类严重肥胖的少数配体-受体对之一。除了全长TrkB受体酪氨酸激酶(TrkB-FL)外，TrkB基因还产生缺失酪氨酸激酶结构域的截短TrkB(TrkB-T)。我们提出的假设是HFD诱导星形细胞TrkB-T表达，从而导致星形胶质细胞增生，下调神经元BDNF-to-TrkB-FL信号，并随后导致肥胖。我们将通过检查喂食高脂饮食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细胞增生来检验这一假设。如果这一探索性研究项目证明这一假说是正确的，我们将提供证据表明星形胶质细胞增生和TrkB-T在DIO的发病机制中发挥重要作用。未来对TrkB-T基因表达调控的研究可能为开发治疗常见肥胖症的方法提供靶点。