Human adipose tissue in control of sympathetic tone and metabolic rate
人类脂肪组织控制交感神经张力和代谢率
基本信息
- 批准号:10749552
- 负责人:
- 金额:$ 72.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdipocytesAdipose tissueAdrenergic AgentsAdrenergic ReceptorAffectAntidepressive AgentsBasal metabolic rateBiological AvailabilityBlood GlucoseBlood VesselsBody TemperatureBody Weight decreasedBrainCRISPR/Cas technologyCaloriesCellsClosure by clampCommunicationCuesDependenceDevelopmentEnzymesExperimental ModelsExposure toFastingFatty AcidsFatty acid glycerol estersForms ControlsGenesGrantHealthHeartHeart DiseasesHomeostasisHormone secretionHumanHuman bodyHybridsHyperglycemiaImmunocompromised HostImplantKnock-outLipolysisLiverMeasuresMediatingMesenchymal Stem CellsMetabolicMetabolic DiseasesMetabolismMethodologyModelingMonoamine Oxidase AMusMuscleNRIP1 geneNerveNeuronsNeurotransmittersNon-Insulin-Dependent Diabetes MellitusNorepinephrineObesityOrganOrgan TemperaturesPhysiologicalPlayPositioning AttributePredispositionProbabilityProteinsRecyclingRespirationRoleSignal TransductionSiteStimulusTechniquesTechnologyTestingTherapeuticThermogenesisTissuesVascularizationWeight GainWorkblood glucose regulationcomparison controldesigndisorder riskfatty liver diseaseglucose disposalglucose metabolismimplantationimprovedin vivoinsulin sensitivityknock-downmetabolic ratemonoaminenanoparticlenerve supplynovelnovel strategiesnovel therapeuticsoverexpressionpharmacologicresponsestem cellssubcutaneousvirtual
项目摘要
ABSTRACT
Sympathetic outflow to adipose tissue regulates whole body energy homeostasis by stimulating lipolysis in
white adipocytes and thermogenesis in brown or beige adipocytes. Using a novel approach to study human
adipose tissue in mice [1, 2], we have found that, during development, human adipocytes express a high level
of monoamine oxidase A (MAOA), a major mechanism for degradation of norepinephrine, and a known
target of antidepressant drugs [3]. Notably, expression of Maoa is virtually undetectable in mouse adipocytes,
indicating that this control mechanism may have evolved to meet the metabolic features of larger species. We
find that human adipocyte MAOA is decreased during beige adipose tissue development, potentially increasing
norepinephrine bioavailability, adrenergic tone and thermogenic capacity. Thus, MAOA expression in human
adipocytes is a previously underappreciated, key mechanism controlling adipose tissue functions,
potentially underlying susceptibility to obesity and metabolic disease. In this proposal, we will further test
the hypothesis that adipocyte MAOA controls systemic energy homeostasis through its effects on adipose tissue
sympathetic responsiveness. We have developed methodologies to obtain large numbers of human multipotent
mesenchymal progenitor cells that can differentiate into multiple adipocyte subtypes, and can generate
functional adipose tissue upon implantation in vivo. We have also successfully deleted MAOA from these cells
using a novel nanoparticle-based, CRISPR-Cas9 protein delivery technique, resulting in a >90% depletion of
MAOA protein while avoiding non-specific effects of expressed Cas9. Leveraging these technologies, we
shall: Aim 1. Test the hypothesis that human adipocyte MAOA limits lipolytic and thermogenic responses to
norepinephrine. We will measure lipolysis and induction of thermogenesis in control and MAOA-deleted
human adipocytes exposed to norepinephrine, as well as steady-state norepinephrine levels and dependency on
the monoamine transporter Oct3. Aim 2. We will test the hypothesis that MAOA in human adipocytes
regulates the development and responsiveness of thermogenic adipose tissue in vivo. We will measure the
rate and extent of vascularization and innervation, and thermogenic responsiveness to environmental stimuli of
tissue developed in NSG mice from control or MAOA deleted human adipocytes. Aim 3. We will test the
hypothesis that expression of MAOA in adipocytes will determine susceptibility to obesity, systemic insulin
sensitivity and systemic glucose homeostasis. We will analyze weight gain, adipocyte size, insulin sensitivity,
glucose disposal under hyper insulinemic, hyperglycemic clamps, and basal metabolic rate in mice harboring
adipose depots formed from control or MAOA deleted human adipocytes, and in mice overexpressing MaoA in
subcutaneous adipose tissue. These aims will provide the basis for further development of tissue specific
MAOA-targeting strategies as novel therapeutics for metabolic disease.
摘要
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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Silvia Corvera其他文献
Silvia Corvera的其他文献
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{{ truncateString('Silvia Corvera', 18)}}的其他基金
Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
- 批准号:
10019532 - 财政年份:2019
- 资助金额:
$ 72.54万 - 项目类别:
Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
- 批准号:
10166839 - 财政年份:2019
- 资助金额:
$ 72.54万 - 项目类别:
Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
- 批准号:
10418655 - 财政年份:2019
- 资助金额:
$ 72.54万 - 项目类别:
University of Massachusetts Center for Clinical and Translational Science
马萨诸塞大学临床与转化科学中心
- 批准号:
9127400 - 财政年份:2015
- 资助金额:
$ 72.54万 - 项目类别:
FASEB SRC on Glucose transport: Gateway for metabolic systems Biology
FASEB SRC 关于葡萄糖转运:代谢系统生物学的门户
- 批准号:
8595738 - 财政年份:2013
- 资助金额:
$ 72.54万 - 项目类别:
Medical Scientist Training at UMMS Administrative Supplement
UMMS 医学科学家培训行政补充
- 批准号:
9900318 - 财政年份:2013
- 资助金额:
$ 72.54万 - 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
- 批准号:
8187450 - 财政年份:2011
- 资助金额:
$ 72.54万 - 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
- 批准号:
8470640 - 财政年份:2011
- 资助金额:
$ 72.54万 - 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
- 批准号:
8668046 - 财政年份:2011
- 资助金额:
$ 72.54万 - 项目类别:
FASEB SRC on Glucose Transporters, Signaling and Diabetes
关于葡萄糖转运蛋白、信号传导和糖尿病的 FASEB SRC
- 批准号:
8200163 - 财政年份:2011
- 资助金额:
$ 72.54万 - 项目类别:
相似国自然基金
支链氨基酸代谢紊乱调控“Adipocytes - Macrophages Crosstalk”诱发2型糖尿病脂肪组织功能和结构障碍的作用及机制
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