Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
批准号:
10447012
负责人:
Ormond A MacDougald
金额:
$35.1万
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:
2020-07-07 至 2023-05-31
关键词:
3T3-L1 CellsAddressAdipocytesAdipose tissueAdolescenceAdultAffectAgeAllelesAnimal ModelAnimalsAppearanceAreaAutophagocytosisBiologyBlood GlucoseBrown FatCell DeathCellsCellularityCharacteristicsChromosome StructuresCultured CellsDataDefectDepositionDevelopmentDiabetes MellitusDiseaseExhibitsFamilial partial lipodystrophyFastingFatty LiverFatty acid glycerol estersGene ExpressionGenesGlucose IntoleranceHumanImmune TargetingImpairmentIn VitroInsulinInsulin ResistanceKnowledgeLamin Type ALeptinLeptin deficiencyLifeLinkLipodystrophyLiteratureLiverLoxP-flanked alleleMaintenanceMesenchymalMetabolicMetabolic dysfunctionMorphologyMusMuscular DystrophiesMusculoskeletalMutationNuclear LaminNuclear StructurePathway interactionsPatientsPhenotypePremature aging syndromePubertySignal PathwayTestingTimeTissuesTransgenic MiceWorkadipocyte differentiationadiponectinautosomal dominant mutationexperimental studyglucose metabolismhuman diseasein vivolamin Clipid biosynthesislipid metabolismloss of functionloss of function mutationmouse modelmutantnew therapeutic targetnoveloverexpressionpatient populationpostnatalprematurepreventtranscription factor
中文摘要
摘要
脂肪营养不良是一种以脂肪组织丢失和重新分布为特征的疾病,
相关的代谢并发症,包括糖尿病。最常见的单基因形式
脂肪营养不良是家族性部分脂肪营养不良2型(FPLD2),是由基因突变引起的
LMNA 基因,编码核纤层蛋白 A 和 C。脂肪组织的机制
在青春期正常发育后丢失的情况是未知的。为了解决这一不足,
我们选择性地删除了小鼠脂肪细胞(LMNAADKO)中的LMNA。我们观察到显着的损失
成年 LMNAADKO 小鼠的白色脂肪组织,以及肝脏中脂肪沉积的增加,
空腹和进食状态下血糖水平升高,循环胰岛素水平升高
与 LMNAfl/fl 对照相比。对年轻小鼠的分析揭示了白色的发育
LMNAADKO 小鼠的脂肪组织随着青春期逐渐消失。这些
表型与人类 FPLD2 患者中观察到的表型非常相似。重要的是,我们还有
接触尚未表现出症状的高度积极的 LMNA R482Q 患者群体
脂肪营养不良。对他们的 WAT 的分析将提供前所未有的进步机会
我们对这种疾病及其进展的了解。我们建议在组织中进行实验
这些患者能够查明 WAT 细胞结构的最早缺陷,包括
脂肪细胞基因表达。为了检验我们的假设,我们提出以下具体目标:
SA1) 确定 LMNAADKO 小鼠是否因核纤层蛋白 A/C 缺乏而导致脂肪组织损失
由于脂肪生成受损或脂肪细胞更新增加的结果,SA2)确定
LMNAADKO 小鼠脂肪细胞的损失是通过内在还是外在细胞发生的
机制和 SA3)在尚未表现出明显体征的年轻 FPLD2 患者中进行评估
脂肪营养不良,LMNA 突变对形态、基因表达、信号传导的影响
脂肪组织库的途径和细胞组成。
英文摘要
Abstract
Lipodystrophy is a disorder characterized by adipose tissue loss and redistribution, with
associated metabolic complications including diabetes. The most common form of monogenic
lipodystrophy is familial partial lipodystrophy type 2 (FPLD2), which is caused by a mutation in
the LMNA gene, encoding nuclear lamins A and C. The mechanisms for how adipose tissues
are lost, after developing normally through adolescence are unknown. To address this shortfall,
we selectively deleted LMNA in adipocytes (LMNAADKO) of mice. We observed a striking loss of
white adipose tissue in adult LMNAADKO mice, along with increased fat deposition in the liver,
elevated blood glucose levels in both fasting and fed states, increased circulating insulin levels
compared to the LMNAfl/fl controls. Analyses of young mice revealed development of white
adipose tissue in LMNAADKO mice, which is progressively lost coincident with puberty. These
phenotypes closely mirror those observed in human FPLD2 patients. Importantly, we also have
access to a highly motivated LMNA R482Q patient population, who are not yet exhibiting signs
of lipodystrophy. Analyses of their WAT will provide an unprecedented opportunity to advance
our understanding of this disease and its progression. We propose experiments in tissue from
these patients to pinpoint the earliest defects in WAT cellularity, including specific alterations in
adipocyte gene expression. To test our hypotheses, we propose the following specific aims:
SA1) determine in LMNAADKO mice whether loss of adipose tissues with lamin A/C deficiency is
due to impaired adipogenesis or is the result of increased adipocyte turnover, SA2) ascertain in
LMNAADKO mice whether loss of adipocytes occurs through intrinsic or extrinsic cellular
mechanisms, and SA3) evaluate in young FPLD2 patients, who are not yet showing overt signs
of lipodystrophy, the effects of LMNA mutation on morphology, gene expression, signaling
pathways and cellular composition of adipose tissue depots.
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DOI:
10.1159/000533992
发表时间:
2024
期刊:
Obesity facts
影响因子:
3.6
作者:
[]
通讯作者:
DOI:
10.1016/j.beem.2021.101547
发表时间:
2021-07
期刊:
Best practice & research. Clinical endocrinology & metabolism
影响因子:
--
作者:
[Li Z, MacDougald OA]
通讯作者:
MacDougald OA
Homozygous LMNA p.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy.
纯合 LMNA p.R582H 致病性变异揭示了对脂肪营养不良中脂肪减少严重程度的影响越来越大。
DOI:
10.1186/s40842-020-00100-9
发表时间:
2020
期刊:
Clinical diabetes and endocrinology
影响因子:
--
作者:
[Soyaltin,UtkuErdem, Simsir,IlginYildirim, Akinci,Baris, Altay,Canan, Adiyaman,SuleymanCem, Lee,Kristen, Onay,Huseyin, Oral,ElifArioglu]
通讯作者:
Oral,ElifArioglu
DOI:
10.1038/s42255-021-00372-0
发表时间:
2021-04
期刊:
Nature metabolism
影响因子:
20.8
作者:
[Seeley RJ, MacDougald OA]
通讯作者:
MacDougald OA
Efficacy and Safety of Glucagon-Like Peptide 1 Agonists in a Retrospective Study of Patients With Familial Partial Lipodystrophy.
胰高血糖素样肽 1 激动剂在家族性部分性脂肪营养不良患者的回顾性研究中的功效和安全性。
DOI:
10.2337/dc23-1614
发表时间:
2024
期刊:
Diabetes care
影响因子:
16.2
作者:
[Foss-Freitas,MariaC, Imam,Salman, Neidert,Adam, Gomes,AnabelaDill, Broome,DavidT, Oral,ElifA]
通讯作者:
Oral,ElifA
Effects of Wnt/β-catenin signaling on adipocytes
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批准号:10540392
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项目类别:
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资助金额:$44.46万
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财政年份:2021
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依托单位:
Effects of Wnt/β-catenin signaling on adipocytes
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Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
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Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
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批准号:10212385
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依托单位:
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财政年份:2012
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