Regulation of energy and glucose homeostasis by endogenous hypothalamic FGF1
Regulation of energy and glucose homeostasis by endogenous hypothalamic FGF1
批准号:
10368119
负责人:
Jarrad M Scarlett
金额:
$13.24万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-04-01 至 2023-03-31
关键词:
AcuteAdultAffectAnimalsAntibodiesAntidiabetic DrugsAreaAwardBilateralBiochemicalBody WeightBody Weight decreasedBrainCaloriesCell LineCell NucleusCellsCerebrospinal FluidChronicChronic DiseaseConsumptionDataDependovirusDesire for foodDiabetes MellitusDietDisease remissionEnterobacteria phage P1 Cre recombinaseExpenditureFGF1 geneFGF19 geneFGF21 geneFamilyFastingFibroblast Growth FactorFoodFundingGliosisGlucoseGlucose IntoleranceHomeostasisHypothalamic structureImmunohistochemistryIn Situ HybridizationInfusion proceduresInjectionsInvestigationKnock-outLipidsLoxP-flanked alleleMedicalMessenger RNAMetabolicMicroinjectionsModelingModernizationMorbidity - disease rateMusNeurogliaNeuronal InjuryNeuronsNon-Insulin-Dependent Diabetes MellitusNutritional statusObesityPatient-Focused OutcomesPeripheralPhysiologicalPlayPopulationPrimatesProteinsPublic HealthRegulationReportingResearchResourcesRodentRodent ModelRoleSignal TransductionSocietiesSurveysSynapsesTestingTreatment outcomeWeight GainWorkbaseblood glucose regulationcell typecostdiabeticeffective therapyenergy balanceglucose tolerancehuman modelimprovedinterestlaser capture microdissectionmembermetabolic phenotypemind controlmortalitynovelobesity developmentobesity treatmentpre-clinicalresponsesedentary lifestylestemtargeted treatmentwestern diet
中文摘要
项目摘要
在过去的30年里,肥胖和2型糖尿病(T2D)已经成为最常见和最常见的糖尿病之一。
现代社会所面临的昂贵的慢性病。肥胖患者的治疗结局,或
由于缺乏非手术药物治疗,T2D显示出最小的改善,
持续的功效。因此,迫切需要新的、更有效的治疗选择,
针对大脑的战略具有满足这一需求的重要潜力。作为相关临床前
工作,我们的小组最近表明,信号在大脑中的外源性管理的成员,
成纤维细胞生长因子(FGF)家族产生有效的减肥和抗糖尿病作用。我们的K08提案
集中在持续的抗糖尿病作用的基础上的综合中枢和外周机制
在肥胖和T2D啮齿动物模型中的外源性FGF 1。在这个应用中,我们提出了一个平行的研究路线,
该研究将研究内源性下丘脑FGF 1信号传导在能量和葡萄糖调节中的作用
体内平衡我们最近发现,FGF 1是内源性表达的伸长细胞和细胞分布,
在许多关键的下丘脑区域,涉及体重和葡萄糖的控制。您因前述
观察到内源性下丘脑FGF1表达受禁食和再喂养的调节,
研究表明,从下丘脑神经元或伸长细胞中删除FGF1会导致体重增加和葡萄糖
对食物不耐受。这些数据支持了内源性下丘脑FGF 1信号传导发挥作用的前提,
在能量和葡萄糖稳态调节中的生理作用。我们将调查这一假设,
确定表达FGF 1的特定下丘脑核和细胞类型,
人群对代谢状态和饮食的急性和慢性变化的反应,以及干扰的程度。
内源性下丘脑FGF 1信号传导足以促进肥胖和葡萄糖代谢的发展。
不容忍从这些调查中获得的数据将形成一个新的研究路线的基础,
内源性下丘脑FGF1信号传导作为治疗肥胖和T2D的新靶点。
英文摘要
Project Summary
Over the past 3 decades, obesity and type 2 diabetes (T2D) have emerged as among the most common and
costly chronic diseases confronting modern society. Treatment outcomes for patients affected with obesity or
T2D have shown minimal improvement due to the absence of non-surgical medical treatments that have
sustained efficacy. Therefore, an urgent need for new, more effective treatment options therefore exists, and
strategies targeting the brain have important potential to meet this need. As one example of relevant preclinical
work, our group has recently shown that signaling in the brain by exogenous administration of members of the
fibroblast growth factor (FGF) family produces potent weight-loss and anti-diabetic effects. Our K08 proposal
focused on the integrated central and peripheral mechanisms underlying the sustained anti-diabetic action of
exogenous FGF1 in rodent models of obesity and T2D. In this application, we propose a parallel line of studies
that will investigate the role of endogenous hypothalamic FGF1 signaling in the regulation of energy and glucose
homeostasis. We have recently found that FGF1 is endogenously expressed by tanycytes and cells distributed
in a number of key hypothalamic areas implicated in the control of body weight and glucose. Further, we have
observed that endogenous hypothalamic FGF1 expression is regulated fasting and refeeding and in preliminary
studies that deleting FGF1 from either hypothalamic neurons or tanycytes induces weight gain and glucose
intolerance on chow diet. These data support the premise that endogenous hypothalamic FGF1 signaling plays
a physiologic role in the regulation of energy and glucose homeostasis. We will investigate this hypothesis by
determining the specific hypothalamic nuclei and cell types that express FGF1, identify which of these
populations respond to acute and chronic changes in metabolic status and diet, and the extent to which disrupting
endogenous hypothalamic FGF1 signaling is sufficient to promote the development of obesity and glucose
intolerance. The data obtained from these investigations will form the basis of a new line of research centered
on endogenous hypothalamic FGF1 signaling as a novel target to treat obesity and T2D.
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会议论文
Regulation of energy and glucose homeostasis by endogenous hypothalamic FGF1
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批准号:10191788
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项目类别:
-
资助金额:$13.24万
-
财政年份:2021
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负责人:Jarrad M Scarlett
-
依托单位:
Central and Peripheral Mechanisms of FGF1-Mediated Remission of Diabetic Hyperglycemia
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批准号:9370073
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项目类别:
-
资助金额:$16.38万
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财政年份:2017
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负责人:Jarrad M Scarlett
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依托单位:
Regulation of glucose homeostasis by intestinal macronutrients and surgery
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批准号:8832013
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项目类别:
-
资助金额:$5.89万
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财政年份:2014
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负责人:Jarrad M Scarlett
-
依托单位:
Regulation of glucose homeostasis by intestinal macronutrients and surgery
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批准号:9017811
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项目类别:
-
资助金额:$6.41万
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财政年份:2014
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负责人:Jarrad M Scarlett
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依托单位:
海外基金