Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor
通过胰高血糖素样肽-1 受体调节食物摄入
基本信息
- 批准号:8577512
- 负责人:
- 金额:$ 42.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-12 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAcetyl-CoA CarboxylaseAcuteAgonistAppetite DepressantsAttenuatedBody Weight decreasedBrainBrain regionCardiovascular DiseasesCell LineCell NucleusCellsChildClinicalConsumptionDataDeoxyglucoseDietDietary CarbohydratesDisaccharidesEatingEnergy IntakeEpidemicFailureFeedbackFeeding behaviorsFoodFood Intake RegulationFructoseGlucansGlucoseGlycolysisGlycolysis InhibitionGoalsHormonesHypothalamic structureInfusion proceduresInsulinIntakeLeadLeptinLinkMalignant NeoplasmsMalonyl Coenzyme AMeasuresMediatingMolecularMusNatureNeuraxisNon-Insulin-Dependent Diabetes MellitusNutrientObesityOralOrganismPharmaceutical PreparationsProcessReceptor ActivationReceptor SignalingResistanceRisk FactorsRoleSatiationSignal PathwaySignaling ProteinSiteStarchSucroseTestingTherapeutic Interventionbasedesigndiabeticenergy balanceexenatidefeedinggain of functionglucagon-like peptideglucose metabolismglucose uptakeimprovedinhibitor/antagonistloss of functionnovelnovel strategiesobesity treatmentpreventprotein kinase modulatorpublic health relevancereceptorrelating to nervous systemresearch studyresponsesensorsugar
项目摘要
DESCRIPTION (provided by applicant): Satiety hormones such as glucagon-like peptide-1 (Glp1) are secreted in response to feeding and activate neural processes that subsequently suppress food intake. While the satiety effects of Glp1 have been known for over 15 years, the mechanism mediating this effect is not clearly defined. This is significant since some Glp1-based therapies for type 2 diabetes display modest weight loss effects. Understanding how Glp1 regulates food intake may, therefore, lead to the design of therapeutic interventions with improved efficacy for weight loss. Based on our preliminary data, we hypothesize that the anorectic effect mediated via the central Glp1 receptor (Glp1r) is integrated with hypothalamic signaling proteins that respond to changes in circulating glucose. Activation of the hypothalamic Glp1 receptor (Glp1r) inhibits the cellular energy sensor AMP-activated protein kinase (AMPK). Considering that the anorectic effects of leptin, insulin and glucose are mediated in part by inhibition of hypothalamic AMPK, we hypothesize that this is also a mechanism by which Glp1 suppresses food intake. We also show that inhibition of AMPK by the Glp1r agonist Exendin-4 (Ex4) in hypothalamic cell lines occurs only with increasing glucose concentration. Ex4 also stimulates glucose uptake and metabolism in a glucose concentration-dependent manner. Since increased glucose metabolism inhibits AMPK, we hypothesize that central Glp1r activation inhibits AMPK and subsequently reduces food intake by stimulating central glucose metabolism. Supporting this hypothesis, we show that inhibition of glycolysis in the brain blocks the anorectic
effect of Ex4. Contrasting the effects of glucose, central administration of fructose attenuates the anorectic effect of Ex4. Fructose activates hypothalamic AMPK. This suggests that by activating hypothalamic AMPK fructose can "short-circuit" the Glp1r signaling pathway and promote central Glp1 resistance. This could partially explain our observation that mice fed a sucrose diet, which provides fructose and glucose, eat more compared to mice fed an isocaloric starch diet that only provides glucose. This also has clinical implications based on the association between increased fructose consumption and the obesity epidemic, particularly in children. Since the Glp1r is expressed in multiple hypothalamic nuclei, the first aim is to identiy hypothalamic regions mediating the anorectic effect of Glp1r agonists. The second aim will combine hypothalamic nuclei- specific modulation of the Glp1r with pharmacological agents that target processes we hypothesize are downstream of the Glp1r - glucose metabolism and AMPK activity. The final aim will assess whether dietary fructose is an inhibitor of the satiety effects
mediated by central Glp1r activation. The long-term goal of this application is to elucidate the mechanisms that regulate multiple aspects of feeding behavior. Defining the mechanisms by which the central Glp1r regulates food intake will identify key control points that could be sites for disruption by obesogenic factors and targets for therapeutic intervention.
描述(由申请人提供):饱腹激素如胰高血糖素样肽-1 (Glp1)是在进食反应中分泌的,并激活随后抑制食物摄入的神经过程。虽然已知Glp1的饱腹感效应已经超过15年,但介导这种效应的机制尚未明确定义。这很重要,因为一些基于glp1的2型糖尿病治疗显示出适度的减肥效果。因此,了解Glp1如何调节食物摄入可能会导致设计出具有更好减肥功效的治疗干预措施。根据我们的初步数据,我们假设通过中枢Glp1受体(Glp1r)介导的厌食效应与响应循环葡萄糖变化的下丘脑信号蛋白相结合。下丘脑Glp1受体(Glp1r)的激活抑制细胞能量传感器amp活化蛋白激酶(AMPK)。考虑到瘦素、胰岛素和葡萄糖的厌食作用部分是通过抑制下丘脑AMPK介导的,我们假设这也是Glp1抑制食物摄入的机制之一。我们还发现,Glp1r激动剂Exendin-4 (Ex4)对下丘脑细胞系AMPK的抑制作用仅在葡萄糖浓度增加时发生。Ex4也以葡萄糖浓度依赖的方式刺激葡萄糖摄取和代谢。由于葡萄糖代谢增加抑制AMPK,我们假设中枢Glp1r激活抑制AMPK,随后通过刺激中枢葡萄糖代谢减少食物摄入。为了支持这一假设,我们发现大脑中糖酵解的抑制可以阻断厌食
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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Julio E Ayala其他文献
Julio E Ayala的其他文献
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{{ truncateString('Julio E Ayala', 18)}}的其他基金
Molecular mechanisms mediating metabolic benefits of glucagon-like peptide-1 receptor agonists
介导胰高血糖素样肽 1 受体激动剂代谢益处的分子机制
- 批准号:
10583838 - 财政年份:2023
- 资助金额:
$ 42.41万 - 项目类别:
Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor
通过胰高血糖素样肽-1 受体调节食物摄入
- 批准号:
9579802 - 财政年份:2017
- 资助金额:
$ 42.41万 - 项目类别:
Promethion Mouse Multiplexed Metabolic System
Promethion 小鼠多重代谢系统
- 批准号:
9075738 - 财政年份:2016
- 资助金额:
$ 42.41万 - 项目类别:
Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor
通过胰高血糖素样肽-1 受体调节食物摄入
- 批准号:
9270543 - 财政年份:2013
- 资助金额:
$ 42.41万 - 项目类别:
Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor
通过胰高血糖素样肽-1 受体调节食物摄入
- 批准号:
9057535 - 财政年份:2013
- 资助金额:
$ 42.41万 - 项目类别:
Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor
通过胰高血糖素样肽-1 受体调节食物摄入
- 批准号:
8831646 - 财政年份:2013
- 资助金额:
$ 42.41万 - 项目类别:
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