BMP7 and the regulation of central and peripheral energy balance
BMP7与中枢和外周能量平衡的调节
基本信息
- 批准号:8309738
- 负责人:
- 金额:$ 5.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-06-07 至 2013-06-06
- 项目状态:已结题
- 来源:
- 关键词:AdenovirusesAdrenergic AgentsAffectAgonistAppetite DepressantsAppetite RegulationBMP7 geneBiochemicalBody WeightBone Morphogenetic ProteinsBrainBrain StemBrown FatCell NucleusCellsCommunicationComplexDesire for foodDevelopmentDiabetes MellitusDietEatingEnergy IntakeEnergy MetabolismEpidemicEquationEquilibriumExhibitsFamilyFatty acid glycerol estersFunctional disorderGoalsGrowth FactorHomeostasisHumanHyperphagiaHypothalamic structureLaboratoriesLeadLinkLower OrganismManuscriptsMeasuresMediatingMetabolicMetabolic PathwayMetabolismMethodsModelingMolecularMorphogenesisMusNervous system structureNeuraxisNeuronsNeuropeptidesNucleus solitariusObesityOxygen ConsumptionPathway interactionsPeripheralPhenotypePhysiologicalPlayPrevention strategyRegulationRegulatory PathwayResearchRoleSatiationScienceSignal TransductionSympathectomySympathetic Nervous SystemSystemTherapeuticThermogenesisadipocyte differentiationadrenergicbone morphogenetic protein receptorsenergy balancehuman FRAP1 proteininterestmelanocortin receptormetabolic abnormality assessmentmouse modelnerve supplynovelpopulation healthpreventreceptorresponse
项目摘要
DESCRIPTION (provided by applicant): Obesity is currently a worldwide epidemic, therefore preventing and reversing obesity is of utmost importance for the general health of the population. Body weight regulation is maintained through a balance of energy intake versus energy expenditure, and targeting appetite or metabolic pathways via obesity therapeutics is a current goal in obesity research. The brain is the center for control and coordination of body weight. Hypothalamic melanocortin system activation reduces appetite, and also sends signals to the nucleus of the solitary tract (NTS) which activates sympathetic nervous system (SNS) innervation of brown adipose tissue (BAT), leading to increased thermogenesis (energy expenditure). The aim of this proposal is to further investigate a family of molecules recently found to be involved in metabolism. The bone morphogenetic proteins (BMPs) are growth factors, and recent studies have demonstrated roles for the BMPs in metabolism and satiety in lower organisms. Our laboratory has also shown that BMP7 in mice is able to stimulate brown adipocyte differentiation and to induce BAT thermogenesis. Additionally, we have shown that BMP7 and its receptors are expressed in the hypothalamus and BMP7 delivery (either i.c.v. or systemically via adenovirus) produces an anorexigenic effect, at least in part through the hypothalamic mTOR pathway and activation of the melanocortin system. However, much is still unknown about the metabolic and physiological roles of BMP signaling in energy balance. Therefore, the overarching goal of this project is to identify how BMP7 impacts whole body energy balance by affecting appetite pathways and BAT thermogenesis. Thus far, we have found that mice with BMP7 haploinsufficiency (BMP7-/+) on a high fat diet (HFD) are more obese and hyperphagic than littermate controls, with decreased energy expenditure (oxygen consumption/VO2) levels. Therefore, our first objective is to determine the physiological mechanism for BMP7's effects on energy balance, with the hypothesis that BMP7 is regulating the hypothalamic-NTS melanocortin system which regulates both central appetite pathways as well as energy expenditure pathways (via sympathetic innervation of BAT). We have also shown that mice with POMC-neuron (ie: in hypothalamus and NTS/brainstem) deletion of BMPR1a (a BMP7 receptor) exhibit hyperphagia as well as increased energy expenditure and BAT thermogenesis. Therefore our second objective is to determine whether the mechanism for POMC-neuron BMPR1a action is through hypothalamic melanocortin pathway inhibition to induce hyperphagia, and through the NTS-SNS pathways to increase thermogenesis in BAT. These studies will utilize novel mouse models for metabolic studies, including an important model linking central BMP signaling disruption with peripheral energy expenditure effects, and will investigate a novel class of appetite factors: the BMP growth factors. Therefore, the research outlined in this proposal could provide important new findings for the field of obesity research, and potentially lead to development of new obesity therapeutics.
