Circadian SCN-Liver Axis in the Neuroendocrine Response to Calorie Restriction
昼夜节律 SCN-肝轴对热量限制的神经内分泌反应
基本信息
- 批准号:10585791
- 负责人:
- 金额:$ 52.84万
- 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:2023-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:ARNTL geneAblationAcetylationBehavioralBioenergeticsBody TemperatureBrainCRISPR/Cas technologyCaloric RestrictionCell RespirationCellsCommunicationDarknessDeacetylaseDeacetylationDietDisinhibitionEpigenetic ProcessExhibitsFastingGeneticGenetic TranscriptionGoalsHealthHealth BenefitHepaticHomeostasisHypothalamic structureKnock-in MouseLactobacillus brevisLightLinkLiverMaintenanceMammalsMedial Dorsal NucleusMetabolicMetabolic PathwayMetabolismMitochondriaMolecularMusMutant Strains MiceNADHNADH oxidaseNeuronsNeurosecretory SystemsNicotinamide adenine dinucleotideNutrientNutrient availabilityOutputOxidation-ReductionPacemakersPathway interactionsPeriodicityPeripheralPhysiological AdaptationPost-Translational Protein ProcessingProtocols documentationPublishingReactionResistanceRespirationRoleSIRT1 geneSignal TransductionSleepSleep Wake CycleSystemTestingThermogenesisTissuesWatercircadiancircadian pacemakerdetection of nutrientfeedinggain of functiongenetic approachgenetic manipulationimprovedinnovationloss of functionmimeticsneural circuitprogramsresponsesleep regulationsuprachiasmatic nucleustool
项目摘要
In mammals, the hypothalamic pacemaker clock synchronizes peripheral tissue clocks to temporally partition
oxidative and reductive metabolic pathways to align fuel utilization with nutrient availability. Yet how the circadian
clock in brain and peripheral tissues integrates nutrient state with transcription to promote energy conservation
and metabolic homeostasis during sleep and in nutrient scarce conditions remains obscure. An exciting clue as
to how nutrient signals control circadian transcription emerged from the discovery in our group and others that
nicotinamide adenine dinucleotide (NAD+) and the NAD+-dependent deacetylase SIRT1 regulate circadian
behavioral and mitochondrial rhythms through posttranslational modification of the core clock repressor PER2,
indicating that NAD+-SIRT1 controls clock cycles within both neurons and peripheral cells. Interconversion of
NAD+ with its reduced form NADH during redox reactions is dependent upon nutrient state. In new results
published after our first submission, we show that NADH accumulation in liver during healthful calorie restriction
inhibits SIRT1 and reduces daytime body temperature and oxidative metabolism. Surprisingly, reducing NADH
levels through hepatic transduction of the water-forming NADH oxidase Lactobacillus brevis (LbNOX) disinhibits
SIRT1 and augments oxidative cycles of metabolism and transcription. Further, our newly-generated PER2K680Q
acetyl-mimetic knockin mice, which are resistant to SIRT1-induced deacetylation, exhibit profound period
lengthening, while clock ablation in the suprachiasmatic nucleus (SCN) abrogates rhythmic feeding and
thermogenesis. We are now poised with innovative genetic tools and circadian protocols to dissect how the
circadian clock promotes energy constancy during sleep and in adaptation to calorie restriction at the level of the
liver (Aim 1) and hypothalamic pacemaker neurons (Aim 2). Aim 1 will specifically test the hypothesis that nutrient
sensing by the clock involves NAD(H)-SIRT1 signaling. We propose to dissect the role of redox state in clock
function and metabolism during sleep and calorie restriction by genetically manipulating NAD(H) levels using
LbNox in combination with hepatic clock ablation or PER2K680Q acetyl-mimetic knockin mice. Aim 2 will examine
the role of hypothalamic pacemaker neuron subtypes in synchronizing thermogenesis, feeding, and metabolic
rhythms with sleep and in the adaptive response to calorie restriction by utilizing an innovative combination of
CRISPR-Cas9 clock ablation, loss and gain of function studies, and projection-based chemogenetic manipulation
of pacemaker neurons. Collectively, our proposed studies will elucidate circadian mechanisms involved in
maintenance of energy constancy across the sleep-wake cycle and how clock adaptations contribute to health
benefits of hypocaloric diet.
