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

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

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.
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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