Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis
感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态
基本信息
- 批准号:10341181
- 负责人:
- 金额:$ 51.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-09 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAdipose tissueAfferent NeuronsAnimal ModelAppetite StimulantsBody TemperatureBrainBrown FatCaliberCapsaicinCardiovascular DiseasesDependovirusDyslipidemiasEatingEndocrineEnergy MetabolismEpidemicFiberFood deprivation (experimental)GHS-R1aGastrointestinal tract structureGoalsGrantHigh Fat DietHomeostasisHormonesHumanInjectionsInsulin ResistanceInternal Ribosome Entry SiteKnowledgeLarge IntestineMalignant NeoplasmsMapsMeasuresMediatingMediator of activation proteinMelanocortin 4 ReceptorMetabolicMetabolic ControlMetabolic DiseasesMusNerveNeuronsNeurosecretory SystemsNodose GanglionNon-Insulin-Dependent Diabetes MellitusNorepinephrineNutrientObesityOrganPathway interactionsPeripheralRegulationReporterRisk FactorsRoleSensorySensory GangliaSignal PathwaySignal TransductionSmall IntestinesSpinalSpinal GangliaStimulusStomachStretchingTestingThermogenesisTracerVagotomyViralWorkafferent nervecell motilitydesigner receptors exclusively activated by designer drugsdiet-induced obesitygastrointestinalghrelinghrelin receptorgrowth hormone secretagogue receptorlipid metabolismnerve supplyneuronal circuitrynew therapeutic targetnovelobesity treatmentpreventresponse
项目摘要
Obesity has become a world-wide epidemic problem, and is an independent risk factor for a panel of metabolic
diseases, including insulin resistance/type 2 diabetes, dyslipidemia, cardiovascular diseases, and cancer. The
stomach-derived orexigenic hormone ghrelin acting through its receptor growth hormone secretagogue receptor
1a (GHSR) is a key mediator of energy homeostasis. GHSR is widely expressed in the brain and on
gastrointestinal vagal sensory neurons. In the current proposal, we discovered that in addition to the well
characterized vagal GHSRs, gastrointestinal sensory neurons emanating from spinal dorsal root ganglia (DRG)
robustly express GHSRs. In addition, DRG GHSR-containing neurons innervates the gastrointestinal tract, and
DRG GHSR is markedly induced by energetic challenges, including food deprivation and cold exposure,
suggesting DRG ghrelin/GHSR signaling is important in regulating energy homeostasis. Interestingly, sensory
GHSR deletion protects against diet-induced obesity primarily due to increased energy expenditure via increased
adipose tissue sympathetic outflow and thermogenesis. Thus, we have identified a novel pathway in which gut
non-vagal sensory GHSR neurons negatively regulate energy homeostasis via suppression of adipose tissue
sympathetic outflow, thermogenesis and whole body energy expenditure. The overall goal of this project is to
test the importance of ghrelin/GHSR signaling on peripheral sensory neurons in regulating whole body metabolic
homeostasis, and to investigate the neuronal mechanisms by which sensory GHSR regulates adipose tissue
sympathetic outflow. In Specific Aim 1, the importance of sensory GHSR in regulating energy homeostasis will
be tested using DRG sensory neuron-specific deletion or re-activation of GHSR. In Specific Aim 2, the neuronal
circuitry connecting gut sensory GHSR signaling to adipose tissue sympathetic outflow will be investigated via
viral tract tracer mapping. In addition, the possible involvement of central melanocortin signaling pathways as a
downstream target connecting sensory GHSR signaling to adipose tissue sympathetic outflow will be tested.
Completing this project will greatly expand our current knowledge of the neuroendocrine regulation of energy
homeostasis, and will provide novel therapeutic targets in the preventing and treatment of obesity.
