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
基本信息
- 批准号:9047998
- 负责人:
- 金额:$ 24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationAnimalsAstrocytesBody WeightBrain-Derived Neurotrophic FactorCaloriesCarbon DioxideConsumptionDietDominant-Negative MutationDown-RegulationEatingEncephalitisEpidemicExcisionExposure toFat-Restricted DietFatty acid glycerol estersFutureGene ExpressionGenesGlial Fibrillary Acidic ProteinGliosisHomeostasisHumanHypothalamic structureIndividualInflammationInflammatoryInflammatory ResponseInterleukin-6InterventionKnockout MiceLeadLengthLeptinLigandsMeasurementMeasuresMelanocortin 4 ReceptorMicrogliaModelingMorbid ObesityMotor ActivityMusMutant Strains MiceNerve DegenerationNeuraxisNeuronsNeurotrophic Tyrosine Kinase Receptor Type 2ObesityPathogenesisPeripheralPhasePlayProductionProtein Tyrosine KinaseRecruitment ActivityRegulationResearch Project GrantsResistanceRodentRoleSaturated Fatty AcidsSecondary toSignal TransductionTestingTimeTissuesTumor Necrosis Factor-alphaTyrosine Kinase DomainUp-Regulationalpha-Melanocyte stimulating hormoneastrogliosiscommon treatmentcytokineenergy balancefeedinggenome wide association studyleptin receptorneuron lossnovelpromoterpublic health relevancereceptorresponse
项目摘要
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.
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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{{ truncateString('BAOJI XU', 18)}}的其他基金
Astrocytic regulation of energy balance on high-fat diet
星形胶质细胞对高脂饮食能量平衡的调节
- 批准号:
10734911 - 财政年份:2023
- 资助金额:
$ 24万 - 项目类别:
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 - 财政年份:2015
- 资助金额:
$ 24万 - 项目类别:
Unraveling the role of PVH BDNF neurons in energy balance
揭示 PVH BDNF 神经元在能量平衡中的作用
- 批准号:
9912758 - 财政年份:2015
- 资助金额:
$ 24万 - 项目类别:
Unraveling the role of PVH BDNF neurons in energy balance
揭示 PVH BDNF 神经元在能量平衡中的作用
- 批准号:
10393558 - 财政年份:2015
- 资助金额:
$ 24万 - 项目类别:
Distinct roles of somatically and dendritically synthesized BDNF in spine morphog
体细胞和树突状合成的 BDNF 在脊柱形态中的不同作用
- 批准号:
8279188 - 财政年份:2011
- 资助金额:
$ 24万 - 项目类别:
Distinct roles of somatically and dendritically synthesized BDNF in spine morphog
体细胞和树突状合成的 BDNF 在脊柱形态中的不同作用
- 批准号:
8087264 - 财政年份:2011
- 资助金额:
$ 24万 - 项目类别:
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