Investigating sex-specific metabolic effects of disrupted selenocysteine lyase and selenocysteine tRNA in Agrp hypothalamic neurons
Investigating sex-specific metabolic effects of disrupted selenocysteine lyase and selenocysteine tRNA in Agrp hypothalamic neurons
批准号:
10343833
负责人:
Daniel J. Torres
金额:
$7.17万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-02-16 至 2023-02-15
关键词:
AblationAlanineAmino AcidsAntioxidantsApplications GrantsAreaAttentionBiologicalBloodBlood - brain barrier anatomyBrainBrown FatCommunitiesComplexDataDefense MechanismsDevelopmentDiabetes MellitusDietDietary SeleniumDiseaseElectrophysiology (science)Energy MetabolismEnzymesEpidemicEtiologyExhibitsFeeding behaviorsFellowshipFemaleGlucoseGoalsHealthHigh Fat DietHomeostasisHumanHypothalamic dysfunctionHypothalamic structureImmunohistochemistryImpairmentInvestigationKnock-outKnockout MiceLeptinLeptin resistanceLightLyaseMaintenanceMediatingMediator of activation proteinMentorsMetabolicMetabolic DiseasesMetabolic syndromeMetabolismMonitorMusNatureNerve DegenerationNeuraxisNeurologicNeuronsNeurophysiology - biologic functionNeurosciencesNon-Insulin-Dependent Diabetes MellitusObesityOxidation-ReductionOxidative StressPathologyPeptidesPhenotypePituitary HormonesPlayPopulationPredispositionPrevalencePrevention strategyProductionPropertyRecyclingRegimenRegulationRegulatory PathwayResistanceRiskRoleScientistSeleniumSelenocysteineSex DifferencesSignal PathwaySignaling MoleculeSliceTechniquesTestingTherapeuticThermogenesisThyroid Function TestsThyroid HormonesTimeTissuesTrace ElementsTrainingUnderweightUnited StatesUnited States National Institutes of HealthWeight Gaincareer developmentdiet-induced obesitydietary controldietary supplementsexperienceexperimental studyglucose tolerancein vivoinsightinterestmalemale fertilitymetabolic phenotypemetabolic profilemouse modelneurogenesisnovelobesogenicpreventprogramsprogressive neurodegenerationrelating to nervous systemresponseselenocysteine lyaseselenocysteine-tRNAselenoproteinsexsexual dimorphism
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Widely used as a dietary supplement, the antioxidant trace element selenium (Se) is essential for human
health. Se is known for its role in curbing oxidative stress and in the regulation of thyroid function and male
fertility. Past studies have associated altered selenoprotein expression with increased risk for metabolic
syndrome (MetS). Whole-body knockout (KO) of the intracellular Sec decomposition enzyme Sec lyase (Scly)
in mice increases susceptibility to MetS and diet-induced obesity (DIO), accompanied by decreased
selenoprotein expression in the hypothalamus, a key mediator of energy homeostasis. Surprisingly, mice with
targeted Scly KO in agouti-related peptide (Agrp)-positive neurons of the hypothalamus are protected from DIO
and leptin resistance, an effect that may be influenced by thyroid hormone function in males. Mice with Agrp
neuron-specific deletion of the selenocysteine-tRNA (Trsp), which is essential for selenoprotein expression,
display metabolic effects similar to those observed in Scly-Agrp KO mice. These results are specific to female
mice, however, as male Trsp-Agrp KO mice show no significant differences from controls.
The overall goal of this proposal is to elucidate the mechanisms that underlie the metabolic phenotype of
Scly-Agrp KO mice and the sex differences observed in Trsp-Agrp KO mice. The central hypothesis is that
Agrp neurons depend on Se utilization to mediate high-fat diet-induced changes via sex-specific mechanisms.
Specifically, this proposal investigates the possibility that loss of Scly protects Agrp neurons from developing
early leptin resistance to prevent downstream hypothalamic leptin resistance and limit weight gain by
maintaining brown adipose tissue thermogenesis. This project will also test the hypothesis that loss of Trsp
causes progressive neurodegeneration of Agrp neurons, which impacts sex-specific differences in
hypothalamic neurogenic mechanisms to result in the metabolic phenotypes observed. These hypotheses will
be tested using these mouse models and a combination of in vivo phenotyping, tissue analysis, and ex vivo
electrophysiology on live hypothalamic brain slices.
This fellowship will take place under the guidance of an experienced mentor and pioneer in the Se field,
and an accomplished co-mentor with an extensive background in neuroscience. The proposed individualized
training plan includes specific educational and career development activities, and benefits from the expertise of
a collaborative community of scientists implementing an intensive team mentoring program. It is anticipated
that the experiments proposed herein will shed light on the important roles of Se utilization and selenoproteins
in metabolic disease pathology, provide new information on the interplay between the central nervous system
and whole-body energy metabolism, and may potentially identify key targets of interest for preventative
strategies or therapeutic treatments for metabolic disorders.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
Juvenile Selenium Deficiency Impairs Cognition, Sensorimotor Gating, and Energy Homeostasis in Mice.
DOI:
10.3389/fnut.2021.667587
发表时间:
2021
期刊:
Frontiers in nutrition
影响因子:
5
作者:
[Kilonzo VW, Sasuclark AR, Torres DJ, Coyle C, Pilat JM, Williams CS, Pitts MW]
通讯作者:
Pitts MW
DOI:
10.1016/j.tem.2021.08.001
发表时间:
2021-12
期刊:
Trends in endocrinology and metabolism: TEM
影响因子:
--
作者:
[Torres DJ, Pitts MW]
通讯作者:
Pitts MW
DOI:
10.3389/fnins.2021.631825
发表时间:
2021
期刊:
Frontiers in neuroscience
影响因子:
4.3
作者:
[Torres DJ, Yorgason JT, Mitchell CC, Hagiwara A, Andres MA, Kurokawa S, Steffensen SC, Bellinger FP]
通讯作者:
Bellinger FP
海外基金