肥胖已成为一个世界性的流行病,并且是一组代谢性疾病的独立危险因素。
疾病,包括胰岛素抵抗/2型糖尿病、血脂异常、心血管疾病和癌症。这
胃源性食欲激素胃饥饿素通过其受体生长激素促分泌素受体发挥作用
1a (GHSR) 是能量稳态的关键调节因子。 GHSR 广泛表达于大脑和
胃肠道迷走神经感觉神经元。在当前的提案中,我们发现除了井
迷走神经 GHSR,源自脊髓背根神经节 (DRG) 的胃肠道感觉神经元
强烈表达 GHSR。此外,含有 GHSR 的 DRG 神经元支配胃肠道,并且
DRG GHSR 明显是由能量挑战引起的,包括食物匮乏和寒冷暴露,
表明 DRG ghrelin/GHSR 信号传导对于调节能量稳态很重要。有趣的是,感官
GHSR 缺失可防止饮食诱发的肥胖,主要是由于通过增加能量消耗而增加
脂肪组织交感神经流出和产热。因此,我们发现了一条新的途径,其中肠道
非迷走神经感觉 GHSR 神经元通过抑制脂肪组织负向调节能量稳态
交感神经流出、产热和全身能量消耗。该项目的总体目标是
测试外周感觉神经元上的 ghrelin/GHSR 信号在调节全身代谢中的重要性
体内平衡,并研究感觉 GHSR 调节脂肪组织的神经机制
同情心流出。在具体目标 1 中,感觉 GHSR 在调节能量稳态中的重要性将
使用 DRG 感觉神经元特异性删除或重新激活 GHSR 进行测试。在具体目标 2 中,神经元
连接肠道感觉 GHSR 信号与脂肪组织交感神经流出的电路将通过以下方式进行研究
病毒道示踪剂图谱。此外,中枢黑皮质素信号通路可能参与
将测试连接感觉 GHSR 信号与脂肪组织交感神经流出的下游目标。
完成这个项目将大大扩展我们目前对能量神经内分泌调节的认识
体内平衡,将为预防和治疗肥胖提供新的治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bingzhong Xue其他文献
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{{ truncateString('Bingzhong Xue', 18)}}的其他基金
Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis
感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态
- 批准号:
10555316 - 财政年份:2020
- 资助金额:
$ 51.72万 - 项目类别:
Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis
感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态
- 批准号:
10621522 - 财政年份:2020
- 资助金额:
$ 51.72万 - 项目类别:
Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis
感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态
- 批准号:
10621045 - 财政年份:2020
- 资助金额:
$ 51.72万 - 项目类别:
Histone methyltransferase SUV420H2 regulates brown/beige adipocyte thermogenesis and energy homeostasis
组蛋白甲基转移酶 SUV420H2 调节棕色/米色脂肪细胞产热和能量稳态
- 批准号:
9416995 - 财政年份:2016
- 资助金额:
$ 51.72万 - 项目类别:
Macrophage AMPK, Inflammation, and Atherosclerosis
巨噬细胞 AMPK、炎症和动脉粥样硬化
- 批准号:
8470984 - 财政年份:2011
- 资助金额:
$ 51.72万 - 项目类别:
Macrophage AMPK, Inflammation, and Atherosclerosis
巨噬细胞 AMPK、炎症和动脉粥样硬化
- 批准号:
8236575 - 财政年份:2011
- 资助金额:
$ 51.72万 - 项目类别:
Macrophage AMPK, Inflammation, and Atherosclerosis
巨噬细胞 AMPK、炎症和动脉粥样硬化
- 批准号:
8586350 - 财政年份:2011
- 资助金额:
$ 51.72万 - 项目类别:
Macrophage AMPK, Inflammation, and Atherosclerosis
巨噬细胞 AMPK、炎症和动脉粥样硬化
- 批准号:
8389887 - 财政年份:2011
- 资助金额:
$ 51.72万 - 项目类别:
Peptidergic Control of Appetitive Ingestive Behaviors
食欲摄取行为的肽能控制
- 批准号:
8997072 - 财政年份:2007
- 资助金额:
$ 51.72万 - 项目类别:
Peptidergic Control of Appetitive Ingestive Behaviors
食欲摄取行为的肽能控制
- 批准号:
8815294 - 财政年份:2007
- 资助金额:
$ 51.72万 - 项目类别:
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