描述(由申请人提供):肥胖目前是一种世界性的流行病,因此预防和扭转肥胖对人口的总体健康至关重要。体重调节是通过能量摄入和能量消耗的平衡来维持的,通过肥胖治疗来瞄准食欲或代谢途径是当前肥胖研究的目标。大脑是控制和协调体重的中心。下丘脑黑素皮质素系统的激活降低食欲,并向孤立束核(NTS)发送信号,激活棕色脂肪组织(BAT)的交感神经系统(SNS)神经支配,导致产热(能量消耗)增加。这项提议的目的是进一步研究最近发现的参与新陈代谢的分子家族。骨形态发生蛋白(BMPs)是一种生长因子,最近的研究表明BMPs在低等生物的代谢和饱腹感中起着重要作用。我们的实验室也表明,小鼠BMP7能够刺激棕色脂肪细胞分化并诱导BAT产热。此外,我们已经证明BMP7及其受体在下丘脑中表达,BMP7的递送(通过体外或通过腺病毒全身递送)产生厌氧作用,至少部分是通过下丘脑mTOR途径和黑素皮质素系统的激活。然而,BMP信号在能量平衡中的代谢和生理作用尚不清楚。因此,本项目的首要目标是确定BMP7如何通过影响食欲通路和BAT产热作用来影响全身能量平衡。到目前为止,我们已经发现BMP7单倍功能不全(BMP7-/+)的小鼠在高脂肪饮食(HFD)中比对照组更肥胖和嗜食,能量消耗(耗氧量/摄氧量)水平降低。因此,我们的第一个目标是确定BMP7对能量平衡影响的生理机制,假设BMP7调节下丘脑- nts黑素皮质素系统,该系统调节中枢食欲通路和能量消耗通路(通过BAT的交感神经支配)。我们还表明,pomc神经元(即下丘脑和NTS/脑干)缺失BMPR1a(一种BMP7受体)的小鼠表现出嗜食、能量消耗和BAT产热增加。因此,我们的第二个目标是确定pomc -神经元BMPR1a的作用机制是否通过下丘脑黑素皮质素通路抑制诱导贪食,以及通过NTS-SNS通路增加BAT的生热作用。这些研究将利用新的小鼠模型进行代谢研究,包括一个将中枢BMP信号中断与外周能量消耗效应联系起来的重要模型,并将研究一类新的食欲因子:BMP生长因子。因此,本提案概述的研究可能为肥胖研究领域提供重要的新发现,并可能导致新的肥胖治疗方法的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Kristy L Townsend其他文献
Kristy L Townsend的其他文献
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{{ truncateString('Kristy L Townsend', 18)}}的其他基金
Peripheral Neurotrophic Factors in the Regulation of Adipose Tissue Energy Expenditure
周围神经营养因子调节脂肪组织能量消耗
- 批准号:
10323153 - 财政年份:2021
- 资助金额:
$ 5.57万 - 项目类别:
Peripheral Neurotrophic Factors in the Regulation of Adipose Tissue Energy Expenditure
周围神经营养因子调节脂肪组织能量消耗
- 批准号:
9522965 - 财政年份:2018
- 资助金额:
$ 5.57万 - 项目类别:
BMP7 and the regulation of central and peripheral energy balance
BMP7与中枢和外周能量平衡的调节
- 批准号:
8202892 - 财政年份:2011
- 资助金额:
$ 5.57万 - 项目类别:
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