Brainstem nutrient sensing in the integrative control of food intake
脑干营养传感在食物摄入综合控制中的应用
基本信息
- 批准号:9247175
- 负责人:
- 金额:$ 37.58万
- 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:2015-04-15 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:70-kDa Ribosomal Protein S6 KinasesAddressAdipose tissueAffectAmino AcidsAnimalsAttenuatedAutomobile DrivingBehavioralBody WeightBrain StemCardiovascular DiseasesCatabolismCellsCholecystokininChronicComorbidityComplexDataDevelopmentDiabetes MellitusDietDorsalDoseDuodenumEatingEndocrineEnergy IntakeEnergy MetabolismEnergy-Generating ResourcesEpidemicEquilibriumEssential Amino AcidsEventExtracellular Signal Regulated KinasesFOS geneFRAP1 geneFeedbackFeeding behaviorsFoodFood EnergyGastrointestinal tract structureHealthHigh Fat DietHormonesHumanHyperphagiaHypertensionHypothalamic structureImpairmentIndividualIngestionIntestinesLearningLeptinLeucineMAPK3 geneMaintenanceMalignant NeoplasmsMammalsMeasuresMediatingMetabolicMetabolismMitogen-Activated Protein KinasesMolecularMolecular GeneticsNeurobiologyNeuronsNucleus solitariusNutrientObesityOralPathologicPathway interactionsPeptidesPharmacologyPhysical activityPhysiologicalPropertyProtein-Serine-Threonine KinasesPublishingRiskSatiationSignal PathwaySignal TransductionSiteStimulusStomachStrokeUnited StatesWeight GainWorkbehavioral pharmacologycardiovascular disorder riskcostdetection of nutrientdisorder riskenergy balanceexperimental studyfeedinggenetic approachmortalityneurophysiologyneuroregulationneurotransmissionnovelpublic health relevancereduced food intakerelating to nervous system
项目摘要
DESCRIPTION (provided by applicant): Central nutrient sensing of the essential amino acid l-leucine is a critical determinant of food intake and meal size. We have shown that: 1) endogenous central levels of leucine are rapidly elevated after a meal, 2) blocking endogenous leucine catabolism within the mediobasal hypothalamus (MBH), thereby promoting local leucine availability, reduces food intake, 3) MBH leucine administration reduces food intake by reducing meal size, 4) blocking downstream intracellular cascades of leucine signaling in the MBH promote feeding, while 5) chronic activation of these downstream pathways in the MBH limit high fat diet hyperphagia and associated weight gain. These actions appear to be mediated by two intracellular signaling pathways: the mammalian target of rapamycin (mTOR) - serine/threonine kinase p70S6K (S6K) pathway, and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. MBH leucine at feeding inhibitory doses also activates the brainstem dorsal vagal complex of the caudal brainstem, particularly the caudomedial region of the nucleus of the solitary tract (cmNTS), where meal-related gut negative feedback signals converge and are integrated to mediate the neural control of meal size. Our recent published and preliminary results support the identification of the cmNTS as a site where local leucine acts to reduce food intake by limiting meal size and by increasing the feeding inhibitory potency of CCK. These actions appear to be mediated by both mTOR-S6K and ERK pathways as well. Furthermore, diet induced obesity (DIO) attenuates cmNTS leucine's feeding inhibitory actions. Taken together, these data suggest a new brainstem nutrient sensing capability, and its novel integration with direct controls of meal size. Studies in this proposal will apply a coordinated combination of behavioral, neurophysiological, pharmacological, immunohistochemical and molecular genetic approaches to identify and characterize the neural and molecular mechanisms underlying brainstem nutrient sensing in the control of feeding, how it is disrupted in DIO, and how it can be targeted to control food intake and body weight in obesity.
描述(由适用提供):必需氨基酸L-亮氨酸的中心营养敏感性是食物摄入和进餐大小的关键决定剂。 We have shown that: 1) endogenous central levels of leucine are rapidly elevated after a meal, 2) blocking endogenous leucine catabolism within the mediobasal hypothalamus (MBH), thereby promoting local leucine availability, reduces food intake, 3) MBH leucine administration reduces food intake by reducing meal size, 4) blocking downstream intracellular cascades of leucine signaling in MBH促进喂养,而5)在MBH中,这些下游途径的慢性激活限制了高脂肪饮食饮食倍率和相关的体重增加。这些作用似乎是由两个细胞内信号通路介导的:雷帕霉素(MTOR)的哺乳动物靶标 - 丝氨酸/苏氨酸激酶p70s6k(S6K)途径,以及细胞外信号调节激酶1/2(ERK1/2)途径。进食抑制剂量时的MBH亮氨酸还激活了尾脑干的脑干背迷走神经复合物,尤其是固体道核(CMNT)核的尾部区域(CMNT),其中与粉状相关的肠道负面反馈信号融合并集成以介导餐食的神经控制量。我们最近发表的初步结果支持将CMNT鉴定为一个地点,在该地点,局部亮氨酸通过限制餐食的大小和增加CCK的喂养抑制效力来减少食物摄入量。这些动作似乎也由MTOR-S6K和ERK途径介导。此外,饮食诱导的肥胖症(DIO)减弱了CMNT Leucine的进食抑制作用。综上所述,这些数据表明了新的脑干营养敏感性及其与直接控制膳食大小的新型整合。该提案中的研究将采用行为,神经生理学,药物学,免疫组织化学和分子遗传学方法的协调组合,以识别和表征脑干营养敏感性的神经元和分子机制在喂养方面的控制,以及如何在DIO中受到攻击,以及如何对其进行攻击。
项目成果
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{{ truncateString('GARY J SCHWARTZ', 18)}}的其他基金
Brainstem nutrient sensing in the integrative control of food intake
脑干营养传感在食物摄入综合控制中的应用
- 批准号:
9049493 - 财政年份:2015
- 资助金额:
$ 37.58万 - 项目类别:
Brainstem nutrient sensing in the integrative control of food intake
脑干营养传感在食物摄入综合控制中的应用
- 批准号:
8876024 - 财政年份:2015
- 资助金额:
$ 37.58万 - 项目类别:
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Brainstem nutrient sensing in the integrative control of food intake
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