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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：
Ormond A MacDougald
金额：
$ 35.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
https://reporter.nih.gov/project-details/10447012
关键词：
3T3-L1 Cells Address Adipocytes Adipose tissue Adolescence Adult Affect Age Alleles Animal Model Animals Appearance Area Autophagocytosis Biology Blood Glucose Brown Fat Cell Death Cells Cellularity Characteristics Chromosome Structures Cultured Cells Data Defect Deposition Development Diabetes Mellitus Disease Exhibits Familial partial lipodystrophy Fasting Fatty Liver Fatty acid glycerol esters Gene Expression Genes Glucose Intolerance Human Immune Targeting Impairment In Vitro Insulin Insulin Resistance Knowledge Lamin Type A Leptin Leptin deficiency Life Link Lipodystrophy Literature Liver LoxP-flanked allele Maintenance Mesenchymal Metabolic Metabolic dysfunction Morphology Mus Muscular Dystrophies Musculoskeletal Mutation Nuclear Lamin Nuclear Structure Pathway interactions Patients Phenotype Premature aging syndrome Puberty Signal Pathway Testing Time Tissues Transgenic Mice Work adipocyte differentiation adiponectin autosomal dominant mutation experimental study glucose metabolism human disease in vivo lamin C lipid biosynthesis lipid metabolism loss of function loss of function mutation mouse model mutant new therapeutic target novel overexpression patient population postnatal premature prevent transcription 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

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：
Obesity facts
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：
Best practice & research. Clinical endocrinology & metabolism
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：
Clinical diabetes and endocrinology
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：
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