在哺乳动物中,下丘脑起搏时钟使外周组织时钟暂时分开,
氧化和还原代谢途径,使燃料利用率与营养素可用性相一致。然而,
脑和外周组织中的生物钟将营养状态与转录整合以促进能量守恒
睡眠期间和营养缺乏条件下的代谢稳态仍然不清楚。一个令人兴奋的线索,
营养信号如何控制昼夜节律的转录,这一发现来自我们小组和其他人的发现,
烟酰胺腺嘌呤二核苷酸(NAD+)和NAD+依赖性脱乙酰酶SIRT 1调节昼夜节律
通过核心时钟阻遏物PER 2的翻译后修饰来调节行为和线粒体节律,
表明NAD+-SIRT 1控制神经元和外周细胞内的时钟周期。的相互转化
NAD+及其还原形式的NADH在氧化还原反应期间取决于营养状态。在新的结果中
发表后,我们的第一次提交,我们表明,在健康的热量限制,
抑制SIRT 1,降低日间体温和氧化代谢。令人惊讶的是,还原NADH
通过肝脏转导的水形成的NADH氧化酶水平短乳杆菌(LbNOX)解除抑制
SIRT 1和增强代谢和转录的氧化循环。此外,我们新一代的PER 2K 680 Q
乙酰基模拟敲入小鼠对SIRT 1诱导的去乙酰化具有抗性,
延长,而视交叉上核(SCN)中的时钟消融废除了节律性进食,
产热作用我们现在已经准备好使用创新的遗传工具和昼夜节律协议来剖析人类如何
生物钟促进睡眠期间的能量稳定性,并在适应卡路里限制的水平上,
肝脏(Aim 1)和下丘脑起搏神经元(Aim 2)。目标1将具体检验营养素
通过时钟进行的感测涉及NAD(H)-SIRT 1信令。我们建议剖析氧化还原态在生物钟中的作用
功能和代谢在睡眠和热量限制通过遗传操纵NAD(H)水平,
LbNox与肝时钟消融或PER 2K 680 Q乙酰基模拟物敲入小鼠的组合。目标2将检查
下丘脑起搏神经元亚型在同步产热、摄食和代谢中的作用
节律与睡眠和适应性反应的热量限制,通过利用创新的组合,
CRISPR-Cas9时钟消融,功能研究的丧失和获得,以及基于投影的化学遗传操作
起搏器神经元。总的来说,我们提出的研究将阐明昼夜节律机制,
在睡眠-觉醒周期中维持能量恒定以及生物钟适应如何有助于健康
低热量饮食的好处
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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Joseph Bass其他文献
Joseph Bass的其他文献
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{{ truncateString('Joseph Bass', 18)}}的其他基金
Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network
昼夜节律基因网络整合进食时间和葡萄糖代谢
- 批准号:
10490335 - 财政年份:2021
- 资助金额:
$ 52.84万 - 项目类别:
Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network
昼夜节律基因网络整合进食时间和葡萄糖代谢
- 批准号:
10668512 - 财政年份:2021
- 资助金额:
$ 52.84万 - 项目类别:
Cross-regulation of Immunometabolism and Circadian Pathways in Obesity Pathophysiology
肥胖病理生理学中免疫代谢和昼夜节律途径的交叉调节
- 批准号:
10597527 - 财政年份:2021
- 资助金额:
$ 52.84万 - 项目类别:
Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network
昼夜节律基因网络整合进食时间和葡萄糖代谢
- 批准号:
10366269 - 财政年份:2021
- 资助金额:
$ 52.84万 - 项目类别:
Cross-regulation of Immunometabolism and Circadian Pathways in Obesity Pathophysiology
肥胖病理生理学中免疫代谢和昼夜节律途径的交叉调节
- 批准号:
10390430 - 财政年份:2021
- 资助金额:
$ 52.84万 - 项目类别:
Bioenergetic Mechanisms Underlying Circadian Dietary Intervention
昼夜节律饮食干预的生物能量机制
- 批准号:
10426118 - 财政年份:2019
- 资助金额:
$ 52.84万 - 项目类别:
Bioenergetic Mechanisms Underlying Circadian Dietary Intervention
昼夜节律饮食干预的生物能量机制
- 批准号:
10661568 - 财政年份:2019
- 资助金额:
$ 52.84万 - 项目类别:
Bioenergetic Mechanisms Underlying Circadian Dietary Intervention
昼夜节律饮食干预的生物能量机制
- 批准号:
10165455 - 财政年份:2019
- 资助金额:
$ 52.84万 - 项目类别:
Bioenergetic Mechanisms Underlying Circadian Dietary Intervention
昼夜节律饮食干预的生物能量机制
- 批准号:
10018627 - 财政年份:2019
- 资助金额:
$ 52.84万 - 项目类别:
The Circadian System as a Neuronal Regulator of Feeding Time and Body Weight Setpoint
昼夜节律系统作为喂养时间和体重设定值的神经调节器
- 批准号:
10220955 - 财政年份:2018
- 资助金额:
$ 52.84万 - 项目类别:
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