Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
小鼠和人类核纤层病诱导的脂肪营养不良中脂肪细胞损失的机制
基本信息
- 批准号:10447012
- 负责人:
- 金额:$ 35.1万
- 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:2020-07-07 至 2023-05-31
- 项目状态:已结题
- 来源:
- 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
项目摘要
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.
摘要
脂肪营养不良是一种以脂肪组织损失和再分布为特征的疾病,
相关的代谢并发症,包括糖尿病。最常见的单基因
脂肪营养不良是家族性部分脂肪营养不良2型(FPLD 2),其由以下突变引起:
LMNA基因,编码核纤层蛋白A和C。脂肪组织
在青春期正常发育后丢失,是未知的。为了弥补这一不足,
我们选择性地删除小鼠脂肪细胞中的LMNA(LMNAADKO)。我们观察到一个惊人的损失,
成年LMNAADKO小鼠中的白色脂肪组织,沿着肝脏中脂肪沉积增加,
空腹和进食状态下血糖水平升高,循环胰岛素水平升高
与LMNAf 1/fl对照相比。对年轻小鼠的分析显示白色
LMNAADKO小鼠中的脂肪组织,其与青春期一致地逐渐丧失。这些
表型与在人FPLD 2患者中观察到的表型密切对应。重要的是,我们还有
获得高度积极的LMNA R482 Q患者人群,他们尚未表现出症状
脂肪代谢障碍分析他们的WAT将提供一个前所未有的机会,
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,
这些患者可以确定WAT细胞结构的最早缺陷,包括WAT细胞的特定改变。
脂肪细胞基因表达为了检验我们的假设,我们提出了以下具体目标:
SA 1)在LMNAADKO小鼠中确定核纤层蛋白A/C缺乏引起的脂肪组织损失是否是
由于脂肪形成受损或脂肪细胞更新增加的结果,SA 2)确定
LMNAADKO小鼠的脂肪细胞损失是否通过内源性或外源性细胞
机制和SA 3)在尚未显示明显体征的年轻FPLD 2患者中进行评估
LMNA突变对形态学、基因表达、信号传导的影响
途径和脂肪组织库的细胞组成。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Very-Low-Calorie Diet Can Cause Remission of Diabetes Mellitus and Hypertriglyceridemia in Familial Partial Lipodystrophy.
- DOI:10.1159/000533992
- 发表时间:2024
- 期刊:
- 影响因子:3.6
- 作者:
- 通讯作者:
Preclinical models for investigating how bone marrow adipocytes influence bone and hematopoietic cellularity.
- DOI:10.1016/j.beem.2021.101547
- 发表时间:2021-07
- 期刊:
- 影响因子:0
- 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:
- 影响因子:0
- 作者:Soyaltin,UtkuErdem;Simsir,IlginYildirim;Akinci,Baris;Altay,Canan;Adiyaman,SuleymanCem;Lee,Kristen;Onay,Huseyin;Oral,ElifArioglu
- 通讯作者:Oral,ElifArioglu
Mice as experimental models for human physiology: when several degrees in housing temperature matter.
- DOI:10.1038/s42255-021-00372-0
- 发表时间:2021-04
- 期刊:
- 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:
- 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
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Ormond A MacDougald其他文献
Ormond A MacDougald的其他文献
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{{ truncateString('Ormond A MacDougald', 18)}}的其他基金
Effects of Wnt/β-catenin signaling on adipocytes
Wnt/β-连环蛋白信号对脂肪细胞的影响
- 批准号:
10540392 - 财政年份:2021
- 资助金额:
$ 35.1万 - 项目类别:
Effects of Wnt/β-catenin signaling on adipocytes
Wnt/β-连环蛋白信号对脂肪细胞的影响
- 批准号:
10337561 - 财政年份:2021
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms by which adipocytes adapt to cool environmental temperatures
脂肪细胞适应凉爽环境温度的机制
- 批准号:
10408152 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
小鼠和人类核纤层病诱导的脂肪营养不良中脂肪细胞损失的机制
- 批准号:
10029064 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms by which adipocytes adapt to cool environmental temperatures
脂肪细胞适应凉爽环境温度的机制
- 批准号:
10627980 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
小鼠和人类核纤层病诱导的脂肪营养不良中脂肪细胞损失的机制
- 批准号:
10212385 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms by which adipocytes adapt to cool environmental temperatures
脂肪细胞适应凉爽环境温度的机制
- 批准号:
10212377 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans
小鼠和人类核纤层病诱导的脂肪营养不良中脂肪细胞损失的机制
- 批准号:
10837652 - 财政年份:2020
- 资助金额:
$ 35.1万 - 项目类别:
Multidisciplinary Training Program in Basic Diabetes Research
基础糖尿病研究多学科培训计划
- 批准号:
9421217 - 财政年份:2014
- 资助金额:
$ 35.1万 - 项目类别:
Multidisciplinary Training Program in Basic Diabetes Research
基础糖尿病研究多学科培训计划
- 批准号:
9339668 - 财政年份:2014
- 资助金额:
$ 35.1万 - 项目类别:
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