Hypothalamic leptin and insulin signals aligning metabolic state and fertility
下丘脑瘦素和胰岛素信号调节代谢状态和生育能力
基本信息
- 批准号:7827384
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-06-01 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressAdolescenceAdolescentAnimalsAnovulationAreaBody WeightBrainChildChildhoodChronicCommunicationDataDevelopmentDiabetes MellitusEatingElectrophysiology (science)Energy MetabolismEpidemicFeeding behaviorsFellowshipFertilityGeneticGenetic DeterminismGoalsHealthHomeostasisHypothalamic structureIn VitroInfertilityInsulinInsulin ReceptorInsulin ResistanceKnock-outKnowledgeLeptinMediator of activation proteinMenstruationMentorsMetabolicMetabolismMethodsModelingMolecular GeneticsMusNeuronsNutritionalObesityOverweightPathway interactionsPeripheralPhasePhenotypePopulationPostdoctoral FellowPrevalenceQualifyingReceptor SignalingRegulationReproductionReproductive HealthReproductive systemResearchResistanceResistance developmentRestRiskSignal PathwaySignal TransductionSiteSystemTestingTimeUnited StatesWorkblood glucose regulationdesignearly onsetfeedinggirlsinsulin signalingleptin receptornew therapeutic targetnext generationnovelnovel strategiesobesity in childrenobesity preventionpreventprogramsreceptorreproductivereproductive axisreproductive functionresponsetool
项目摘要
The dramatic increases in childhood and adolescent obesity in the U.S. have serious consequences for
the health of the next generation. Along with its well-known health risks, childhood obesity impairs
reproductive health and development. Indeed, early onset of obesity in girls, particularly during adolescence,
favors the development of menses irregularities, chronic anovulation, infertility, and PCOS in adulthood.
While the primary cause of this relationship is uncertain, central resistance to insulin and leptin, circulating
markers of adiposity, appears to inhibit the reproductive axis. The key sites of communication between the
metabolic and reproductive systems, however, remain unclear.
This proposal is designed to advance our long-term goal of elucidating the molecular and genetic
determinants of metabolic infertility. We hypothesize that leptin and insulin act directly on hypothalamic
POMC and NPY/AgRP neurons that provide input to GnRH neurons. This hypothesis rests on findings that
altered activity of POMC and NPY/AgRP neurons in response to leptin and insulin appear to depend on the
phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway. In addition, previous studies have shown
that brain-specific leptin receptor and insulin receptor knockouts have dramatic effects on the reproductive
axis, but preventing leptin receptor signaling through non-PI3K pathways does not impair fertility. Thus, our
studies will determine if insulin and leptin signaling through PI3K is required for normal (1) energy
homeostasis and (2) reproductive functioning and in POMC neurons and/or in NPY/AgRP neurons.
To accomplish these goals, we will genetically target the critical neurons using the cre/lox system.
Specifically, we will examine the metabolic and reproductive phenotype of mice lacking insulin and leptin
receptors or functional PI3K only in POMC neurons and only in NPY/AgRP neurons. We will then use
electrophysiology and a novel method of visualizing Akt signaling in vitro to determine the impact of PI3K deletion on neuronal function. Collectively, these data may provide a new target for therapeutic advances in the treatment and prevention of obesity-related infertility.
With a background in the diverse fields of reproduction and metabolism, Dr. Hill is uniquely qualified to undertake these studies. The novel genetic approaches assembled during her post-doctoral fellowship will be powerful tools for investigating the understudied area of interacting hypothalamic metabolic and reproductive pathways. By providing a vehicle for her transition to research independence, this proposal lays the groundwork for a research program focused on reproductive health and the discovery of new approaches for treating nutritional and obesity-related infertility.
美国儿童和青少年肥胖率的急剧上升对健康造成了严重的影响
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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Jennifer Wootton Hill其他文献
Jennifer Wootton Hill的其他文献
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{{ truncateString('Jennifer Wootton Hill', 18)}}的其他基金
Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism
星形胶质细胞胰岛素抵抗诱导青春期延迟和低促性腺激素性性腺功能减退症的神经内分泌缺陷
- 批准号:
10392144 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Astrocyte insulin resistance-induced neuroendocrine defects in pubertal delay and hypogonadotropic hypogonadism
星形胶质细胞胰岛素抵抗诱导青春期延迟和低促性腺激素性性腺功能减退症的神经内分泌缺陷
- 批准号:
10612727 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Defective melanocortin signaling underlying T2D-associated erectile dysfunction
T2D 相关勃起功能障碍潜在的黑皮质素信号传导缺陷
- 批准号:
9034454 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Defective melanocortin signaling underlying T2D-associated erectile dysfunction
T2D 相关勃起功能障碍潜在的黑皮质素信号传导缺陷
- 批准号:
8888203 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Inflammatory triggers of polycystic ovarian syndrome.
多囊卵巢综合征的炎症触发因素。
- 批准号:
8441506 - 财政年份:2012
- 资助金额:
$ 24.9万 - 项目类别:
Inflammatory triggers of polycystic ovarian syndrome.
多囊卵巢综合征的炎症触发因素。
- 批准号:
8303668 - 财政年份:2012
- 资助金额:
$ 24.9万 - 项目类别:
Hypothalamic leptin and insulin signals aligning metabolic state and fertility
下丘脑瘦素和胰岛素信号调节代谢状态和生育能力
- 批准号:
7899757 - 财政年份:2008
- 资助金额:
$ 24.9万 - 项目类别:
Hypothalamic leptin and insulin signals aligning metabolic state and fertility
下丘脑瘦素和胰岛素信号调节代谢状态和生育能力
- 批准号:
7471088 - 财政年份:2008
- 资助金额:
$ 24.9万 - 项目类别:
Hypothalamic leptin and insulin signals aligning metabolic state and fertility
下丘脑瘦素和胰岛素信号调节代谢状态和生育能力
- 批准号:
8076785 - 财政年份:2008
- 资助金额:
$ 24.9万 - 项目类别:
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