The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations
综合应激反应在棕色脂肪组织介导的代谢适应中的作用
基本信息
- 批准号:10202593
- 负责人:
- 金额:$ 38.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdipocytesAdipose tissueAdrenergic AgentsAffectBody TemperatureBrown FatCardiovascular DiseasesChemicalsChimeric ProteinsDataDiabetes MellitusEndocrineEndoplasmic ReticulumEnergy MetabolismExhibitsGDF15 geneGenerationsGeneticHomeostasisIn VitroInjectionsKnockout MiceLeadLightMediatingMetabolicMetabolismMitochondriaMitochondrial ProteinsMolecularMusNerve Growth Factor ReceptorsOPA1 geneObesityObesity associated diseaseOptic AtrophyPERK kinasePathway interactionsPharmacologyPhosphotransferasesPhysiologicalPhysiologyPlayProtein KinaseProteinsResistanceRespirationRoleSignal TransductionStimulusStressTestingTherapeuticThermogenesisThinnessWeight Gainactivating transcription factor 4biological adaptation to stresscardiovascular healthcombatcomorbiditydesigndiet-induced obesityfibroblast growth factor 21hindbrainimprovedin vivometabolic fitnessmouse modelnew therapeutic targetnovelnovel therapeutic interventionobesity treatmentoverexpressionprotective effectprotein activationprotein kinase Rreceptorresponsetoolupstream kinase
项目摘要
This project seeks to understand the role of the integrated stress response (ISR) in brown adipose tissue
(BAT) for systemic metabolic homeostasis. The studies proposed herein have the potential of uncovering a
novel pathway to amplify thermogenic activation of BAT and to induce the BAT secretome, that might be
independent of β3-adrenergic activation, and might be leveraged to combat obesity and its comorbidities.
BAT plays a critical role in maintaining core body temperature through adaptive thermogenesis, and can affect
adiposity by regulating key pathways in energy homeostasis. Accordingly, strategies designed to activate
BAT, as well as to promote browning of white adipose tissue (WAT), could be attractive for combating obesity
and associated diseases, such as diabetes and cardiovascular disease (CVD). Recent studies demonstrated
that the ISR is activated in BAT in response to acute cold exposure, which correlated with induction of the
unfolded protein response (UPR) and secretion of batokines known to exert protective effects on systemic
metabolism, such as fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15).
We have generated preliminary data confirming these findings. In addition, we observed similar inductions of
the UPR and the ISR in mice with BAT-specific deletion of the mitochondrial protein Optic atrophy 1 (OPA1).
Interestingly, these mice had improved metabolic fitness and were better able to adapt to cold. Although
studies suggest that BAT-derived FGF21 plays a negligible role on the systemic metabolic adaptations to cold
exposure, the contribution of BAT-derived GDF15 on adaptive thermogenesis and on systemic metabolic
homeostasis is incompletely understood. Therefore, we hypothesized that cold exposure and mitochondrial
stress lead to the induction of the ISR and its master regulator activating transcription factor 4 (ATF4) in BAT,
via the activation of the UPR kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) to
induce BAT secretion of GDF15, thereby improving systemic metabolic homeostasis. Extensive examination
of the ISR in BAT will shed light on BAT physiology and adaptation to stress and may uncover novel
therapeutic targets for the treatment of obesity, diabetes and CVD. Aim 1 of this proposal will investigate the
requirement of PERK for ISR and ATF4 activation in BAT in response to cold and mitochondrial stress. Aim
2 will determine whether ATF4 is required and sufficient for GDF15 induction and for proper adaptive
thermogenesis. Aim 3 will determine whether GDF15 is required to mediate the systemic metabolic
adaptations following cold exposure and mitochondrial stress in BAT, and whether it mediates its effects
through central activation of its receptor glial-derived neurotrophic factor receptor alpha-like (GFRAL).
Generation of novel genetic mouse models will reveal the molecular mechanisms underlying ISR activation
and the physiological roles of ATF4 and GDF15 in BAT, which may inform novel therapeutic strategies to
combat obesity and its comorbidities.
本项目旨在了解综合应激反应(ISR)在棕色脂肪组织中的作用
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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Renata Pereira Alambert其他文献
Renata Pereira Alambert的其他文献
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{{ truncateString('Renata Pereira Alambert', 18)}}的其他基金
The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations
综合应激反应在棕色脂肪组织介导的代谢适应中的作用
- 批准号:
10398910 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations
综合应激反应在棕色脂肪组织介导的代谢适应中的作用
- 批准号:
10029774 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations
综合应激反应在棕色脂肪组织介导的代谢适应中的作用
- 批准号:
10614488 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
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