Lipid metabolism and adipose tissue function
Lipid metabolism and adipose tissue function
批准号:
10390756
负责人:
Jun Liu
金额:
$50.49万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-12-01 至 2025-11-30
关键词:
AblationAcuteAdipocytesAdipose tissueAdultAffectAgonistApolipoproteinsAttenuatedBindingBody TemperatureBody WeightBody Weight decreasedBody fatBrown FatCarbonCell LineCell modelCellsChronicDataDevelopmentEnergy MetabolismEnzymesEpidemicExhibitsFamilyFatty AcidsFatty acid glycerol estersGlucoseGoalsGuanosine Triphosphate PhosphohydrolasesHousingHumanIn VitroInsulin ResistanceKnock-outKnockout MiceMammalsMass Spectrum AnalysisMeasuresMetabolicMetabolic DiseasesMetabolic syndromeMitochondriaModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusNormal tissue morphologyObesityOrganOxygen ConsumptionPathogenesisPhenotypePhysiologicalPlayPrevalenceProteinsRegulationRespirationRodentRoleStable Isotope LabelingTemperatureTestingThermogenesisTissuesTransgenic MiceTransgenic Organismsadipocyte differentiationattenuationbasecell typecombatdesigndiet-induced obesitydietaryenergy balanceenzyme activityfat burningfatty acid oxidationgain of functionglucose metabolismglucose toleranceimproved outcomein vivoinhibitorinsightinsulin sensitivitylipid metabolismloss of functionmembermouse modelnovelnovel therapeutic interventionobese patientsoxidationrecruitsubcutaneous
中文摘要
项目摘要
肥胖症的流行在世界范围内已经上升到流行的程度。功能失调性白色脂肪
组织(WAT)和棕色脂肪组织(BAT)与肥胖的发病机制有关。
相关代谢综合征。蝙蝠体内密布着线粒体,需要脂肪酸(FA)氧化才能
支持生热。相比之下,WAT是一种主要的储能器官,而FA氧化在
Wat在环境温度下相对较低。慢性冷暴露引起皮下积水褐变
增加FA的氧化能力,使其成为发热米色AT。尽管已知FA氧化是一种
在人类和啮齿动物中,关键和根本的代谢终点,目前还不完全清楚
脂肪细胞FA氧化的翻译后调控及其对全身能量的贡献
以自主方式进行新陈代谢。在这方面,我们的初步研究提供了令人信服的证据
载脂蛋白6(ApoL6)是线粒体三功能蛋白的选择性调节蛋白
是催化FAβ氧化的关键酶。载脂蛋白L6在Wat中高表达并分化
脂肪细胞。相比之下,BAT通常表达低水平的ApoL6,在肥胖或
中温性导致的美白。我们发现在基础状态下,ApoL6定位于线粒体,
导致线粒体FA氧化的减弱。在BAT中表达ApoL6的转基因小鼠表现出
冷暴露时产热能力降低,能量消耗减少,同时增加
肥胖症。相反,接受高脂饮食的脂肪ApoL6基因敲除小鼠的体重和脂肪质量都有所下降
收获。基于这些初步数据,我们假设通过抑制线粒体FA氧化和
因此,ApoL6在以下方面起关键作用:(1)维持WAT和
全身能量平衡,以及(2)阻止白化蝙蝠的非颤抖产热。一共有三个
目的:在目标1中,我们将确定线粒体定位的载脂蛋白L6在脂肪细胞FA中的机制作用
使用功能增益型和功能损失型细胞模型进行氧化。在目标2中,我们将确定脂肪的特异性
ApoL6消融对饮食诱导的肥胖及其包括胰岛素在内的相关代谢变化的影响
抵抗。在目标3中,我们将使用功能丧失和功能获得的小鼠模型来定义ApoL6在
肥胖和热中性诱导的美白过程中蝙蝠产热的调节。派生的证据
这一项目将为调节FA氧化的分子基础提供新的见解
脂肪组织中的能量代谢,从而提高了开发新型
与肥胖和2型糖尿病作斗争的治疗方法。
英文摘要
Project Summary
The prevalence of obesity has increased worldwide to epidemic proportions. Dysfunctional white adipose
tissue (WAT) and brown adipose tissue (BAT) have been implicated in the pathogenesis of obesity and its
related metabolic syndrome. BAT is densely packed with mitochondria and requires fatty acid (FA) oxidation to
support thermogenesis. In comparison, WAT serves as a main energy storage organ and the FA oxidation in
WAT is relatively low at ambient temperature. Chronic cold exposure induces browning of subcutaneous WAT
to become thermogenic beige AT with increased FA oxidation capacity. Although FA oxidation is known to be a
critical and fundamental metabolic end point in both humans and rodents, it is not completely clear how
adipocyte FA oxidation is regulated post-translationally and how it contributes to whole-body energy
metabolism in an autonomous manner. In this regard, our preliminary studies provide compelling evidence that
a protein encoded by Apolipoprotein 6 (ApoL6) is a selective regulator of mitochondrial trifunctional protein
(TFP), the key enzyme catalyzing FA β-oxidation. ApoL6 is highly expressed in WAT and differentiated
adipocytes. In contrast, BAT normally expresses low levels of ApoL6, which increases during obesity or
thermoneutrality-induced whitening. We found that in the basal condition, ApoL6 is localized to mitochondria,
resulting in attenuation of mitochondrial FA oxidation. Transgenic mice expressing ApoL6 in BAT exhibited a
lower thermogenic capacity upon cold exposure, and decreased energy expenditure along with increased
adiposity. Conversely, adipose ApoL6 knockout mice on HFD showed a decreased body weight and fat mass
gain. Based on these preliminary data, we hypothesize that by inhibiting mitochondrial FA oxidation and
thereby decreasing energy expenditure, ApoL6 plays a key role in (1) maintaining fat storage in WAT and
whole-body energy balance, and (2) impeding non-shivering thermogenesis in whitened BAT. There are three
aims: In aim 1, we will determine the mechanistic role of mitochondrially localized ApoL6 in adipocyte FA
oxidation by using gain- and loss-of-function cell models. In Aim 2 we will determine how adipose specific
ApoL6 ablation in mice affects diet-induced obesity and its related metabolic changes including insulin
resistance. In Aim 3 we will use both loss- and gain-of-function mouse models to define the role of ApoL6 in
the regulation of BAT thermogenesis during obesity- and thermoneutrality-induced whitening. Evidence derived
from this project should provide novel insight into the molecular basis for the regulation of FA oxidation and
energy metabolism in adipose tissue, thereby advancing the possibilities for the development of novel
therapeutic approaches to combat obesity and type 2 diabetes.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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